10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026

Single-pill antihypertensive combinations may improve medication-taking behavior in some individuals.

“Single-pill antihypertensive combinations may improve medication-taking behavior in some individuals (60,61).”

• cites [60] Choudhry, 2022, Medication adherence and blood pressure control: a scientific statement from the American Heart Association, Hypertension sourceSupported
• cites [61] Wang, 2023, Efficacy and safety of low-dose triple and quadruple combination pills vs monotherapy, usual care, or placebo for the initial management of hypertension: a systematic review and meta-analysis, JAMA Cardiol sourceDisputed

  The Results (Adverse Effects and Tolerability; page not provided) report similar self-reported treatment adherence with low-dose combination therapy and active comparators, rather than an improvement. The paper does not report an adherence benefit for a subgroup of individuals. (LLM, conf=0.82)

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The CAROLINA study demonstrated noninferiority between linagliptin and glimepiride on cardiovascular outcomes despite lower rates of hypoglycemia in the linagliptin treatment group.

“The CAROLINA (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Type 2 Diabetes) study demonstrated noninferiority between a DPP-4 inhibitor, linagliptin, and a sulfonylurea, glimepiride, on cardiovascular outcomes despite lower rates of hypoglycemia in the linagliptin treatment group (267).”

• cites [267] Marx, 2015, Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA), Diab Vasc Dis Res sourceDisputed

  The Discussion describes CAROLINA as an ongoing trial designed to test cardiovascular noninferiority, not a trial that had demonstrated it. It attributes the lower incidence of hypoglycaemia with linagliptin to a former study, not to CAROLINA results. (LLM, conf=0.91)

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Most people with HFpEF have obesity.

“Increasing evidence has demonstrated the benefits of GLP-1 RA or dual GIP/GLP-1 RA on symptoms and outcomes for people with HFpEF and obesity, and while most people with HFpEF have obesity, approximately 45% have diabetes (304,305).”

• cites [304] Echouffo-Tcheugui, 2016, Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: findings from Get With The Guidelines-Heart Failure registry, Am Heart J sourceNot checked — no full text of the source
• cites [305] Haass, 2011, Body mass index and adverse cardiovascular outcomes in heart failure patients with preserved ejection fraction: results from the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial, Circ Heart Fail sourceDisputed

  The Results, Baseline Characteristics section (page unavailable) reports that 41.3% of the HFpEF patients in the I-PRESERVE cohort had a BMI greater than 30 kg/m²—not most. The paper’s figure of more than 83% combines overweight and obese patients, so it does not support the claim that most had obesity. (LLM, conf=0.88)

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Diabetes itself confers independent ASCVD risk.

“Diabetes itself confers independent ASCVD risk, and among people with diabetes, all major cardiovascular risk factors, including hypertension, hyperlipidemia, and obesity, are clustered and common (2).”

• cites [2] Weng, 2019, The prevalence of cardiovascular disease and antidiabetes treatment characteristics among a large type 2 diabetes population in the United States, Endocrinol Diabetes Metab sourcePartly supported

  The Results (Study population and Subgroup analysis by age category; page unavailable) show that hypertension and dyslipidemia were common among patients with type 2 diabetes, and the Discussion reports that 45.2% had ASCVD. The paper does not establish that diabetes independently confers ASCVD risk or report obesity as a common, clustered risk factor. (LLM, conf=0.86)

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Diabetes is a risk factor for incident heart failure.

“diabetes is a risk factor for incident heart failure, which is at least twofold more prevalent in people with diabetes compared with those without diabetes and is a major cause of morbidity and mortality (11).”

• cites [11] Kodama, 2020, Diabetes mellitus and risk of new-onset and recurrent heart failure: a systematic review and meta-analysis, ESC Heart Fail sourceSupported

Managing individual cardiovascular risk factors prevents or slows ASCVD in people with diabetes.

“Numerous studies have shown the efficacy of managing individual cardiovascular risk factors in preventing or slowing ASCVD in people with diabetes.”

• cites [3] Gæde, 2016, Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial, Diabetologia sourceSupported
• cites [4] Gaede, 2008, Effect of a multifactorial intervention on mortality in type 2 diabetes, N Engl J Med sourceSupported
• cites [5] Khunti, 2018, Legacy benefits of blood glucose, blood pressure and lipid control in individuals with diabetes and cardiovascular disease: time to overcome multifactorial therapeutic inertia?, Diabetes Obes Metab sourceNot checked — no full text of the source

When all major cardiovascular risk factors are treated to within target ranges, people with type 2 diabetes have risk of death, MI, or stroke similar to that of the general population.

“when all major cardiovascular risk factors are treated to within the target ranges, people with type 2 diabetes have risk of death, MI, or stroke similar to that of the general population (6).”

• cites [6] Rawshani, 2018, Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes, N Engl J Med sourcePartly supported

  The Discussion (p. 7) reports that patients with type 2 diabetes whose five selected risk factors were within target ranges had, at most, marginally higher risks of death, myocardial infarction, and stroke than the general population. But the paper’s limitations (p. 11) say it did not distinguish patients medically treated to reach those ranges from patients already within them without treatment. The comparison is supported; attributing it specifically to treatment is not. (LLM, conf=0.88)

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People with diabetes are at risk for developing structural heart disease and HFrEF in the absence of obstructive coronary artery disease.

“people with diabetes are at risk for developing structural heart disease and HFrEF in the absence of obstructive coronary artery disease (15).”

• cites [15] Marwick, 2018, Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy, J Am Coll Cardiol sourcePartly supported

  The Epidemiology of Diabetes-Associated HF section reports increased heart-failure risk in people with diabetes, and the paper describes structural and functional myocardial abnormalities. It does not specifically establish that people with diabetes develop HFrEF in the absence of obstructive coronary artery disease; the epidemiology section says most published data do not distinguish HFrEF from HFpEF. Page numbers were not available in our copy. (LLM, conf=0.83)

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Under the current paradigm of comprehensive risk factor modification, cardiovascular morbidity and mortality have notably decreased in people with both type 1 and type 2 diabetes.

“Under the current paradigm of comprehensive risk factor modification, cardiovascular morbidity and mortality have notably decreased in people with both type 1 and type 2 diabetes (1).”

• cites [1] Rawshani, 2017, Mortality and cardiovascular disease in type 1 and type 2 diabetes, N Engl J Med sourceSupported

People with diabetes may present with a wide spectrum of heart failure, including HFpEF, HFmrEF, or HFrEF.

“People with diabetes may present with a wide spectrum of heart failure, including heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), or heart failure with reduced ejection fraction (HFrEF) (12,13).”

• cites [12] Maddox, 2024 ACC expert consensus decision pathway for treatment of heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee, J Am Coll Cardiol sourcePartly supported

  Section 4.9 (page unavailable) says diabetes is common among people with HF and is strongly associated with incident HF. The paper focuses on HFrEF; our copy does not establish that people with diabetes may present across all three listed ejection-fraction categories, particularly HFpEF and HFmrEF. (LLM, conf=0.84)

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• cites [13] Kittleson, 2023, 2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction, J Am Coll Cardiol sourceSupported

Heart failure is a major cause of morbidity and mortality in people with diabetes.

“and is a major cause of morbidity and mortality (11).”

• cites [11] Kodama, 2020, Diabetes mellitus and risk of new-onset and recurrent heart failure: a systematic review and meta-analysis, ESC Heart Fail sourcePartly supported

  The Introduction describes heart failure as a major clinical and public-health problem that impairs daily living, and the Results report higher risks of new-onset and recurrent heart failure in people with diabetes. This supports the morbidity aspect. The Methods say the analysis included fatal and nonfatal heart-failure events but excluded studies with only heart-failure mortality as an endpoint; the cited findings do not establish that heart failure is a major cause of mortality in people with diabetes. (LLM, conf=0.84)

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Among people with diabetes, all major cardiovascular risk factors, including hypertension, hyperlipidemia, and obesity, are clustered and common.

“among people with diabetes, all major cardiovascular risk factors, including hypertension, hyperlipidemia, and obesity, are clustered and common (2).”

• cites [2] Weng, 2019, The prevalence of cardiovascular disease and antidiabetes treatment characteristics among a large type 2 diabetes population in the United States, Endocrinol Diabetes Metab sourcePartly supported

  The Results (Study population, Table 1; page unavailable) report that hypertension (79.1%) and dyslipidemia (77.8%) were common in the studied US population with type 2 diabetes. Our copy does not report obesity prevalence or establish that these risk factors cluster in the same individuals, so it does not support the claim about all three factors being clustered and common. (LLM, conf=0.87)

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ASCVD is the leading cause of morbidity and mortality in people with diabetes.

“ASCVD broadly refers to a history of acute coronary syndrome, myocardial infarction (MI), stable or unstable angina or coronary or other arterial revascularization, stroke, or peripheral artery disease (PAD) including aortic aneurysm and is the leading cause of morbidity and mortality in people with diabetes (1).”

• cites [1] Rawshani, 2017, Mortality and cardiovascular disease in type 1 and type 2 diabetes, N Engl J Med sourcePartly supported

  The Outcomes and Mortality sections assess cardiovascular events and cardiovascular deaths in people with diabetes, supporting the claim that cardiovascular disease contributes to morbidity and mortality. The paper does not establish that ASCVD, specifically, is the leading cause of either, and its cardiovascular outcomes include heart failure rather than being limited to ASCVD. Page numbers are unavailable in our copy. (LLM, conf=0.83)

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Secondary analyses of ACCORD BP and SPRINT suggest that clinical factors can help identify individuals more likely to benefit from and less likely to be harmed by intensive blood pressure management.

“Secondary analyses of ACCORD BP and SPRINT suggest that clinical factors can help identify individuals more likely to benefit from and less likely to be harmed by intensive blood pressure management (49,50).”

• cites [49] Basu, 2017, Benefit and harm of intensive blood pressure treatment: derivation and validation of risk models using data from the SPRINT and ACCORD trials, PLoS Med sourceSupported
• cites [50] Phillips, 2018, Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension, J Am Coll Cardiol sourceSupported

Lifestyle intervention including weight loss, increased physical activity, and medical nutrition therapy allows some individuals with diabetes to reduce ASCVD risk factors such as hypertension, dyslipidemia, or obesity.

“Lifestyle intervention, including weight loss in people with overweight or obesity (when appropriate) (22,86), increased physical activity, and medical nutrition therapy, allows some individuals to reduce ASCVD risk factors such as hypertension, dyslipidemia, or obesity.”

• cites [22] Arnett, 2019, 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, Circulation sourceSupported
• cites [86] Virani, 2023, 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines, Circulation sourceSupported

MRAs reduce albuminuria in people with diabetic nephropathy.

“In addition, MRAs reduce albuminuria in people with diabetic nephropathy (83–85).”

• cites [83] Sato, 2003, Effectiveness of aldosterone blockade in patients with diabetic nephropathy, Hypertension sourceSupported
• cites [84] Mehdi, 2009, Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy, J Am Soc Nephrol sourceSupported
• cites [85] Bakris, 2015, Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial, JAMA sourceNot checked — no full text of the source

A systematic review of 10 randomized controlled trials reported that compared with control diet, the modified DASH eating pattern could reduce mean systolic (−3.26 mmHg [95% CI −5.58 to −0.94 mmHg]; P = 0.006) and diastolic (−2.07 mmHg [95% CI −3.68 to −0.46 mmHg]; P = 0.01) blood pressure.

“A systematic review of 10 randomized controlled trials reported that compared with control diet, the modified Dietary Approaches to Stop Hypertension (DASH) eating pattern could reduce mean systolic (−3.26 mmHg [95% CI −5.58 to −0.94 mmHg]; P = 0.006) and diastolic (−2.07 mmHg [95% CI −3.68 to −0.46 mmHg]; P = 0.01) blood pressure (54).”

• cites [54] Guo, 2021, Effects of the modified DASH diet on adults with elevated blood pressure or hypertension: a systematic review and meta-analysis, Front Nutr sourceSupported

The use of both ACE inhibitors and ARBs in combination, or the combination of an ACE inhibitor or ARB and a direct renin inhibitor, is contraindicated given the lack of added ASCVD benefit and increased rate of adverse events-namely, hyperkalemia, syncope, and AKI.

“However, the use of both ACE inhibitors and ARBs in combination, or the combination of an ACE inhibitor or ARB and a direct renin inhibitor, is contraindicated given the lack of added ASCVD benefit and increased rate of adverse events—namely, hyperkalemia, syncope, and AKI (74–76).”

• cites [74] Yusuf, 2008, Telmisartan, ramipril, or both in patients at high risk for vascular events, N Engl J Med sourcePartly supported

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• cites [75] Fried, 2013, Combined angiotensin inhibition for the treatment of diabetic nephropathy, N Engl J Med sourceNot checked — no full text of the source
• cites [76] Makani, 2013, Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials, BMJ sourcePartly supported

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MRAs, including spironolactone and eplerenone, are effective for management of resistant hypertension in people with type 2 diabetes when added to existing treatment with an ACE inhibitor or ARB, thiazide-like diuretic, or dihydropyridine calcium channel blocker.

“MRAs, including spironolactone and eplerenone, are effective for management of resistant hypertension in people with type 2 diabetes when added to existing treatment with an ACE inhibitor or ARB, thiazide-like diuretic, or dihydropyridine calcium channel blocker (82).”

• cites [82] Williams, 2015, Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial, Lancet sourcePartly supported

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In SPRINT, adverse outcomes including hypotension, syncope, electrolyte abnormality, and acute kidney injury were more common in the intensive treatment arm.

“Adverse outcomes, including hypotension, syncope, electrolyte abnormality, and acute kidney injury (AKI), were more common in the intensive treatment arm”

• cites [44] Wright, 2015, A randomized trial of intensive versus standard blood-pressure control, N Engl J Med sourceSupported

In individuals receiving ACE inhibitor or ARB therapy, continuation of those medications as kidney function declines to eGFR <30 mL/min/1.73 m2 may provide cardiovascular benefit without significantly increasing the risk of kidney failure.

“In individuals receiving ACE inhibitor or ARB therapy, continuation of those medications as kidney function declines to eGFR <30 mL/min/1.73 m2 may provide cardiovascular benefit without significantly increasing the risk of kidney failure (68).”

• cites [68] Qiao, 2020, Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate, JAMA Intern Med sourceSupported

Use of internet or mobile-based digital platforms to reinforce healthy behaviors may enhance the efficacy of medical therapy for hypertension.

“Use of internet or mobile-based digital platforms to reinforce healthy behaviors may be considered as a component of care, as these interventions have been found to enhance the efficacy of medical therapy for hypertension (55,56).”

• cites [55] Mao, 2020, Impact and efficacy of mobile health intervention in the management of diabetes and hypertension: a systematic review and meta-analysis, BMJ Open Diabetes Res Care sourcePartly supported

  The Results (Primary outcome of intervention; page unavailable) report greater reductions in systolic and diastolic blood pressure with mHealth interventions than with traditional treatment. The Results (Secondary results of intervention; page unavailable) also report changes in eating habits and physical activity. The paper does not establish that reinforcing those behaviors specifically enhances the efficacy of antihypertensive medication. (LLM, conf=0.82)

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• cites [56] Stogios, 2020, Advancing digital health interventions as a clinically applied science for blood pressure reduction: a systematic review and meta-analysis, Can J Cardiol sourceSupported

Absolute benefit from blood pressure reduction correlated with absolute baseline cardiovascular risk in SPRINT and in earlier clinical trials conducted at higher baseline blood pressure levels.

“Absolute benefit from blood pressure reduction correlated with absolute baseline cardiovascular risk in SPRINT and in earlier clinical trials conducted at higher baseline blood pressure levels (50,51).”

• cites [50] Phillips, 2018, Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension, J Am Coll Cardiol sourceSupported
• cites [51] Blood Pressure Lowering Treatment Trialists’ Collaboration., 2014, Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data, Lancet sourceNot checked — no full text of the source

In IMPROVE-IT, the addition of ezetimibe to a moderate-intensity statin led to a 6.4% relative benefit in major adverse cardiovascular events.

“The trial showed the addition of ezetimibe to a moderate-intensity statin led to a 6.4% relative benefit and a 2% absolute reduction in major adverse cardiovascular events (atherosclerotic cardiovascular events), with the degree of benefit being directly proportional to the change in LDL cholesterol (112).”

• cites [112] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med sourceSupported

Multiple clinical trials have demonstrated beneficial effects of statin therapy on ASCVD outcomes in subjects with and without established ASCVD.

“Multiple clinical trials have demonstrated the beneficial effects of statin therapy on ASCVD outcomes in subjects with and without established ASCVD (92,93).”

• cites [92] Fulcher, 2015, Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials, Lancet sourceNot checked — no full text of the source
• cites [93] Mihaylova, 2012, The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials, Lancet sourceSupported

The addition of PCSK9 monoclonal antibodies evolocumab and alirocumab to maximum tolerated doses of statin therapy in participants at high risk for ASCVD demonstrated an average reduction in LDL cholesterol ranging from 52% to 65%.

“The addition of the PCSK9 monoclonal antibodies evolocumab and alirocumab to maximum tolerated doses of statin therapy in participants who were at high risk for ASCVD demonstrated an average reduction in LDL cholesterol ranging from 52% to 65% (120,121).”

• cites [120] Moriarty, 2014, Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial, J Clin Lipidol sourceNot checked — no full text of the source
• cites [121] Toth, 2022, Network meta-analysis of randomized trials evaluating the comparative efficacy of lipid-lowering therapies added to maximally tolerated statins for the reduction of low-density lipoprotein cholesterol, J Am Heart Assoc sourcePartly supported

  The Results section (Primary Objective: Placebo-Corrected LDL-C Reduction at Week 12; page unavailable) reports substantial reductions with both antibodies: 62.80% for evolocumab, 64.80% for alirocumab 150 mg, and 53.97% for alirocumab 75 mg in a subgroup of trials whose populations were predominantly, not entirely, patients with ASCVD. This supports the general magnitude of the claimed range, but does not establish a 52% lower endpoint for these antibodies or that all participants were at high risk for ASCVD. (LLM, conf=0.83)

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Intensive therapy has been shown to be of benefit in multiple large meta-analyses and randomized cardiovascular outcomes trials in people with diabetes and established ASCVD.

“Intensive therapy is indicated because cardiovascular event rates are increased in people with diabetes and established ASCVD, and it has been shown to be of benefit in multiple large meta-analyses and randomized cardiovascular outcomes trials (93,101,104,112,115).”

• cites [93] Mihaylova, 2012, The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials, Lancet sourcePartly supported

  The Results (page unavailable) say that the more-versus-less-intensive statin trials enrolled patients with previous coronary disease, and the Discussion reports that more intensive regimens further reduced major vascular events. The copy does not establish that this intensive-therapy benefit was demonstrated specifically in people with both diabetes and established ASCVD. (LLM, conf=0.84)

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• cites [101] Kearney, 2008, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis, Lancet sourceNot checked — no full text of the source
• cites [104] Baigent, 2005, Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins, Lancet sourceNot checked — no full text of the source

Subgroup analyses of people with diabetes in larger trials and trials in people with diabetes showed significant primary and secondary prevention of ASCVD events and CHD death in people with diabetes.

“Subgroup analyses of people with diabetes in larger trials (94–98) and trials in people with diabetes (99,100) showed significant primary and secondary prevention of ASCVD events and coronary heart disease (CHD) death in people with diabetes.”

• cites [94] Pyŏrälä, 1997, Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S), Diabetes Care sourceNot checked — no full text of the source
• cites [95] Collins, 2003, MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial, Lancet sourceNot checked — no full text of the source
• cites [96] Goldberg, 1998, Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators, Circulation sourcePartly supported

  The Results (page not supplied) report a significant 25% reduction in a composite of recurrent coronary events among patients with diabetes, supporting secondary prevention. But CARE studied myocardial infarction survivors, not primary prevention, and the Results say CHD death did not decline in the diabetes subgroup. (LLM, conf=0.90)

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• cites [97] Shepherd, 2006, Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study, Diabetes Care sourcePartly supported

  The Efficacy outcomes section (page unavailable) reports a significant reduction in major cardiovascular events among patients with diabetes and established CHD, supporting the secondary-prevention portion. This study did not assess primary prevention, and its reduction in CHD death in the diabetes subgroup was not statistically significant (P = 0.203). (LLM, conf=0.88)

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• cites [98] Sever, 2005, Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial–lipid-lowering arm (ASCOT-LLA), Diabetes Care sourcePartly supported

  In the Results passage labeled “Statistical methods” (page not provided), atorvastatin significantly reduced total cardiovascular events and procedures in the diabetic subgroup, including participants without preexisting cardiovascular disease. But the paper says the reduction in its primary endpoint of fatal CHD and nonfatal myocardial infarction was not statistically significant in that subgroup; Table 4 also shows no significant reduction in CHD death. This source therefore supports the cardiovascular-event portion, not the claim of significant prevention of CHD death. (LLM, conf=0.89)

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• cites [99] Knopp, 2006, Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN), Diabetes Care sourceNot checked — no full text of the source
• cites [100] Colhoun, 2004, Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, Lancet sourceNot checked — no full text of the source

Cardiovascular event rates are increased in people with diabetes and established ASCVD.

“Intensive therapy is indicated because cardiovascular event rates are increased in people with diabetes and established ASCVD, and it has been shown to be of benefit in multiple large meta-analyses and randomized cardiovascular outcomes trials (93,101,104,112,115).”

• cites [93] Mihaylova, 2012, The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials, Lancet sourcePartly supported

  The Results link a history of vascular disease to higher predicted major vascular-event risk: almost all participants with predicted five-year risk of at least 20% came from trials of patients with prior vascular disease. The Discussion considers increased cardiovascular risk after a new diabetes diagnosis only as a hypothetical (“If new diagnoses of diabetes were associated with an immediate doubling”); it does not establish higher event rates in people with diabetes as the claim states. Page numbers are unavailable in our copy. (LLM, conf=0.82)

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• cites [101] Kearney, 2008, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis, Lancet sourceNot checked — no full text of the source
• cites [104] Baigent, 2005, Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins, Lancet sourceNot checked — no full text of the source

In IMPROVE-IT, the addition of ezetimibe to a moderate-intensity statin led to a 2% absolute reduction in major adverse cardiovascular events.

“The trial showed the addition of ezetimibe to a moderate-intensity statin led to a 6.4% relative benefit and a 2% absolute reduction in major adverse cardiovascular events (atherosclerotic cardiovascular events), with the degree of benefit being directly proportional to the change in LDL cholesterol (112).”

• cites [112] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med sourceSupported

Recent data from the PCSK9 inhibitor trial FOURIER suggest that LDL cholesterol-lowering benefit has important cardiovascular risk reduction benefits in people with type 1 diabetes and established CVD.

“Recent data from the PCSK9 inhibitor trial FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) suggest that LDL cholesterol–lowering benefit has important cardiovascular risk reduction benefits in people with type 1 diabetes and established CVD, as discussed in secondary prevention (people with ascvd), below (114).”

• cites [114] Kang, 2025, Cardiovascular outcomes and efficacy of the PCSK9 inhibitor evolocumab in individuals with type 1 diabetes: insights from the FOURIER trial, Diabetes Care sourceSupported

Monitoring lipid profiles after initiation of statin therapy and during therapy increases the likelihood of dose titration and following the statin treatment plan.

“Monitoring lipid profiles after initiation of statin therapy and during therapy increases the likelihood of dose titration and following the statin treatment plan (88–90).”

• cites [88] Jia, 2019, Association between lipid testing and statin adherence in the Veterans Affairs health system, Am J Med sourceNot checked — no full text of the source
• cites [89] Rana, 2022, Association of low-density lipoprotein testing after an atherosclerotic cardiovascular event with subsequent statin adherence and intensification, Am J Med sourcePartly supported

  The Results report that LDL-C testing after an ASCVD event was associated with higher statin adherence and treatment intensification. But the Discussion says the observational design cannot establish causation, and the study does not establish this effect for statin users generally after initiation or throughout therapy. (LLM, conf=0.88)

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• cites [90] Tran, 2022, Adherence to lipid monitoring and its impact on treat intensification of LDL-C lowering therapies at an urban academic medical center, J Clin Lipidol sourceNot checked — no full text of the source

Absolute reductions in ASCVD outcomes (CHD death and nonfatal MI) are greatest in people with high baseline ASCVD risk (known ASCVD and/or very high LDL cholesterol levels).

“As in those without diabetes, absolute reductions in ASCVD outcomes (CHD death and nonfatal MI) are greatest in people with high baseline ASCVD risk (known ASCVD and/or very high LDL cholesterol levels), but the overall benefits of statin therapy in people with diabetes at moderate or even low risk for ASCVD are convincing (102,103).”

• cites [102] Taylor, 2013, Statins for the primary prevention of cardiovascular disease, Cochrane Database Syst Rev sourceNot checked — no full text of the source
• cites [103] Carter, 2013, Risk of incident diabetes among patients treated with statins: population based study, BMJ sourceCould not verify

  The Introduction says statins have established benefits for patients at risk of cardiovascular events, but it does not compare absolute reductions across baseline-risk groups. The Results and Discussion address incident diabetes, not reductions in CHD death or nonfatal MI; searches for those outcomes and risk-specific benefits found no supporting passage in our copy. No page numbers were provided. (LLM, conf=0.76)

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High-intensity versus moderate-intensity statin therapy reduces cardiovascular event rates in high-risk individuals with established CVD in randomized trials.

“These recommendations are based on the observation that high-intensity versus moderate-intensity statin therapy reduces cardiovascular event rates in high-risk individuals with established CVD in randomized trials (93).”

• cites [93] Mihaylova, 2012, The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials, Lancet sourceSupported

A meta-analysis suggests that there is a cardiovascular benefit of adding ezetimibe or PCSK9 inhibitors to treatment for people at high risk.

“A meta-analysis suggests that there is a cardiovascular benefit of adding ezetimibe or PCSK9 inhibitors to treatment for people at high risk (111).”

• cites [111] Khan, 2022, PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis, BMJ sourceSupported

In IMPROVE-IT, the degree of benefit from adding ezetimibe to a moderate-intensity statin was directly proportional to the change in LDL cholesterol.

“The trial showed the addition of ezetimibe to a moderate-intensity statin led to a 6.4% relative benefit and a 2% absolute reduction in major adverse cardiovascular events (atherosclerotic cardiovascular events), with the degree of benefit being directly proportional to the change in LDL cholesterol (112).”

• cites [112] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med sourceSupported

Overall benefits of statin therapy in people with diabetes at moderate or even low risk for ASCVD are convincing.

“As in those without diabetes, absolute reductions in ASCVD outcomes (CHD death and nonfatal MI) are greatest in people with high baseline ASCVD risk (known ASCVD and/or very high LDL cholesterol levels), but the overall benefits of statin therapy in people with diabetes at moderate or even low risk for ASCVD are convincing (102,103).”

• cites [102] Taylor, 2013, Statins for the primary prevention of cardiovascular disease, Cochrane Database Syst Rev sourceNot checked — no full text of the source
• cites [103] Carter, 2013, Risk of incident diabetes among patients treated with statins: population based study, BMJ sourcePartly supported

  The Introduction says statins have established benefits in patients at risk of cardiovascular events, supporting only the general benefit claim. The Methods (Cohort definition) exclude patients with established diabetes, and the paper does not establish cardiovascular benefits specifically for people with diabetes at moderate or low ASCVD risk. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In FOURIER, participants with type 1 diabetes randomly assigned to placebo had a higher rate of major cardiovascular events (Kaplan-Meier event rate 20.4%) than those with type 2 diabetes (15.2%) and those without diabetes (11.0%).

“Participants with type 1 diabetes randomly assigned to placebo had a higher rate of major cardiovascular events (Kaplan-Meier event rate 20.4%) than those with type 2 diabetes (15.2%) and those without diabetes (11.0%).”

• cites [114] Kang, 2025, Cardiovascular outcomes and efficacy of the PCSK9 inhibitor evolocumab in individuals with type 1 diabetes: insights from the FOURIER trial, Diabetes Care sourceSupported

In ORION-3, an LDL cholesterol reduction of ∼45% was maintained through the end of year 4.

“Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol [ORION-3]), where an LDL cholesterol reduction of ∼45% was maintained through the end of year 4 (133).”

• cites [133] Ray, 2023, Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial, Lancet Diabetes Endocrinol sourceSupported

When added to a maximally tolerated statin, PCSK9 monoclonal antibodies significantly reduced the risk of major adverse cardiovascular events by 15-20% in the FOURIER and ODYSSEY OUTCOMES trials.

“When added to a maximally tolerated statin, these agents reduced LDL cholesterol by ∼60% (115) and significantly reduced the risk of major adverse cardiovascular events by 15–20% in the FOURIER (evolocumab) and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trials (115,117,122).”

• cites [115] Sabatine, 2017, Evolocumab and clinical outcomes in patients with cardiovascular disease, N Engl J Med sourcePartly supported

  The Discussion reports that adding evolocumab to statin therapy in FOURIER significantly reduced the primary composite cardiovascular endpoint by 15% and the key secondary endpoint by 20%. The Trial Population section describes an optimized statin regimen, preferably high-intensity, but does not establish that every participant received a maximally tolerated dose. This paper reports FOURIER, not ODYSSEY OUTCOMES; the citing sentence supplies other citations for its combined trial claim. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [117] Schwartz, 2018, Alirocumab and cardiovascular outcomes after acute coronary syndrome, N Engl J Med sourceSupported
• cites [122] Giugliano, 2020, Stroke prevention with the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab added to statin in high-risk patients with stable atherosclerosis, Stroke sourcePartly supported

  The Discussion (page unavailable in our copy) reports that evolocumab added to statin therapy reduced FOURIER’s primary cardiovascular composite by 15% and a narrower composite by 20%. The Study Population and Procedures section specifies moderate- or high-intensity statin therapy, not necessarily a maximally tolerated dose. This paper does not report the claimed 15–20% result for ODYSSEY OUTCOMES. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In GAUSS 3, after 24 weeks, LDL cholesterol reductions were 54.5% with evolocumab compared with 16.7% with ezetimibe.

“Similar LDL cholesterol reductions were demonstrated in the GAUSS 3 trial after 24 weeks (54.5% with evolocumab compared with 16.7% with ezetimibe), with slightly higher rates of musculoskeletal adverse events (20.7% with evolocumab and 28.8% with ezetimibe).”

• cites [131] Nissen, 2016, Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial, JAMA sourcePartly supported

  Table 3 (Coprimary End Points) reports LDL-C reductions of 54.5% with evolocumab and 16.7% with ezetimibe for the mean of weeks 22 and 24. At week 24 specifically, the reductions were 52.8% and 16.7%, respectively, so the claim assigns the evolocumab figure to a more specific time point than the paper does. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

For individuals requiring primary prevention, bempedoic acid resulted in a 30% reduction in primary composite outcome compared with placebo.

“For individuals requiring primary prevention, the use of bempedoic acid resulted in a 30% reduction in primary composite outcome compared with placebo (137).”

• cites [137] Nissen, 2023, Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients, JAMA sourcePartly supported

  The Clinical End Points section reports a primary composite outcome hazard ratio of 0.70 for bempedoic acid versus placebo, supporting the stated 30% relative reduction. The Study Population and Conclusion sections limit this finding to high-risk primary prevention patients unable to tolerate recommended statin doses; the claim does not retain those population qualifiers. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

In ODYSSEY ALTERNATIVE, after 24 weeks, alirocumab lowered LDL cholesterol levels by 54.8% versus 20.1% with ezetimibe.

“After the 24 weeks, alirocumab lowered LDL cholesterol levels by 54.8% versus 20.1% with ezetimibe.”

• cites [128] Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol sourceSupported

In FOURIER, the relative reduction in the risk of the primary major adverse cardiovascular event outcome with active compared with placebo evolocumab was similar across different types or statuses of diabetes.

“The relative reduction in the risk of the primary major adverse cardiovascular event outcome with active compared with placebo evolocumab was similar across different types or statuses of diabetes (type 1 diabetes HR 0.66, 95% CI 0.32–1.38; type 2 diabetes HR 0.84, 95% CI 0.75–0.93; no diabetes HR 0.87, 95% CI 0.79–0.96).”

• cites [114] Kang, 2025, Cardiovascular outcomes and efficacy of the PCSK9 inhibitor evolocumab in individuals with type 1 diabetes: insights from the FOURIER trial, Diabetes Care sourcePartly supported

  The Results (page unavailable) report exactly the three cited hazard ratios and confidence intervals for the primary outcome. However, they describe the relative risk reduction as numerically greater in type 1 diabetes (34% versus 16% and 13%), rather than similar across groups. The Conclusions note that the small type 1 diabetes group limited power to detect differences between groups. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Inclisiran has demonstrated the ability to reduce LDL cholesterol by 49-52% in trials evaluating individuals with established CVD or ASCVD risk equivalent.

“In addition to the monoclonal antibodies, an siRNA, inclisiran, which also targets PSCK9 and is referred to as a PCSK9 siRNA in this section, has demonstrated the ability to reduce LDL cholesterol by 49–52% in trials evaluating individuals with established CVD or ASCVD risk equivalent (123).”

• cites [123] Ray, 2020, Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol, N Engl J Med sourceSupported

In GAUSS 3, musculoskeletal adverse event rates were 20.7% with evolocumab and 28.8% with ezetimibe.

“Similar LDL cholesterol reductions were demonstrated in the GAUSS 3 trial after 24 weeks (54.5% with evolocumab compared with 16.7% with ezetimibe), with slightly higher rates of musculoskeletal adverse events (20.7% with evolocumab and 28.8% with ezetimibe).”

• cites [131] Nissen, 2016, Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial, JAMA sourceSupported

The absolute risk reduction of major cardiovascular events with evolocumab in individuals with type 1 diabetes was at least as large, if not larger, than that seen for type 2 diabetes or no diabetes.

“These observations suggest that the absolute risk reduction of major cardiovascular events with evolocumab in individuals with type 1 diabetes was at least as large, if not larger, than that seen for type 2 diabetes or no diabetes.”

• cites [114] Kang, 2025, Cardiovascular outcomes and efficacy of the PCSK9 inhibitor evolocumab in individuals with type 1 diabetes: insights from the FOURIER trial, Diabetes Care sourceSupported

In CLEAR Outcomes prespecified subanalyses, bempedoic acid reduced four-point major adverse cardiovascular events by 17% in individuals with diabetes.

“Prespecified subanalyses evaluated the impact for individuals with diabetes and showed a 17% reduction in four-point major adverse cardiovascular events when treated with bempedoic acid (136).”

• cites [136] Ray, 2024, Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial, Lancet Diabetes Endocrinol sourceSupported

When added to a maximally tolerated statin, PCSK9 monoclonal antibodies reduced LDL cholesterol by ∼60%.

“When added to a maximally tolerated statin, these agents reduced LDL cholesterol by ∼60% (115) and significantly reduced the risk of major adverse cardiovascular events by 15–20% in the FOURIER (evolocumab) and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trials (115,117,122).”

• cites [115] Sabatine, 2017, Evolocumab and clinical outcomes in patients with cardiovascular disease, N Engl J Med sourcePartly supported

  The Discussion reports that adding evolocumab to statin therapy lowered LDL cholesterol by 59% versus placebo, supporting the approximate 60% figure. The Trial Population section describes an optimized statin regimen, preferably high-intensity but permitting at least atorvastatin 20 mg daily or equivalent; it does not establish that every patient was taking a maximally tolerated dose. The trial directly tested evolocumab, not PCSK9 monoclonal antibodies as a group. Page numbers are not available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Use of bempedoic acid with ezetimibe results in an additional 19% reduction in LDL cholesterol.

“Use of this agent with ezetimibe results in an additional 19% reduction in LDL cholesterol (134).”

• cites [134] De Filippo, 2023, Safety and efficacy of bempedoic acid: a systematic review and meta-analysis of randomised controlled trials, Cardiovasc Diabetol sourceSupported

Statins did not increase teratogenic effects for individuals with familial hypercholesterolemia.

“Although the evidence is limited, statins did not increase teratogenic effects for individuals with familial hypercholesterolemia (141,142), and a meta-analysis of pravastatin in pregnant individuals showed a reduction in preeclampsia, premature birth, and neonatal intensive care unit admissions (143).”

• cites [141] Botha, 2018, Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies, Atherosclerosis sourceNot checked — no full text of the source
• cites [142] Toleikyte, 2011, Pregnancy outcomes in familial hypercholesterolemia: a registry-based study, Circulation sourcePartly supported

  The Congenital Malformations section reports no significant change in malformation frequency among women with familial hypercholesterolemia before versus after statins were introduced, and no malformations among 19 women who took lipid-lowering drugs during pregnancy. The Prematurity, Drug Use, and Mutation Types section identifies 15 of those women as statin users. These limited observations do not establish that statin exposure itself did not increase teratogenic risk. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

In ARRIVE, the primary end point occurred in 4.29% vs 4.48% of individuals in the aspirin versus placebo groups (HR 0.96 [95% CI 0.81-1.13]; P = 0.60).

“In ARRIVE, with 12,546 individuals over a period of 60 months of follow-up, the primary end point occurred in 4.29% vs. 4.48% of individuals in the aspirin versus placebo groups (HR 0.96 [95% CI 0.81–1.13]; P = 0.60).”

• cites [174] Gaziano, 2018, Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial, Lancet sourceSupported

In the ACCORD study, in people with type 2 diabetes at high risk for ASCVD, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone.

“In the ACCORD study, in people with type 2 diabetes who were at high risk for ASCVD, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone (153).”

• cites [153] Ginsberg, 2010, Effects of combination lipid therapy in type 2 diabetes mellitus, N Engl J Med sourceSupported

In the AIM-HIGH trial, there was a possible increased risk of ischemic stroke.

“In fact, there was a possible increased risk of ischemic stroke in the AIM-HIGH trial (154) and an increased incidence of new-onset diabetes (absolute excess, 1.3 percentage points; P < 0.001) and disturbances in diabetes management among those with diabetes in the HPS2-THRIVE trial in those on combination therapy (155).”

• cites [154] Boden, 2011, Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N Engl J Med sourceSupported

In an individual participant-level meta-analysis of six large trials of aspirin for primary prevention in the general population, aspirin reduced the risk of serious vascular events by 12% (relative risk 0.88 [95% CI 0.82-0.94]).

“Overall, they found that aspirin reduced the risk of serious vascular events by 12% (relative risk 0.88 [95% CI 0.82–0.94]).”

• cites [172] Baigent, 2009, Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials, Lancet sourceSupported

In primary prevention among individuals with no previous cardiovascular events, the net benefit of aspirin is more controversial.

“In primary prevention, however, among individuals with no previous cardiovascular events, its net benefit is more controversial (156,168).”

• cites [156] Rajpathak, 2009, Statin therapy and risk of developing type 2 diabetes: a meta-analysis, Diabetes Care sourceCould not verify

  The Results and Conclusions (page unavailable) discuss statin trials, cardiovascular prevention, and diabetes risk, not aspirin. Searches for aspirin’s net benefit and bleeding risk in primary prevention found no passage addressing the claim. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [168] Perk, 2012, European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts), Eur Heart J sourceNot checked — no full text of the source

In the ASCEND trial, during a mean follow-up of 7.4 years, aspirin 100 mg daily significantly reduced the primary efficacy end point (vascular death, MI, stroke, or transient ischemic attack) by 12% (8.5% vs 9.6%; P = 0.01).

“During a mean follow-up of 7.4 years, there was a significant 12% reduction in the primary efficacy end point (8.5% vs. 9.6%; P = 0.01).”

• cites [173] Bowman, 2018, Effects of aspirin for primary prevention in persons with diabetes mellitus, N Engl J Med sourceSupported

No change in cognitive function has been reported in studies with the addition of ezetimibe or PCSK9 monoclonal antibodies to statin therapy, including among individuals treated to very low LDL cholesterol levels.

“In addition, no change in cognitive function has been reported in studies with the addition of ezetimibe (112) or PCSK9 monoclonal antibodies (115,164) to statin therapy, including among individuals treated to very low LDL cholesterol levels.”

• cites [112] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med sourceCould not verify

  The End Points section lists the trial’s prespecified safety measures but does not include cognitive function. The Lipid Data and Discussion sections report LDL lowering with ezetimibe and no significant differences in the specified safety end points, but neither reports cognitive outcomes, including among patients with very low LDL levels. Searched for cognitive function, neurocognitive impairment, and memory; this citation is attached to the ezetimibe part of the sentence, not the PCSK9 part. (LLM, conf=0.77)

  Experimental — accuracy not yet measured
• cites [115] Sabatine, 2017, Evolocumab and clinical outcomes in patients with cardiovascular disease, N Engl J Med sourcePartly supported

  The Results report no significant difference in neurocognitive events between evolocumab and placebo when added to statin therapy; Table 3 gives rates of 1.6% and 1.5%. The paper also reports a median LDL cholesterol level of 30 mg/dL with evolocumab. It does not report a direct measure of cognitive function or a separate cognitive analysis of patients who reached very low LDL levels. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [164] Giugliano, 2017, Cognitive function in a randomized trial of evolocumab, N Engl J Med sourceSupported

The absolute risk increase of incident diabetes with rosuvastatin was small: over 5 years of follow-up, 1.2% of participants on placebo developed diabetes and 1.5% on rosuvastatin developed diabetes.

“The absolute risk increase was small (over 5 years of follow-up, 1.2% of participants on placebo developed diabetes and 1.5% on rosuvastatin developed diabetes) (158).”

• cites [158] Ridker, 2012, Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial, Lancet sourcePartly supported

  The Results report more incident diabetes with rosuvastatin than placebo (270 versus 216 cases), supporting a small absolute increase. But the paper does not report that 1.5% and 1.2% of participants developed diabetes over five years: the Methods say follow-up was up to five years, and the Discussion says median follow-up was two years. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Three large randomized trials of statin versus placebo with specific cognitive tests found no differences between statin and placebo.

“First, there are three large, randomized trials of statin versus placebo where specific cognitive tests were performed, and no differences were seen between statin and placebo (160–163).”

• cites [160] Heart Protection Study Collaborative Group, 2002, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial, Lancet sourceNot checked — no full text of the source
• cites [161] Shepherd, 2002, Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial, Lancet sourceNot checked — no full text of the source
• cites [162] Trompet, 2010, Pravastatin and cognitive function in the elderly. Results of the PROSPER study, J Neurol sourceNot checked — no full text of the source
• cites [163] Yusuf, 2016, Cholesterol lowering in intermediate-risk persons without cardiovascular disease, N Engl J Med sourcePartly supported

  The Methods (p. 1) describe a large randomized trial comparing rosuvastatin with placebo. The available passages report cardiovascular outcomes, not specific cognitive tests or cognitive results, so they do not support the claimed absence of a cognitive difference. This paper also cannot by itself establish the sentence’s count of three trials. (LLM, conf=0.79)

  Experimental — accuracy not yet measured

Large clinical trials, including AIM-HIGH and HPS2-THRIVE, failed to demonstrate a benefit of adding niacin to individuals on appropriate statin therapy.

“Large clinical trials, including the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) and Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials, failed to demonstrate a benefit of adding niacin to individuals on appropriate statin therapy.”

• cites [154] Boden, 2011, Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N Engl J Med sourcePartly supported

  The Discussion reports that AIM-HIGH found no incremental cardiovascular benefit from adding niacin to intensive statin therapy. It describes HPS2-THRIVE as still in follow-up, so this paper does not support the claim that HPS2-THRIVE had also failed to demonstrate a benefit. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [155] Landray, 2014, Effects of extended-release niacin with laropiprant in high-risk patients, N Engl J Med sourceNot checked — no full text of the source

Systematic reviews of randomized controlled trials and prospective cohort studies evaluating cognition in individuals receiving statins found that published data do not reveal an adverse effect of statins on cognition.

“In addition, systematic reviews of randomized controlled trials and prospective cohort studies evaluating cognition in individuals receiving statins found that published data do not reveal an adverse effect of statins on cognition (165,166).”

• cites [165] Olmastroni, 2022, Statin use and risk of dementia or Alzheimer’s disease: a systematic review and meta-analysis of observational studies, Eur J Prev Cardiol sourcePartly supported

  The Introduction says short-term data suggest no adverse effect of statins on cognition, and the Discussion reports no worsening of cognitive decline in several randomized trials. However, the Studies selection section says this review included observational cohort and case-control studies of Alzheimer's disease or dementia risk—not randomized trials or cognition outcomes generally. The claim's description of what this review evaluated is therefore not supported. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [166] Richardson, 2013, Statins and cognitive function: a systematic review, Ann Intern Med sourceNot checked — no full text of the source

Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk individuals with previous MI or stroke (secondary prevention).

“Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk individuals with previous MI or stroke (secondary prevention) and is strongly recommended.”

• cites [156] Rajpathak, 2009, Statin therapy and risk of developing type 2 diabetes: a meta-analysis, Diabetes Care sourceCould not verify

  The Results section reports cardiovascular outcomes for statin trials, including secondary-prevention trials, but does not address aspirin. Searches for aspirin, prior MI or stroke, and secondary-prevention recommendations found no passage supporting the attributed claim. Page numbers were not available in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [168] Perk, 2012, European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts), Eur Heart J sourceNot checked — no full text of the source

Several lines of evidence argue against an adverse association between lipid-lowering agents and cognitive function.

“Although concerns regarding a potential adverse impact of lipid-lowering agents on cognitive function have been raised, several lines of evidence argue against this association, as detailed in a 2018 European Atherosclerosis Society Consensus Panel statement (159).”

• cites [159] Mach, 2018, Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract, Eur Heart J sourceSupported

An analysis of one initial study suggested that although statin use was associated with diabetes risk, the cardiovascular event rate reduction with statins far outweighed the risk of incident diabetes, even for individuals at highest risk for diabetes.

“An analysis of one of the initial studies suggested that although statin use was associated with diabetes risk, the cardiovascular event rate reduction with statins far outweighed the risk of incident diabetes, even for individuals at highest risk for diabetes (158).”

• cites [158] Ridker, 2012, Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial, Lancet sourceSupported

Intensive medical therapy provides benefits similar to those of invasive revascularization in high-risk asymptomatic individuals.

“The screening of asymptomatic individuals with high ASCVD risk is not recommended, in part because these high-risk people should already be receiving intensive medical therapy—an approach that provides benefits similar to those of invasive revascularization (197,198).”

• cites [197] Boden, 2007, Optimal medical therapy with or without PCI for stable coronary disease, N Engl J Med sourceNot checked — no full text of the source
• cites [198] Frye, 2009, A randomized trial of therapies for type 2 diabetes and coronary artery disease, N Engl J Med sourcePartly supported

  The Discussion reports similar overall outcomes with intensive medical therapy and prompt revascularization in patients with type 2 diabetes and stable ischemic heart disease. It does not establish the same result for high-risk asymptomatic individuals generally: the Results (Patients; page not provided) say 82.1% had symptomatic ischemia, and the Discussion reports fewer major cardiovascular events with prompt revascularization in patients selected for CABG. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

In ASPREE, the rate of major hemorrhage per 1,000 person-years was 8.6 events versus 6.2 events (HR 1.38 [95% CI 1.18-1.62]; P < 0.001).

“The rate of major hemorrhage per 1,000 person-years was 8.6 events versus 6.2 events, respectively (HR 1.38 [95% CI 1.18–1.62]; P < 0.001).”

• cites [175] McNeil, 2018, Effect of aspirin on cardiovascular events and bleeding in the healthy elderly, N Engl J Med sourceSupported

In ARRIVE, gastrointestinal bleeding events (characterized as mild) occurred in 0.97% of individuals in the aspirin group vs 0.46% in the placebo group (HR 2.11 [95% CI 1.36-3.28]; P = 0.0007).

“Gastrointestinal bleeding events (characterized as mild) occurred in 0.97% of individuals in the aspirin group vs. 0.46% in the placebo group (HR 2.11 [95% CI 1.36–3.28]; P = 0.0007).”

• cites [174] Gaziano, 2018, Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial, Lancet sourceSupported

People with diabetes are at increased risk for developing heart failure, as shown in multiple longitudinal, observational studies.

“People with diabetes are at an increased risk for developing heart failure, as shown in multiple longitudinal, observational studies (205,206).”

• cites [205] McAllister, 2018, Incidence of hospitalization for heart failure and case-fatality among 3.25 million people with and without diabetes mellitus, Circulation sourceSupported
• cites [206] Ohkuma, 2019, Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals, Diabetologia sourceSupported

An increased risk of major bleeding was noted with rivaroxaban added to aspirin treatment in both COMPASS and VOYAGER PAD.

“However, an increased risk of major bleeding was noted with rivaroxaban added to aspirin treatment in both COMPASS and VOYAGER PAD.”

• cites [194] Bhatt, 2020, Role of combination antiplatelet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: insights from the COMPASS trial, Circulation sourcePartly supported

  The Results section reports a significant increase in major bleeding with rivaroxaban plus aspirin versus aspirin alone in COMPASS. Our copy reports no VOYAGER PAD bleeding result, so it does not support the claim about both trials (searched: “VOYAGER PAD” and “VOYAGER”). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [195] Connolly, 2018, Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial, Lancet sourceNot checked — no full text of the source
• cites [196] Bonaca, 2020, Rivaroxaban in peripheral artery disease after revascularization, N Engl J Med sourcePartly supported

  The Abstract and Discussion report significantly more ISTH-defined major bleeding with rivaroxaban plus aspirin in VOYAGER PAD, but no significant difference in the principal TIMI-defined major-bleeding outcome. The Introduction and discussion of COMPASS describe its ischemic benefits, not an increased risk of major bleeding, so our copy does not support that part of the claim. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In ASPREE, for CVD after a median of 4.7 years of follow-up, the rates per 1,000 person-years were 10.7 vs 11.3 events in aspirin vs placebo groups (HR 0.95 [95% CI 0.83-1.08]).

“In ASPREE, which included 19,114 individuals, for CVD (fatal CHD, MI, stroke, or hospitalization for heart failure) after a median of 4.7 years of follow-up, the rates per 1,000 person-years were 10.7 vs. 11.3 events in aspirin vs. placebo groups (HR 0.95 [95% CI 0.83–1.08]).”

• cites [175] McNeil, 2018, Effect of aspirin on cardiovascular events and bleeding in the healthy elderly, N Engl J Med sourceSupported

The association between diabetes and increased heart failure risk is observed in both type 2 and type 1 diabetes.

“This association is not only observed in people with type 2 diabetes but also evident in people with type 1 diabetes (205,206).”

• cites [205] McAllister, 2018, Incidence of hospitalization for heart failure and case-fatality among 3.25 million people with and without diabetes mellitus, Circulation sourceSupported
• cites [206] Ohkuma, 2019, Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals, Diabetologia sourceSupported

Studies have found that a risk factor-based approach to the initial diagnostic evaluation and subsequent follow-up for coronary artery disease fails to identify which people with type 2 diabetes will have silent ischemia on screening tests.

“Studies have also found that a risk factor–based approach to the initial diagnostic evaluation and subsequent follow-up for coronary artery disease fails to identify which people with type 2 diabetes who will have silent ischemia on screening tests (201,202).”

• cites [201] Wackers, 2004, Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study, Diabetes Care sourcePartly supported

  The Clinical implications section (p. 6) says the two-or-more-risk-factor screening recommendation missed many patients with test abnormalities, supporting the claim about initial screening. It also says these data address only silent ischemia at enrollment and that follow-up evaluation was still planned; this paper does not establish the claim about subsequent follow-up. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [202] Scognamiglio, 2006, Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus, J Am Coll Cardiol sourcePartly supported

  The Abstract reports nearly identical rates of abnormal stress screening in asymptomatic patients with type 2 diabetes regardless of risk-factor profile, supporting the claim about initial screening. The Discussion says the five-year follow-up was still pending, so this paper does not establish that a risk factor–based approach fails during subsequent follow-up. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

People with diabetes are at particularly high risk for progression from asymptomatic stage A and B to symptomatic stage C and D heart failure.

“People with diabetes are at particularly high risk for progression from asymptomatic stage A and B to symptomatic stage C and D heart failure (208,209).”

• cites [208] Segar, 2020, Association of long-term change and variability in glycemia with risk of incident heart failure among patients with type 2 diabetes: a secondary analysis of the ACCORD trial, Diabetes Care sourcePartly supported

  The Study Population section (p. 3) says participants had type 2 diabetes and no history of heart failure, and the outcome section (p. 3) tracks incident heart failure. The paper also says heart failure is common in adults with type 2 diabetes (Conclusions, p. 2). It does not establish a particularly high risk relative to people without diabetes or assess progression through stages A/B to C/D. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [209] Echouffo-Tcheugui, 2022, Diabetes and progression of heart failure: the Atherosclerosis Risk In Communities (ARIC) study, J Am Coll Cardiol sourceSupported

A randomized trial demonstrated no clinical benefit of routine screening with adenosine-stress radionuclide myocardial perfusion imaging in asymptomatic people with type 2 diabetes and normal ECGs.

“A randomized trial demonstrated no clinical benefit of routine screening with adenosine-stress radionuclide myocardial perfusion imaging in asymptomatic people with type 2 diabetes and normal ECGs (199).”

• cites [199] Young, 2009, Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial, JAMA sourceSupported

In the COMPASS trial of 27,395 individuals with established coronary artery disease and/or PAD, aspirin plus rivaroxaban 2.5 mg twice daily was superior to aspirin plus placebo in the reduction of cardiovascular ischemic events, including major adverse limb events.

“In the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial of 27,395 individuals with established coronary artery disease and/or PAD, aspirin plus rivaroxaban 2.5 mg twice daily was superior to aspirin plus placebo in the reduction of cardiovascular ischemic events, including major adverse limb events.”

• cites [194] Bhatt, 2020, Role of combination antiplatelet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: insights from the COMPASS trial, Circulation sourceSupported
• cites [195] Connolly, 2018, Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial, Lancet sourceNot checked — no full text of the source

In a large multinational cohort of 750,000 people with diabetes without established CVD, heart failure and CKD were the most frequent first manifestations of cardiovascular or kidney disease.

“In a large multinational cohort of 750,000 people with diabetes without established CVD, heart failure and CKD were the most frequent first manifestations of cardiovascular or kidney disease (207).”

• cites [207] Birkeland, 2020, Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: a large multinational cohort study, Diabetes Obes Metab sourceSupported

In the VOYAGER PAD trial, rivaroxaban 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of ischemic cardiovascular events, including major adverse limb events, compared with placebo plus aspirin.

“Rivaroxaban treatment in this group of individuals was also associated with a significantly lower incidence of ischemic cardiovascular events, including major adverse limb events.”

• cites [196] Bonaca, 2020, Rivaroxaban in peripheral artery disease after revascularization, N Engl J Med sourceSupported

In the ADAPTABLE trial of individuals with established CVD (38% with diabetes), there were no significant differences in cardiovascular events or major bleeding between individuals assigned to 81 mg and those assigned to 325 mg aspirin daily.

“In the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness) trial of individuals with established CVD, 38% of whom had diabetes, there were no significant differences in cardiovascular events or major bleeding between individuals assigned to 81 mg and those assigned to 325 mg aspirin daily (185).”

• cites [185] Jones, 2021, Comparative effectiveness of aspirin dosing in cardiovascular disease, N Engl J Med sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

For people >70 years of age (with or without diabetes), the balance of aspirin appears to have greater risk than benefit.

“For people >70 years of age (with or without diabetes), the balance appears to have greater risk than benefit (173,175).”

• cites [173] Bowman, 2018, Effects of aspirin for primary prevention in persons with diabetes mellitus, N Engl J Med sourcePartly supported

  The Conclusions (p. 1) say that, among people with diabetes and no evident cardiovascular disease, aspirin’s benefits were largely counterbalanced by major bleeding. The paper does not establish that risks exceed benefits specifically for people over 70, with or without diabetes; its reported balance is closer to even than the claim suggests. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [175] McNeil, 2018, Effect of aspirin on cardiovascular events and bleeding in the healthy elderly, N Engl J Med sourcePartly supported

  The Conclusions report more major hemorrhage without a significant reduction in cardiovascular disease, and the Results report no evidence that the cardiovascular or bleeding effects differed by diabetes subgroup (page not provided). But the trial studied aspirin for primary prevention in largely healthy older adults, not all people over 70; the paper notes that aspirin’s benefits can outweigh hemorrhage risk in secondary prevention. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The absolute benefits of aspirin plus rivaroxaban combination therapy appeared larger in people with diabetes, who comprised 10,341 of the COMPASS trial participants.

“The absolute benefits of combination therapy appeared larger in people with diabetes, who comprised 10,341 of the trial participants (194,195).”

• cites [194] Bhatt, 2020, Role of combination antiplatelet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: insights from the COMPASS trial, Circulation sourceSupported
• cites [195] Connolly, 2018, Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial, Lancet sourceNot checked — no full text of the source

The presence of microvascular disease is associated with adverse outcomes in people with PAD, including an increased risk for future limb amputation.

“In addition, the presence of microvascular disease is associated with adverse outcomes in people with PAD, including an increased risk for future limb amputation (228,229).”

• cites [228] Beckman, 2019, Microvascular disease, peripheral artery disease, and amputation, Circulation sourceSupported
• cites [229] Olesen, 2022, Microvascular disease increases the risk of lower limb amputation–a Western Danish cohort study, Eur J Clin Invest sourceNot checked — no full text of the source

The risk for peripheral artery disease in people with diabetes is higher than in people without diabetes.

“The risk for PAD in people with diabetes is higher than that in people without diabetes (220–222).”

• cites [220] Selvin, 2004, Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000, Circulation sourceSupported
• cites [221] Leibson, 2004, Peripheral arterial disease, diabetes, and mortality, Diabetes Care sourceSupported
• cites [222] Murabito, 1997, Intermittent claudication. A risk profile from The Framingham Heart Study, Circulation sourceNot checked — no full text of the source

Cardiovascular outcome trials of ertugliflozin and bexagliflozin have not demonstrated evidence of cardiovascular risk reduction.

“Cardiovascular outcome trials of ertugliflozin and bexagliflozin have not demonstrated evidence of cardiovascular risk reduction (249,250).”

• cites [249] Cannon, 2020, Cardiovascular outcomes with ertugliflozin in type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source
• cites [250] McMurray, 2024, Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin, Diabetes Obes Metab sourceSupported

A positive screening test for PAD in an asymptomatic population has been associated with increased cardiovascular event rates.

“While a positive screening test for PAD in an asymptomatic population has been associated with increased cardiovascular event rates (230,231), prospective, randomized studies addressing whether screening for PAD in”

• cites [230] Smolderen, 2022, Peripheral artery disease screening in the community and 1-year mortality, cardiovascular events, and adverse limb events, AJPM Focus sourcePartly supported

  The Results report higher major adverse cardiovascular event rates after a positive PAD screen than after a negative screen. The Discussion describes participants as previously unknown to have PAD, but does not establish that the screened population was asymptomatic; that qualifier is not supported. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [231] Smolderen, 2022, The Nevada peripheral artery disease screening effort in a Medicare Advantage population and subsequent mortality and major adverse cardiovascular event risk, J Vasc Surg sourceSupported

ACE inhibitors or ARB therapy have well-established long-term benefit in people with diabetes and CKD or hypertension.

“ACE inhibitors or ARB therapy also have well-established long-term benefit in people with diabetes and CKD or hypertension, and these agents are recommended for hypertension management in people with known ASCVD (particularly coronary artery disease) (66,67,238).”

• cites [66] Arnold, 2020, Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association, Circulation sourcePartly supported

  In Blood Pressure Control (page unavailable), the statement recommends ACE inhibitors or ARBs for hypertension in patients with type 2 diabetes and coronary artery disease, and reports renal benefit in patients with albuminuria. It also describes cardiovascular benefits over 4.5 years in a diabetes trial. The claim extends the kidney benefit to people with diabetes and CKD generally, whereas the passage specifies albuminuria. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [67] Yusuf, 2008, Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial, Lancet sourceNot checked — no full text of the source
• cites [238] Braunwald, 2004, Angiotensin-converting-enzyme inhibition in stable coronary artery disease, N Engl J Med sourceNot checked — no full text of the source

Results from several randomized controlled trials revealed that more intensive treatment of risk factors in people with increased levels of natriuretic peptides reduces the risk for symptomatic heart failure, heart failure hospitalization, and newly diagnosed left ventricular dysfunction.

“Results from several randomized controlled trials revealed that more intensive treatment of risk factors in people with increased levels of natriuretic peptides reduces the risk for symptomatic heart failure, heart failure hospitalization, and newly diagnosed left ventricular dysfunction (211,216,217).”

• cites [211] Huelsmann, 2013, PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial, J Am Coll Cardiol sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [216] Gaede, 2003, Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes, N Engl J Med sourcePartly supported

  The Results (statistical analysis; page not available) report fewer cardiovascular events with intensive multifactorial treatment, supporting the broad risk-reduction point. But the trial enrolled patients with type 2 diabetes and microalbuminuria, not people selected for elevated natriuretic peptides; its listed outcomes do not establish reductions in symptomatic heart failure, heart-failure hospitalization, or newly diagnosed left ventricular dysfunction. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [217] Gaede, 2005, Plasma N-terminal pro-brain natriuretic peptide as a major risk marker for cardiovascular disease in patients with type 2 diabetes and microalbuminuria, Diabetologia sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Results of large cardiovascular outcome trials of empagliflozin and canagliflozin showed that treatment with either drug reduced rates of MI, stroke, or cardiovascular death.

“Results of large cardiovascular outcome trials of empagliflozin (10 mg or 25 mg daily) and canagliflozin (100 or 300 mg daily) showed that treatment with either drug reduced rates of MI, stroke, or cardiovascular death.”

• cites [247] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med sourcePartly supported

  The Cardiovascular Outcomes section reports that canagliflozin reduced the composite rate of cardiovascular death, nonfatal MI, or nonfatal stroke, and the Randomization section confirms the 100 mg and 300 mg doses. This paper does not report the empagliflozin trial’s results or substantiate its stated doses; it only references that trial. It also says the individual canagliflozin outcome components did not reach statistical significance. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [248] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, N Engl J Med sourcePartly supported

  The Discussion (page not provided) says the canagliflozin CANVAS results were consistent with lower rates of the composite of cardiovascular death, myocardial infarction, or stroke, and that EMPA-REG OUTCOME showed empagliflozin was superior to placebo. This supports the main cardiovascular-outcome claim, but our copy does not establish the specific daily doses stated in the citing sentence. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Identification, risk stratification, and early treatment of risk factors in people with diabetes and asymptomatic stages of heart failure reduce the risk for progression to symptomatic heart failure.

“Identification, risk stratification, and early treatment of risk factors in people with diabetes and asymptomatic stages of heart failure reduce the risk for progression to symptomatic heart failure (210,211).”

• cites [210] Ledwidge, 2013, Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial, JAMA sourceNot checked — no full text of the source
• cites [211] Huelsmann, 2013, PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial, J Am Coll Cardiol sourcePartly supported

  The Abstract describes NT-proBNP risk selection and intensified treatment in people with type 2 diabetes who were free of cardiac disease, and reports fewer cardiac hospitalizations or deaths. The Conclusions table also shows fewer heart-failure hospitalizations (1 versus 7), but the Cox-model estimate for that endpoint was not statistically significant (p = 0.07). The paper did not establish that participants had asymptomatic-stage heart failure or directly measure progression to symptomatic heart failure. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Results of trials with GLP-1 RAs liraglutide, semaglutide, albiglutide, efpeglenatide, and dulaglutide have all shown evidence of a reduction in major atherosclerotic cardiovascular outcomes (MI, stroke, or cardiovascular death).

“Results of trials with the GLP-1 RAs liraglutide (once daily) and semaglutide, albiglutide, efpeglenatide, and dulaglutide (once weekly) have all shown evidence of a reduction in major atherosclerotic cardiovascular outcomes (MI, stroke, or cardiovascular death) (251–256).”

• cites [251] Marso, 2016, Liraglutide and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported
• cites [252] Marso, 2016, Semaglutide and cardiovascular outcomes in patients with type 2 diabetes, N Engl J Med sourceSupported
• cites [253] Gerstein, 2019, Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial, Lancet sourceNot checked — no full text of the source
• cites [254] Gerstein, 2021, Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes, N Engl J Med sourceSupported
• cites [255] Lee, 2025, Cardiovascular and kidney outcomes and mortality with long-acting injectable and oral glucagon-like peptide 1 receptor agonists in individuals with type 2 diabetes: a systematic review and meta-analysis of randomized trials, Diabetes Care sourceSupported
• cites [256] Hernandez, 2018, Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial, Lancet sourceSupported

In people with type 2 diabetes, measurement of natriuretic peptides, including BNP or NT-proBNP, identifies people at risk for heart failure development, progression of symptoms, and heart failure-related mortality.

“In people with type 2 diabetes, measurement of natriuretic peptides, including B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), identifies people at risk for heart failure development, progression of symptoms, and heart failure–related mortality (212–214).”

• cites [212] Januzzi, 2020, Effects of canagliflozin on amino-terminal pro-B-type natriuretic peptide: implications for cardiovascular risk reduction, J Am Coll Cardiol sourcePartly supported

  The Discussion reports that elevated NT-proBNP is associated with incident heart failure in people with type 2 diabetes, and the results find baseline NT-proBNP prognostic for heart-failure hospitalization. The paper does not establish symptom progression or heart-failure-specific mortality as outcomes predicted by these measurements; it reports cardiovascular-death composites and all-cause death instead. The evidence presented concerns NT-proBNP, not a separate BNP measurement. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [213] Jarolim, 2018, Serial measurement of natriuretic peptides and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE trial, Diabetes Care sourceNot checked — no full text of the source
• cites [214] Pandey, 2021, Biomarker-based risk prediction of incident heart failure in pre-diabetes and diabetes, JACC Heart Fail sourcePartly supported

  The Methods include NT-proBNP in a four-marker score, and the Results report that the score predicts incident heart failure in participants with diabetes and pre-diabetes. The paper does not establish the claim for BNP or for progression of symptoms and heart failure-related mortality; its stated outcome is incident heart failure. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Lixisenatide and extended-release exenatide were not superior to placebo with respect to the primary end point of cardiovascular outcomes.

“Lixisenatide and extended-release exenatide were not superior to placebo with respect to the primary end point of cardiovascular outcomes (260) and therefore are not recommended for CVD risk reduction.”

• cites [260] Holman, 2017, Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

In the SCORED trial, sotagliflozin reduced the primary outcome of death from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure in people with type 2 diabetes, CKD, and risk for CVD.

“Finally, in the Effect of Sotagliflozin on Cardiovascular and Renal Events in Participants With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial, randomization to the SGLT1/2 inhibitor sotagliflozin reduced the primary outcome of death from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure in people with type 2”

• cites [283] Bhatt, 2021, Sotagliflozin in patients with diabetes and chronic kidney disease, N Engl J Med sourceSupported

SGLT2 inhibitors and GLP-1 RAs also reduce risk of heart failure hospitalization and progression of kidney disease in people with established ASCVD, multiple risk factors for ASCVD, or albuminuric kidney disease.

“SGLT2 inhibitors and GLP-1RA also reduce risk of heart failure hospitalization and progression of kidney disease in people with established ASCVD, multiple risk factors for ASCVD, or albuminuric kidney disease (264,265).”

• cites [264] Zelniker, 2019, SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials, Lancet sourceNot checked — no full text of the source
• cites [265] McGuire, 2021, Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis, JAMA Cardiol sourcePartly supported

  The Results (page unavailable) report reduced hospitalization for heart failure and kidney-disease progression with SGLT2 inhibitors, including in analyses by ASCVD status and baseline albuminuria. This paper evaluates SGLT2 inhibitors, not GLP-1 receptor agonists, so it does not support the claim about both drug classes. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In retrospective analyses from the SOLVD and SAVE trials, concomitant use of β-blockers was associated with decreased risk of progression to symptomatic heart failure.

“Subsequent retrospective analyses from both trials revealed that concomitant use of β-blockers was associated with decreased risk of progression to symptomatic heart failure (277,278).”

• cites [277] Exner, 1999, Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the Studies of Left Ventricular Dysfunction, J Am Coll Cardiol sourceSupported
• cites [278] Vantrimpont, 1997, Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) study. SAVE Investigators, J Am Coll Cardiol sourceSupported

In the UKPDS trial, intensive blood pressure management in people with type 2 diabetes reduced the risk for heart failure by 56%.

“For example, in the UK Prospective Diabetes Study (UKPDS) trial, intensive blood pressure management in people with type 2 diabetes reduced the risk for heart failure by 56% (273).”

• cites [273] UK Prospective Diabetes Study Group, 1998, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38, BMJ sourceSupported

A meta-analysis of GLP-1 RA registration trials demonstrated a 14% relative reduction in the risk of hospitalization for heart failure (HR 0.86, 95% CI 0.79-0.93).

“A recently published meta-analysis of GLP-1 RA registration trials, including those for the commonly used medications dulaglutide, liraglutide, and semaglutide (both subcutaneous and oral), demonstrated a 14% relative reduction in the risk of hospitalization for heart failure (HR 0.86, 95% CI 0.79–0.93) (255).”

• cites [255] Lee, 2025, Cardiovascular and kidney outcomes and mortality with long-acting injectable and oral glucagon-like peptide 1 receptor agonists in individuals with type 2 diabetes: a systematic review and meta-analysis of randomized trials, Diabetes Care sourceSupported

In the FIGARO-DKD trial, finerenone reduced the primary outcome of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalization for heart failure (HR 0.87 [95% CI 0.76-0.98]; P = 0.03) in people with type 2 diabetes and CKD.

“In the FIGARO-DKD trial, finerenone reduced the primary outcome of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalization for heart failure (HR 0.87 [95% CI 0.76–0.98]; P = 0.03) in people with type 2 diabetes and CKD (240).”

• cites [240] Pitt, 2021, Cardiovascular events with finerenone in kidney disease and type 2 diabetes, N Engl J Med sourceSupported

In FIDELIO-DKD, the prespecified secondary outcome of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalization for heart failure was reduced by 13% in the finerenone group.

“A prespecified secondary outcome was death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalization for heart failure, which was reduced by 13% in the finerenone group.”

• cites [285] Bakris, 2020, Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes, N Engl J Med sourcePartly supported

  The Outcomes section defines the prespecified key secondary composite as stated, and Primary and Key Secondary Outcomes reports fewer events with finerenone than placebo. The reported hazard ratio is 0.86, corresponding to a 14% lower hazard, not a 13% reduction; 13.0% is the proportion of finerenone patients who had an event. No page number is available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In the SPRINT trial, the risk for development of incident heart failure decreased by 36%.

“Intensive treatment of hypertension in people with diabetes in the BPROAD trial led to a 34% reduction in treatment or hospitalization for heart failure (HR 0.66, 95% CI 0.41–1.04), a finding that parallels observations from the SPRINT trial where the risk for development of incident heart failure decreased by 36% (42,274).”

• cites [42] Bi, 2025, Intensive blood-pressure control in patients with type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source
• cites [274] Upadhya, 2017, Effect of intensive blood pressure treatment on heart failure events in the systolic blood pressure reduction intervention trial, Circ Heart Fail sourcePartly supported

  The Conclusions report a 36% reduction in acute decompensated heart failure (ADHF) with intensive blood-pressure treatment in SPRINT. The Discussion says new outpatient heart failure was not counted, so the result does not establish a 36% reduction in incident heart failure overall. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In the BPROAD trial, intensive treatment of hypertension in people with diabetes led to a 34% reduction in treatment or hospitalization for heart failure (HR 0.66, 95% CI 0.41-1.04).

“Intensive treatment of hypertension in people with diabetes in the BPROAD trial led to a 34% reduction in treatment or hospitalization for heart failure (HR 0.66, 95% CI 0.41–1.04), a finding that parallels observations from the SPRINT trial where the risk for development of incident heart failure decreased by 36% (42,274).”

• cites [42] Bi, 2025, Intensive blood-pressure control in patients with type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source
• cites [274] Upadhya, 2017, Effect of intensive blood pressure treatment on heart failure events in the systolic blood pressure reduction intervention trial, Circ Heart Fail sourceSupported

In FIGARO-DKD, the incidence of hospitalization for heart failure was reduced in the finerenone-allocated treatment arm (HR 0.71 [95% CI 0.56-0.90]).

“Only 7.8% of all participants had a prior history of heart failure, and the incidence of hospitalization for heart failure was reduced in the finerenone-allocated treatment arm (HR 0.71 [95% CI 0.56–0.90]).”

• cites [240] Pitt, 2021, Cardiovascular events with finerenone in kidney disease and type 2 diabetes, N Engl J Med sourceSupported

Meta-analyses of trials reported to date suggest that GLP-1 RAs and SGLT2 inhibitors reduce risk of atherosclerotic major adverse cardiovascular events to a comparable degree in people with type 2 diabetes and established ASCVD.

“Meta-analyses of the trials reported to date suggest that GLP-1 RAs and SGLT2 inhibitors reduce risk of atherosclerotic major adverse cardiovascular events to a comparable degree in people with type 2 diabetes and established ASCVD (262,263).”

• cites [262] Zelniker, 2019, Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus, Circulation sourceNot checked — no full text of the source
• cites [263] Palmer, 2021, Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials, BMJ sourcePartly supported

  The Results > Outcomes section reports that both drug classes reduced non-fatal myocardial infarction, with no detected difference between them. It also reports that GLP-1 receptor agonists reduced non-fatal stroke whereas SGLT-2 inhibitors had little or no effect. The paper does not report a comparable reduction in a composite of atherosclerotic major adverse cardiovascular events specifically among people with established ASCVD. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In FIDELIO-DKD, the incidence of heart failure hospitalization occurred less in the finerenone-treated group.

“The incidence of heart failure hospitalization occurred less in the finerenone-treated group, and only 7.7% of study participants had a prior history of heart failure.”

• cites [285] Bakris, 2020, Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes, N Engl J Med sourceSupported

Emerging data suggest that use of both SGLT2 inhibitors and GLP-1 RAs will provide an additive cardiovascular and kidney outcomes benefit.

“Emerging data suggest that use of both classes of drugs will provide an additive cardiovascular and kidney outcomes benefit; thus, combination therapy with an SGLT2 inhibitor and a GLP-1 RA may be considered to provide the complementary outcomes benefits associated with these classes of medication (254), which are largely independent of glycemic management.”

• cites [254] Gerstein, 2021, Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes, N Engl J Med sourceSupported

An oral formulation of semaglutide has also demonstrated cardiovascular benefit.

“An oral formulation of semaglutide has also demonstrated cardiovascular benefit (257–259).”

• cites [257] Marx, 2025, Oral semaglutide and cardiovascular outcomes in people with type 2 diabetes, according to SGLT2i use: prespecified analyses of the SOUL randomized trial, Circulation sourceSupported
• cites [258] Rebelo, 2025, Effects of oral semaglutide on cardiovascular outcomes: a systematic review and meta-analysis, Int J Cardiol sourceSupported
• cites [259] McGuire, 2023, Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: design and baseline characteristics of SOUL, a randomized trial, Diabetes Obes Metab sourcePartly supported

  The Introduction reports that PIONEER 6 found a significant reduction in cardiovascular death with oral semaglutide versus placebo. It also says the trial demonstrated cardiovascular safety but was not powered to formally assess cardiovascular efficacy, so the unqualified claim of demonstrated cardiovascular benefit overstates what this source establishes. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Early primary prevention strategies and treatment of associated risk factors reduce incident, symptomatic heart failure.

“Early primary prevention strategies and treatment of associated risk factors reduce incident, symptomatic heart failure and should include lifestyle intervention with nutrition, physical activity, weight management, and smoking cessation (268–271) (Fig. 10.5).”

• cites [268] Del Gobbo, 2015, Contribution of major lifestyle risk factors for incident heart failure in older adults: the Cardiovascular Health Study, JACC Heart Fail sourcePartly supported

  The Conclusions (page unavailable) report that physical activity, not smoking, and avoiding obesity were associated with lower incident heart-failure risk in older adults. The Methods confirm that cases had symptoms, but this observational study did not test whether early prevention or treatment of risk factors reduces heart failure. It also found no association between overall dietary patterns and lower heart-failure risk. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [269] Young, 2014, Effects of physical activity and sedentary time on the risk of heart failure, Circ Heart Fail sourcePartly supported

  The Results and Clinical Perspective report that lower physical activity was associated with higher incidence of heart failure in a cohort of middle-aged and older men. The paper does not establish that early prevention strategies or treatment of associated risk factors reduce symptomatic heart failure; it says whether changing these behaviors affects risk remains for future study. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [270] Tektonidis, 2016, Adherence to a Mediterranean diet is associated with reduced risk of heart failure in men, Eur J Heart Fail sourcePartly supported

  The Discussion (page unavailable in our copy) reports that greater adherence to a Mediterranean diet was associated with lower risk of developing heart failure in men, supporting the nutrition aspect of primary prevention. It does not establish that early interventions or treatment of risk factors reduce symptomatic heart failure, and it does not test physical activity, weight management, or smoking cessation as interventions. The observational association also does not establish the causal reduction asserted in the claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [271] Levitan, 2009, Consistency with the DASH diet and incidence of heart failure, Arch Intern Med sourcePartly supported

  The Introduction discusses preventing heart failure through treatment and lifestyle measures targeting risk factors, and the Abstract Conclusions report that diets consistent with DASH were associated with lower heart-failure rates. But this observational finding does not establish that prevention strategies or risk-factor treatment reduce symptomatic heart failure; the paper also does not test physical activity, weight management, or smoking cessation as interventions. The Comment notes that its outcome captures heart failure resulting in hospitalization or death. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Similar results to DAPA-HF were obtained in clinical trials with empagliflozin.

“Similar results were obtained in clinical trials with empagliflozin (291).”

• cites [291] Packer, 2020, Cardiovascular and renal outcomes with empagliflozin in heart failure, N Engl J Med sourceSupported

A large meta-analysis including EMPEROR-Reduced, EMPEROR-Preserved, DAPA-HF, DELIVER, and SOLOIST-WHF (21,947 individuals) demonstrated reduced risk for the composite of cardiovascular death or hospitalization for heart failure, cardiovascular death, first hospitalization for heart failure, and all-cause mortality.

“A large meta-analysis (297) including the EMPEROR-Reduced, EMPEROR-Preserved, DAPA-HF, DELIVER, and SOLOIST-WHF trials included 21,947 individuals and demonstrated reduced risk for the composite of cardiovascular death or hospitalization for heart failure, cardiovascular death, first hospitalization for heart failure, and all-cause mortality.”

• cites [297] Vaduganathan, 2022, SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials, Lancet sourceSupported

In the DELIVER trial, dapagliflozin showed a similar benefit for heart failure outcomes in people with mildly reduced or preserved ejection fraction.

“A similar benefit for heart failure outcomes was seen in the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial for dapagliflozin in people with mildly reduced or preserved ejection fraction (290).”

• cites [290] Solomon, 2022, Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction, N Engl J Med sourceSupported

SGLT2 inhibitors improve clinical stability and functional status in individuals with heart failure.

“In addition to the hospitalization and mortality benefit in people with heart failure, SGLT2 inhibitors improve clinical stability and functional status in individuals with heart failure (289,292–294).”

• cites [289] Nassif, 2021, The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial, Nat Med sourcePartly supported

  The Results (Patients section; page unavailable) report improved symptoms and physical limitations after 12 weeks of dapagliflozin in patients with HFpEF, supporting the functional-status part of the claim. The Trial design section says clinical stability was ensured before randomization; it does not report improved clinical stability as a treatment outcome. The trial's finding is also narrower than the claim's reference to SGLT2 inhibitors in people with heart failure generally. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [292] Packer, 2021, Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial, Circulation sourcePartly supported

  The Results report that empagliflozin reduced worsening heart-failure events and increased the odds of improvement in NYHA functional class. The study concerns patients with reduced ejection fraction, so this source alone does not establish the claim for heart failure more broadly. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [293] Voors, 2022, The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial, Nat Med sourcePartly supported

  The Results (Primary and secondary outcomes; page not provided) report fewer heart-failure events and a greater improvement in symptom scores with empagliflozin than with placebo. These findings support a clinical benefit, but the paper does not establish improved functional status as a separate outcome; its trial was limited to empagliflozin in patients hospitalized for acute heart failure, rather than SGLT2 inhibitors in all individuals with heart failure. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [294] Spertus, 2022, The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial, Nat Med sourcePartly supported

  The Discussion reports that SGLT2 inhibitors improve symptoms, function and quality of life in people with heart failure, supporting the functional-status part of the claim. The Results > Outcomes report fewer patients with moderate or greater symptom-score deterioration on canagliflozin, but the paper does not establish improved clinical stability as a distinct outcome; the Discussion says the trial was not designed or powered to examine clinical events. No page numbers are available in our copy. (LLM, conf=0.79)

  Experimental — accuracy not yet measured

Three other cardiovascular outcomes trials-EXAMINE, TECOS, and CARMELINA-did not find a significant increase in risk of heart failure hospitalization with DPP-4 inhibitor use compared with placebo.

“However, three other cardiovascular outcomes trials—Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) (312), Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) (313), and the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) (314)—did not find a significant increase in risk of heart failure hospitalization with D”

• cites [312] Zannad, 2015, Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial, Lancet sourceNot checked — no full text of the source
• cites [313] Green, 2015, Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported
• cites [314] Rosenstock, 2019, Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial, JAMA sourceSupported

In STEP-HFpEF DM, semaglutide treatment improved 6-min walk distance.

“In addition, in the confirmatory secondary end point, semaglutide treatment improved 6-min walk distance.”

• cites [306] Kosiborod, 2024, Semaglutide in patients with obesity-related heart failure and type 2 diabetes, N Engl J Med sourceSupported

Of the enrolled participants in FINEARTS-HF, 41% had type 2 diabetes.

“Of the enrolled participants, 41% had type 2 diabetes.”

• cites [303] Solomon, 2024, Finerenone in heart failure with mildly reduced or preserved ejection fraction, N Engl J Med sourceSupported

In the SOLOIST-WHF trial, sotagliflozin initiated during or shortly after hospitalization for heart failure in people with diabetes reduced the risk for the primary end point of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure.

“In the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial, sotagliflozin, a combined SGLT1/2 inhibitor, initiated during or shortly after hospitalization for heart failure in people with diabetes, also reduced the risk for the primary end point of deaths from cardiovascular causes and hospitalizations and urgent visits”

• cites [296] Bhatt, 2021, Sotagliflozin in patients with diabetes and recent worsening heart failure, N Engl J Med sourceSupported

The effect of dapagliflozin on the primary outcome in DAPA-HF was consistent regardless of the presence or absence of type 2 diabetes.

“The effect of dapagliflozin on the primary outcome was consistent regardless of the presence or absence of type 2 diabetes (287).”

• cites [287] McMurray, 2019, Dapagliflozin in patients with heart failure and reduced ejection fraction, N Engl J Med sourceSupported

Increasing evidence has demonstrated benefits of GLP-1 RA or dual GIP/GLP-1 RA on symptoms and outcomes for people with HFpEF and obesity.

“Increasing evidence has demonstrated the benefits of GLP-1 RA or dual GIP/GLP-1 RA on symptoms and outcomes for people with HFpEF and obesity, and while most people with HFpEF have obesity, approximately 45% have diabetes (304,305).”

• cites [304] Echouffo-Tcheugui, 2016, Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: findings from Get With The Guidelines-Heart Failure registry, Am Heart J sourceNot checked — no full text of the source
• cites [305] Haass, 2011, Body mass index and adverse cardiovascular outcomes in heart failure patients with preserved ejection fraction: results from the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial, Circ Heart Fail sourceCould not verify

  The Methods describe a BMI analysis of patients in the I-PRESERVE irbesartan trial, and the Discussion reports associations between BMI and cardiovascular outcomes. Searches for GLP-1, GIP/GLP-1, semaglutide, and tirzepatide found no passage addressing whether those treatments benefit symptoms or outcomes in people with HFpEF and obesity. Page numbers are not available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Approximately 45% of people with HFpEF have diabetes.

“Increasing evidence has demonstrated the benefits of GLP-1 RA or dual GIP/GLP-1 RA on symptoms and outcomes for people with HFpEF and obesity, and while most people with HFpEF have obesity, approximately 45% have diabetes (304,305).”

• cites [304] Echouffo-Tcheugui, 2016, Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: findings from Get With The Guidelines-Heart Failure registry, Am Heart J sourceNot checked — no full text of the source
• cites [305] Haass, 2011, Body mass index and adverse cardiovascular outcomes in heart failure patients with preserved ejection fraction: results from the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial, Circ Heart Fail sourceCould not verify

  The Discussion’s Clinical and Demographic Characteristics section says diabetes was less common in the lowest-BMI group, but gives no overall diabetes prevalence. I searched for 45%, diabetes prevalence, and the baseline characteristics in Table 1; the passages retrieved from our copy do not establish the claimed figure. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

ACE inhibitors, ARBs, thiazide-like diuretics, and dihydropyridine calcium channel blockers have been demonstrated to reduce cardiovascular events in people with diabetes.

“Initial treatment for hypertension should include any of the drug classes demonstrated to reduce cardiovascular events in people with diabetes (27): ACE inhibitors (62), angiotensin receptor blockers (ARBs) (62), thiazide-like diuretics (63), or dihydropyridine calcium channel blockers (64).”

• cites [27] Mancia, 2023, 2023 ESH guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA), J Hypertens sourceNot checked — no full text of the source
• cites [62] Ichikawa, 2025, Efficacy of renin-angiotensin system inhibitors, calcium channel blockers, and diuretics in hypertensive patients with diabetes: subgroup analysis based on albuminuria in a systematic review and meta-analysis, Hypertens Res sourceNot checked — no full text of the source
• cites [63] Barzilay, 2004, Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study, J Clin Hypertens (Greenwich) sourceNot checked — no full text of the source

BPROAD provides the strongest evidence to support a systolic blood pressure treatment goal of <120 mmHg.

“BPROAD provides the strongest evidence to support a systolic blood pressure treatment goal of <120 mmHg, as it enrolled people with type 2 diabetes and increased cardiovascular risk with a baseline systolic blood pressure ≥140 mmHg (or 130–180 mmHg if already taking antihypertensive medication).”

• cites [42] Bi, 2025, Intensive blood-pressure control in patients with type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source

Elevations in serum creatinine (up to 30% from baseline) with ACE inhibitors or ARBs must not be confused with AKI.

“Elevations in serum creatinine (up to 30% from baseline) with ACE inhibitors or ARBs must not be confused with AKI (79).”

• cites [79] Bakris, 2000, Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?, Arch Intern Med sourceNot checked — no full text of the source

Targeting an on-treatment systolic blood pressure goal of <120 mmHg in people with high cardiovascular risk is associated with reduction in cardiovascular events compared with systolic blood pressure <140 mmHg.

“The results of BPROAD and ESPRIT highlight that targeting an on-treatment systolic blood pressure goal of <120 mmHg in people with high cardiovascular risk is associated with reduction in cardiovascular events compared with systolic blood pressure <140 mmHg.”

• cites [42] Bi, 2025, Intensive blood-pressure control in patients with type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source
• cites [43] Liu, 2024, Lowering systolic blood pressure to less than 120 mm Hg versus less than 140 mm Hg in patients with high cardiovascular risk with and without diabetes or previous stroke: an open-label, blinded-outcome, randomised trial, Lancet sourceNot checked — no full text of the source

In the ADVANCE trial, the primary end point (composite of cardiovascular death, nonfatal stroke or MI, or new or worsening kidney or eye disease) was reduced by 9% in the combination treatment.

“The primary end point, a composite of cardiovascular death, nonfatal stroke or MI, or new or worsening kidney or eye disease, was reduced by 9% in the combination treatment.”

• cites [46] Patel, 2007, Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial, Lancet sourceNot checked — no full text of the source

In ESPRIT, there was a modest increase in adverse events, including syncope (0.4% vs. 0.1%, HR 3.00, 95% CI 1.35-6.68).

“The investigators reported a modest increase in adverse events, including syncope (0.4% vs. 0.1%, HR 3.00, 95% CI 1.35–6.68) (43).”

• cites [43] Liu, 2024, Lowering systolic blood pressure to less than 120 mm Hg versus less than 140 mm Hg in patients with high cardiovascular risk with and without diabetes or previous stroke: an open-label, blinded-outcome, randomised trial, Lancet sourceNot checked — no full text of the source

In people with diabetes in the HOT trial, there was a significant 51% reduction in MI, stroke, and cardiovascular death in the treatment group with a goal diastolic blood pressure <80 mmHg compared with a goal <90 mmHg.

“However, in people with diabetes, there was a significant 51% reduction in MI, stroke, and cardiovascular death in the treatment group with a goal diastolic blood pressure of <80 mmHg compared with a goal diastolic blood pressure of <90 mmHg.”

• cites [47] Hansson, 1998, Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group, Lancet sourceNot checked — no full text of the source

In the STEP trial, the primary composite outcome occurred in 3.5% of the intensive treatment group versus 4.6% in the standard treatment group (HR 0.74 [95% CI 0.60-0.92]; P = 0.007).

“the primary composite outcome of stroke, acute coronary syndrome, acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes occurred in 3.5% of individuals in the intensive treatment group versus 4.6% in the standard treatment group (HR 0.74 [95% CI 0.60–0.92]; P = 0.007).”

• cites [40] Xie, 2016, Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis, Lancet sourceNot checked — no full text of the source

The Cholesterol Treatment Trialists' Collaboration showed a 21% reduction in major cardiovascular events in people with diabetes for every 39 mg/dL (1 mmol/L) of LDL cholesterol lowering, irrespective of baseline LDL cholesterol or individual characteristics.

“The Cholesterol Treatment Trialists’ Collaboration, involving 26 statin trials, of which 5 compared high-intensity versus moderate-intensity statins, showed a 21% reduction in major cardiovascular events in people with diabetes for every 39 mg/dL (1 mmol/L) of LDL cholesterol lowering, irrespective of baseline LDL cholesterol or individual characteristics (101).”

• cites [101] Kearney, 2008, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis, Lancet sourceNot checked — no full text of the source

Heterogeneity by age has not been seen in the relative benefit of lipid-lowering therapy in trials that included older participants.

“However, heterogeneity by age has not been seen in the relative benefit of lipid-lowering therapy in trials that included older participants (100,101,104), and because older age confers higher risk, the absolute benefits are actually greater (104,112).”

• cites [100] Colhoun, 2004, Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, Lancet sourceNot checked — no full text of the source
• cites [101] Kearney, 2008, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis, Lancet sourceNot checked — no full text of the source
• cites [104] Baigent, 2005, Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins, Lancet sourceNot checked — no full text of the source

People with diabetes and multiple other coronary risk factors have increased risk equivalent to that of those with ASCVD.

“Since cardiovascular risk is enhanced in people with diabetes, as noted above, individuals who also have multiple other coronary risk factors have increased risk, equivalent to that of those with ASCVD.”

In the Heart Protection Study, the subgroup of ∼600 people with type 1 diabetes had a reduction in risk proportionately similar, although not statistically significant, to that in people with type 2 diabetes.

“In the Heart Protection Study (lower age limit 40 years), the subgroup of ∼600 people with type 1 diabetes had a reduction in risk proportionately similar, although not statistically significant, to that in people with type 2 diabetes (95).”

• cites [95] Collins, 2003, MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial, Lancet sourceNot checked — no full text of the source

Effects of statin therapy do not differ based on sex.

“It is important to note that the effects of statin therapy do not differ based on sex (92).”

• cites [92] Fulcher, 2015, Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials, Lancet sourceNot checked — no full text of the source

There is evidence for benefit from even extremely low, less-than-daily statin doses.

“There is evidence for benefit from even extremely low, less-than-daily statin doses (91).”

• cites [91] Meek, 2012, Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study, Curr Med Res Opin sourceNot checked — no full text of the source

In a subanalysis of IMPROVE-IT participants with diabetes, combination treatment with ezetimibe and moderate-intensity statin significantly reduced major adverse cardiovascular events compared with moderate-intensity statin alone.

“A subanalysis of participants with diabetes (27% of the 18,144 participants) showed a significant reduction of major adverse cardiovascular events with the combination treatment over moderate-intensity statin alone (116).”

• cites [116] Giugliano, 2018, Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), Circulation sourceNot checked — no full text of the source

In the meta-analysis, cardiovascular benefit did not depend on baseline LDL cholesterol levels.

“The cardiovascular benefit in this large meta-analysis did not depend on baseline LDL cholesterol levels and was linearly related to the LDL cholesterol reduction without a low threshold beyond which there was no benefit observed (101).”

• cites [101] Kearney, 2008, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis, Lancet sourceNot checked — no full text of the source

Relative benefit of lipid-lowering therapy has been uniform across most subgroups tested, including subgroups that varied with respect to age and other risk factors.

“The relative benefit of lipid-lowering therapy has been uniform across most subgroups tested (101,104), including subgroups that varied with respect to age and other risk factors.”

• cites [101] Kearney, 2008, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis, Lancet sourceNot checked — no full text of the source
• cites [104] Baigent, 2005, Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins, Lancet sourceNot checked — no full text of the source

In people with diabetes, each 1 mmol/L (39 mg/dL) reduction in LDL cholesterol with statin therapy is associated with a 13% reduction in vascular mortality.

“Meta-analyses including data from >18,000 people with diabetes from 14 randomized trials of statin therapy (mean follow-up 4.3 years) demonstrated a 9% proportional reduction in all-cause mortality and 13% reduction in vascular mortality for each 1 mmol/L (39 mg/dL) reduction in LDL cholesterol (101).”

• cites [101] Kearney, 2008, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis, Lancet sourceNot checked — no full text of the source

In people with diabetes, each 1 mmol/L (39 mg/dL) reduction in LDL cholesterol with statin therapy is associated with a 9% proportional reduction in all-cause mortality.

“Meta-analyses including data from >18,000 people with diabetes from 14 randomized trials of statin therapy (mean follow-up 4.3 years) demonstrated a 9% proportional reduction in all-cause mortality and 13% reduction in vascular mortality for each 1 mmol/L (39 mg/dL) reduction in LDL cholesterol (101).”

• cites [101] Kearney, 2008, Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis, Lancet sourceNot checked — no full text of the source

In REDUCE-IT, the composite of cardiovascular death, nonfatal MI, or nonfatal stroke was reduced by 26%.

“The composite of cardiovascular death, nonfatal MI, or nonfatal stroke was reduced by 26% (P < 0.001).”

• cites REDUCE-ITNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The REDUCE-IT trial showed that the addition of icosapent ethyl to statin therapy in individuals with established CVD or risk factors and elevated triglycerides (150-499 mg/dL) after maximizing statin therapy resulted in a 25% relative risk reduction for the primary end point composite compared with placebo.

“The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed that the addition of icosapent ethyl to statin therapy in this population resulted in a 25% relative risk reduction (P < 0.001) for the primary end point composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina compared with placebo.”

• cites REDUCE-ITNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In REDUCE-IT, cardiovascular death was reduced by 20%.

“Additional ischemic end points were significantly lower in the icosapent ethyl group than in the placebo group, including cardiovascular death, which was reduced by 20% (P = 0.03).”

• cites REDUCE-ITNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A subset of individuals experience partial or complete intolerance to statin therapy.

“Statin therapy is a cornerstone of CVD prevention and treatment; however, a subset of individuals experience partial (inability to tolerate sufficient dosage necessary to achieve therapeutic objectives due to adverse effects) or complete (inability to tolerate any dose) intolerance to statin therapy (127).”

• cites [127] Cheeley, 2022, NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient, J Clin Lipidol sourceNot checked — no full text of the source

In REDUCE-IT, the risk reduction was seen in individuals with or without diabetes at baseline.

“This risk reduction was seen in individuals with or without diabetes at baseline.”

• cites REDUCE-ITNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In REDUCE-IT, the proportions of individuals experiencing adverse events and serious adverse events were similar between the active and placebo treatment groups.

“The proportions of individuals experiencing adverse events and serious adverse events were similar between the active and placebo treatment groups.”

• cites REDUCE-ITNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The evidence for the use of drugs that target HDL cholesterol and triglyceride lipid fractions is substantially less robust than that for statin therapy.

“However, the evidence for the use of drugs that target these lipid fractions is substantially less robust than that for statin therapy (149).”

• cites [149] Singh, 2007, High-density lipoprotein as a therapeutic target: a systematic review, JAMA sourceNot checked — no full text of the source

A concern that statins or other lipid-lowering agents might cause cognitive dysfunction or dementia is not currently supported by evidence.

“Therefore, a concern that statins or other lipid-lowering agents might cause cognitive dysfunction or dementia is not currently supported by evidence and should not deter their use in individuals with diabetes at high risk for ASCVD (167).”

• cites [167] Adhikari, 2021, Association between statin use and cognitive function: a systematic review of randomized clinical trials and observational studies, J Clin Lipidol sourceNot checked — no full text of the source

Current evidence from randomized trials does not support cardiovascular risk reduction for other n-3 fatty acids.

“Current evidence from randomized trials does not support cardiovascular risk reduction for other n-3 fatty acids, and results of the REDUCE-IT trial should not be extrapolated to other products (147).”

• cites [147] Bhatt, 2019, Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia, N Engl J Med sourceNot checked — no full text of the source

The excess risk of gastrointestinal bleeding with aspirin may be as high as 5 per 1,000 per year in real-world settings.

“The excess risk may be as high as 5 per 1,000 per year in real-world settings.”

• cites [176] Pignone, 2006, Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis, Ann Intern Med sourceNot checked — no full text of the source

For people with documented ASCVD, use of aspirin for secondary prevention has far greater benefit than risk.

“For people with documented ASCVD, use of aspirin for secondary prevention has far greater benefit than risk; for this indication, aspirin is still recommended (168).”

• cites [168] Perk, 2012, European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts), Eur Heart J sourceNot checked — no full text of the source

A higher incidence of major bleeding, including intracranial hemorrhage, was noted with dual antiplatelet therapy.

“However, a higher incidence of major bleeding, including intracranial hemorrhage, was noted with dual antiplatelet therapy.”

• cites [190] Bhatt, 2019, Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial, Lancet sourceNot checked — no full text of the source

In people with diabetes and stable coronary artery disease, addition of ticagrelor to aspirin reduced the risk of ischemic cardiovascular events compared with aspirin alone.

“Similarly, the addition of ticagrelor to aspirin reduced the risk of ischemic cardiovascular events compared with aspirin alone in people with diabetes and stable coronary artery disease (189,190).”

• cites [189] Steg, 2019, Ticagrelor in patients with stable coronary disease and diabetes, N Engl J Med sourceNot checked — no full text of the source
• cites [190] Bhatt, 2019, Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial, Lancet sourceNot checked — no full text of the source

In people with diabetes and prior MI (1-3 years before), adding ticagrelor to aspirin significantly reduces the risk of recurrent ischemic events, including cardiovascular and CHD death.

“In people with diabetes and prior MI (1–3 years before), adding ticagrelor to aspirin significantly reduces the risk of recurrent ischemic events, including cardiovascular and CHD death (188).”

• cites [188] Bhatt, 2016, Reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54, J Am Coll Cardiol sourceNot checked — no full text of the source

Any benefit of noninvasive coronary artery disease screening methods, such as computed tomography calcium scoring, to identify subgroups for different treatment strategies remains unproven in asymptomatic people with diabetes.

“Any benefit of noninvasive coronary artery disease screening methods, such as computed tomography calcium scoring, to identify subgroups for different treatment strategies remains unproven in asymptomatic people with diabetes, though research is ongoing.”

The main adverse effect of aspirin is an increased risk of gastrointestinal bleeding.

“The main adverse effect is an increased risk of gastrointestinal bleeding.”

• cites [176] Pignone, 2006, Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis, Ann Intern Med sourceNot checked — no full text of the source

Another randomized study showed that routine screening with coronary computed tomography angiography did not reduce the composite rate of all-cause mortality, nonfatal MI, or unstable angina in asymptomatic people with type 1 or type 2 diabetes.

“Another randomized study showed that routine screening with coronary computed tomography angiography did not reduce the composite rate of all-cause mortality, nonfatal MI, or unstable angina in asymptomatic people with type 1 or type 2 diabetes (200).”

• cites [200] Muhlestein, 2014, Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clinical trial, JAMA sourceNot checked — no full text of the source

A similar association and prognostic value of increased NT-proBNP with increased cardiovascular and all-cause mortality has been reported in people with type 1 diabetes.

“A similar association and prognostic values of increased NT-proBNP with increased cardiovascular and all-cause mortality has been reported in people with type 1 diabetes (215).”

• cites [215] Rørth, 2020, Cardiovascular prognostic value of echocardiography and N terminal pro B-type natriuretic peptide in type 1 diabetes: the Thousand & 1 Study, Eur J Endocrinol sourceNot checked — no full text of the source

In the PARTNERS program, 30% of people aged 50-69 years with a history of cigarette smoking or diabetes, or aged ≥70 years regardless of risk factors, had PAD.

“In the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, 30% of people aged 50–69 years with a history of cigarette smoking or diabetes, or aged ≥70 years regardless of risk factors, had PAD (223).”

• cites [223] Hirsch, 2001, Peripheral arterial disease detection, awareness, and treatment in primary care, JAMA sourceNot checked — no full text of the source

Recent clinical trial evidence supports a symptomatic benefit of GLP-1 RA in people with diabetes and PAD.

“or the initiation of GLP-1 RA, as recent clinical trial evidence supports a symptomatic benefit of GLP-1 RA in people with diabetes and PAD (235).”

• cites [235] Bonaca, 2025, Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial, Lancet sourceNot checked — no full text of the source

Clear cardiovascular benefits exist for ACE inhibitor or ARB therapy in people with diabetes.

“Clear cardiovascular benefits exist for ACE inhibitor or ARB therapy in people with diabetes.”

• cites [237] Yusuf, 2000, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients, N Engl J Med sourceNot checked — no full text of the source

In the HOPE study, ramipril significantly reduced cardiovascular and all-cause mortality, MI, and stroke in individuals aged ≥55 years with a history of vascular disease or diabetes plus one other cardiovascular risk factor.

“The Heart Outcomes Prevention Evaluation (HOPE) study randomized 9,297 individuals aged ≥55 years with a history of vascular disease or diabetes plus one other cardiovascular risk factor to either ramipril or placebo. Ramipril significantly reduced cardiovascular and all-cause mortality, MI, and stroke (237).”

• cites [237] Yusuf, 2000, Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients, N Engl J Med sourceNot checked — no full text of the source

In the SAVE study, treatment with captopril reduced the development of heart failure by 37% in asymptomatic people with reduced LVEF after MI.

“In the Survival and Ventricular Enlargement (SAVE) study, which enrolled asymptomatic people with reduced LVEF after MI, including 23% people with diabetes, treatment with captopril reduced the development of heart failure by 37% (276).”

• cites [276] Pfeffer, 1992, Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators, N Engl J Med sourceNot checked — no full text of the source

In a randomized placebo-controlled trial of semaglutide in people with type 2 diabetes and CKD, semaglutide significantly reduced the risk of heart failure.

“In addition, heart failure was a prespecified outcome of the randomized, placebo-controlled trial of semaglutide in people with type 2 diabetes and CKD and found a significant reduction in the risk of heart failure among those randomized to active semaglutide (284).”

• cites [284] Pratley, 2024, Effects of semaglutide on heart failure outcomes in diabetes and chronic kidney disease in the FLOW trial, J Am Coll Cardiol sourceNot checked — no full text of the source

Individuals with type 2 diabetes at higher risk of heart failure, such as those with established ASCVD or CKD, are likely to see a larger absolute risk reduction from GLP-1 RAs than healthier individuals at lower cardiovascular and kidney risk.

“Individuals at even higher risk of heart failure, such as those with established ASCVD or CKD, are likely to see a larger absolute risk reduction than healthier individuals at relatively lower cardiovascular and kidney risk.”

In the REVERT trial, metoprolol improved adverse cardiac remodeling in asymptomatic individuals with an LVEF <40% and mild left ventricular dilatation.

“Finally, in the Reversal of Ventricular Remodeling With Toprol-XL (REVERT) trial, in which 45% of the people enrolled had diabetes, metoprolol improved adverse cardiac remodeling in asymptomatic individuals with an LVEF <40% and mild left ventricular dilatation (280).”

• cites [280] Colucci, 2007, Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial, Circulation sourceNot checked — no full text of the source

Up to 91% of all new heart failure development in the Framingham cohort occurred in people with a previous diagnosis of hypertension.

“The vast majority of incident heart failure is preceded by hypertension; up to 91% of all new heart failure development in the Framingham cohort occurred in people with a previous diagnosis of hypertension (272).”

• cites [272] Levy, 1996, The progression from hypertension to congestive heart failure, JAMA sourceNot checked — no full text of the source

In the SOLVD study, treatment with enalapril reduced incident heart failure in people with asymptomatic left ventricular dysfunction by 20%.

“In the landmark Studies of Left Ventricular Dysfunction (SOLVD) study, in which 15% of people had diabetes, treatment with enalapril reduced incident heart failure in people with asymptomatic left ventricular dysfunction by 20% (275).”

• cites [275] Yusuf, 1992, Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions, N Engl J Med sourceNot checked — no full text of the source

In the SUMMIT trial, the mean KCCQ-CSS improved significantly more in those on active tirzepatide (19.5) than in the placebo group (12.7).

“In addition, the mean KCCQ-CSS improved significantly more in those on active tirzepatide (19.5) than in the placebo group (12.7) (307).”

• cites [307] Packer, 2025, Tirzepatide for heart failure with preserved ejection fraction and obesity, N Engl J Med sourceNot checked — no full text of the source

In the SUMMIT trial, worsening heart failure or cardiovascular death was less frequent in individuals receiving tirzepatide (9.9%) versus placebo (15.3%; HR 0.62, 95% CI 0.41-0.95).

“Worsening heart failure or cardiovascular death was less frequent in individuals receiving tirzepatide (9.9% of individuals) versus placebo (15.3% of individuals; HR 0.62, 95% CI 0.41–0.95).”

• cites [307] Packer, 2025, Tirzepatide for heart failure with preserved ejection fraction and obesity, N Engl J Med sourceNot checked — no full text of the source

In the SAVOR-TIMI 53 study, participants randomized to saxagliptin were more likely to be hospitalized for heart failure than those given placebo.

“in The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study, participants randomized to saxagliptin were more likely to be hospitalized for heart failure than those given placebo (311).”

• cites [311] Scirica, 2013, Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus, N Engl J Med sourceNot checked — no full text of the source

Thiazolidinediones have a strong and consistent relationship with increased risk of heart failure.

“Thiazolidinediones have a strong and consistent relationship with increased risk of heart failure (308,309) and should be avoided in people with heart failure.”

• cites [308] Dormandy, 2005, Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial, Lancet sourceNot checked — no full text of the source
• cites [309] Lincoff, 2007, Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials, JAMA sourceNot checked — no full text of the source

Finerenone improves cardiovascular and kidney outcomes in people with type 2 diabetes.

“Thus, finerenone improves cardiovascular and kidney outcomes in people with type 2 diabetes.”