10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025

Most people with HFpEF have obesity.

“Approximately 45% of people admitted for HFpEF have diabetes, and most people with HFpEF have obesity (320,321).”

• cites [320] 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 [321] 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 reports that 41.3% of the I-PRESERVE HFpEF cohort had obesity (BMI >30 kg/m²), not most patients. The Discussion > Clinical and Demographic Characteristics section says more than 83% were overweight or obese combined; that does not establish that most had obesity. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

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; risk of adverse outcomes needs to be weighed against the cardiovascular benefit of more intensive blood pressure lowering.”

• cites [38] Wright, 2015, A randomized trial of intensive versus standard blood-pressure control, N Engl J Med sourceSupported

In ACCORD BP, adverse events attributed to blood pressure treatment, including hypotension, syncope, bradycardia, hyperkalemia, and elevations in serum creatinine, occurred more frequently in the intensive treatment arm than in the standard therapy arm.

“Adverse events attributed to blood pressure treatment, including hypotension, syncope, bradycardia, hyperkalemia, and elevations in serum creatinine, occurred more frequently in the intensive treatment arm than in the standard therapy arm.”

• cites [40] Cushman, 2010, Effects of intensive blood-pressure control in type 2 diabetes mellitus, N Engl J Med sourcePartly supported

  The Results > Adverse Events section reports more serious events attributed to antihypertensive treatment and more serum-creatinine elevations in the intensive group. It reports hypokalemia, not the claimed hyperkalemia, and does not establish higher rates of syncope or bradycardia; symptoms of orthostatic hypotension were similar between groups. No page number is available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In SPRINT, the primary composite outcome of MI, coronary syndromes, stroke, heart failure, or death from cardiovascular causes was reduced by 25% in the intensive treatment group.

“The primary composite outcome of MI, coronary syndromes, stroke, heart failure, or death from cardiovascular causes was reduced by 25% in the intensive treatment group.”

• cites [38] Wright, 2015, A randomized trial of intensive versus standard blood-pressure control, N Engl J Med sourceSupported

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

“Atherosclerotic cardiovascular disease (ASCVD) broadly refers to a history of acute coronary syndrome, myocardial infarction (MI), stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack, 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 Discussion (page not provided) reports substantial excess rates of cardiovascular outcomes in people with type 1 or type 2 diabetes, supporting the importance of cardiovascular disease as a source of morbidity and mortality. The paper does not establish that ASCVD is the leading cause, and its Outcomes section (page not provided) does not give the cited sentence’s broad definition of ASCVD. (LLM, conf=0.78)

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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.

“In addition, people with diabetes are at risk for developing structural heart disease and HFrEF in the absence of obstructive coronary artery disease (14).”

• cites [14] Marwick, 2018, Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy, J Am Coll Cardiol sourceSupported

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

There is an increasing appreciation of the common pathophysiology and interrelationship of cardiometabolic risk factors leading to both adverse cardiovascular and adverse kidney outcomes in people with diabetes, including ASCVD, heart failure, and CKD.

“There is an increasing appreciation of the common pathophysiology and interrelationship of cardiometabolic risk factors leading to both adverse cardiovascular and adverse kidney outcomes in people with diabetes, including ASCVD, heart failure, and chronic kidney disease (CKD) (16).”

• cites [16] Sperling, 2015, The CardioMetabolic Health Alliance: working toward a new care model for the metabolic syndrome, J Am Coll Cardiol 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.

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A large cohort study confirmed no or only marginally increased mortality, MI, and stroke risk compared with the general population when all major cardiovascular risk factors are managed to goal levels in people with type 2 diabetes.

“In addition to the evidence from prospective intervention studies to support comprehensive ASCVD risk factor reduction, a large cohort study confirmed no or only marginally increased mortality, MI, and stroke risk compared with the general population when all major cardiovascular risk factors are managed to goal levels in people with type 2 diabetes (6).”

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

In ACCORD BP, the primary composite outcome of nonfatal MI, nonfatal stroke, or death from cardiovascular causes was not significantly reduced in the intensive treatment group.

“The primary composite outcome of nonfatal MI, nonfatal stroke, or death from cardiovascular causes was not significantly reduced in the intensive treatment group.”

• cites [40] Cushman, 2010, Effects of intensive blood-pressure control in type 2 diabetes mellitus, N Engl J Med sourceSupported

ACCORD BP provides the strongest direct assessment of the benefits and risks of intensive blood pressure management in people with type 2 diabetes.

“ACCORD BP provides the strongest direct assessment of the benefits and risks of intensive blood pressure management in people with type 2 diabetes (40).”

• cites [40] Cushman, 2010, Effects of intensive blood-pressure control in type 2 diabetes mellitus, N Engl J Med sourceSupported

In ACCORD BP, the prespecified secondary outcome of stroke was significantly reduced by 41% in the intensive treatment group.

“The prespecified secondary outcome of stroke was significantly reduced by 41% in the intensive treatment group.”

• cites [40] Cushman, 2010, Effects of intensive blood-pressure control in type 2 diabetes mellitus, N Engl J Med sourceSupported

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 (À3.26 mmHg [95% CI À5.58 to À0.94 mmHg]; P = 0.006) and diastolic (À2.07 mmHg [95% CI À3.68 to À0.46 mmHg]; P = 0.01) blood pressure (60).”

• cites [60] 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

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 (46,47).”

• cites [46] 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 [47] Phillips, 2018, Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension, J Am Coll Cardiol sourceSupported

Older individuals and those with CKD and frailty have been shown to be at higher risk of adverse effects of intensive blood pressure management.

“Older individuals and those with CKD and frailty have been shown to be at higher risk of adverse effects of intensive blood pressure management (49).”

• cites [49] Sink, 2018, Syncope, hypotension, and falls in the treatment of hypertension: results from the randomized clinical systolic blood pressure intervention trial, J Am Geriatr Soc sourcePartly supported

  The Results (page unavailable in our copy) report higher risks of serious adverse events involving syncope, hypotension, and falls among participants with CKD or frailty and among older participants. But those are higher event risks, not evidence that intensive treatment caused a greater increase in risk in these groups: the Results found no treatment interaction by age or frailty. Intensive treatment increased hypotension risk overall, possibly increased syncope risk, and did not increase falls. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

For individuals with albuminuria (UACR $30 mg/g), initial treatment should include an ACE inhibitor or ARB to reduce the risk of progressive kidney disease.

“For individuals with albuminuria (urine albumin-to-creatinine ratio [UACR] $30 mg/g), initial treatment should include an ACE inhibitor or ARB to reduce the risk of progressive kidney disease (21) (Fig. 10.2).”

• cites [21] de Boer, 2017, Diabetes and hypertension: a position statement by the American Diabetes Association, Diabetes Care 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 (61,62).”

• cites [61] 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 not provided) report greater reductions in systolic and diastolic blood pressure with mHealth interventions than with traditional treatment. The Discussion also says telemedicine and mobile-phone text messages improved blood-pressure levels. The paper does not establish that reinforcing healthy behaviors specifically enhanced the efficacy of medical therapy, rather than improving blood-pressure outcomes more generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [62] 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 (47,48).”

• cites [47] Phillips, 2018, Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension, J Am Coll Cardiol sourcePartly supported

  The Results (page unavailable) report that absolute risk reduction increased across baseline CVD-risk quartiles in SPRINT. The Discussion (page unavailable) says earlier analyses found the greatest absolute risk reduction in those at greatest baseline risk, and separately describes earlier trials with higher blood pressures. It does not establish that those particular earlier trials showed the claimed risk–benefit relationship. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [48] 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 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 end-stage kidney disease.

“In individuals receiving ACE inhibitor or ARB therapy, continuation of those medications as kidney function declines to estimated glomerular filtration rate (eGFR) <30 mL/min/ 1.73 m 2 may provide cardiovascular benefit without significantly increasing the risk of end-stage kidney disease (74).”

• cites [74] 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

Based on meta-analyses stratified by mean baseline or attained blood pressure, antihypertensive treatment appears to be most beneficial when mean baseline blood pressure is $140/90 mmHg.

“Based on these analyses, antihypertensive treatment appears to be most beneficial when mean baseline blood pressure is $140/90 mmHg (20,31,32,(34)(35)(36).”

• cites [20] Whelton, 2018, 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, J Am Coll Cardiol sourceNot checked — no full text of the source
• cites [31] Emdin, 2015, Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis, JAMA sourceNot checked — no full text of the source
• cites [32] Arguedas, 2013, Blood pressure targets for hypertension in people with diabetes mellitus, Cochrane Database Syst Rev sourcePartly supported

  The Authors’ conclusions (page unavailable) say that randomized-trial evidence does not support treatment targets below 140/90 mmHg in people with diabetes. That supports a point about treatment targets, but the review does not establish that antihypertensive treatment is most beneficial at a mean baseline blood pressure of 140/90 mmHg or report a meta-analysis stratified by baseline pressure. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

ACCORD BP demonstrated that intensive blood pressure lowering decreased the risk of cardiovascular events irrespective of baseline diastolic blood pressure in individuals who also received standard glycemic management.

“However, ACCORD BP demonstrated that intensive blood pressure lowering decreased the risk of cardiovascular events irrespective of baseline diastolic blood pressure in individuals who also received standard glycemic management (51).”

• cites [51] Ilkun, 2020, The influence of baseline diastolic blood pressure on the effects of intensive blood pressure lowering on cardiovascular outcomes and all-cause mortality in type 2 diabetes, Diabetes Care 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.

“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 (78)(79)(80).”

• cites [78] Yusuf, 2008, Telmisartan, ramipril, or both in patients at high risk for vascular events, N Engl J Med sourcePartly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

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• cites [79] Fried, 2013, Combined angiotensin inhibition for the treatment of diabetic nephropathy, N Engl J Med sourceNot checked — no full text of the source
• cites [80] Makani, 2013, Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials, BMJ 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.

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In CHAP, the primary outcome, a composite of preeclampsia with severe features, medically indicated preterm birth at <35 weeks of gestation, placental abruption, or fetal or neonatal death, occurred in 30.2% of female participants in the active treatment group versus 37.0% in the control group (P < 0.001).

“The primary outcome, a composite of preeclampsia with severe features, medically indicated preterm birth at <35 weeks of gestation, placental abruption, or fetal or neonatal death, occurred in 30.2% of female participants in the active treatment group versus 37.0% in the control group (P < 0.001).”

• cites [55] Tita, 2022, Treatment for mild chronic hypertension during pregnancy, N Engl J Med sourceSupported

The addition of the PCSK9 inhibitors 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 36% to 59%.

“The addition of the PCSK9 inhibitors 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 36% to 59% (126,127).”

• cites [126] 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 [127] Zhang, 2015, Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials, BMC Med sourcePartly supported

  The Discussion says the LDL-C reductions were largely achieved in patients already receiving stable statin treatment, and the Results report substantial reductions with both evolocumab and alirocumab. However, the paper does not establish a 36%–59% average reduction specifically among high-ASCVD-risk participants taking maximally tolerated statin doses; its 36.3% figure compares evolocumab with ezetimibe, not with statin therapy alone. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In the ODYSSEY ALTERNATIVE trial, 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 [134] 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

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 (101-105) and trials in people with diabetes (106,107) showed significant primary and secondary prevention of ASCVD events and CHD death in people with diabetes.”

• cites [101] 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 [102] 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 [103] 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 report a significant reduction in a composite of recurrent coronary events among patients with diabetes, supporting secondary prevention. But this trial studied myocardial infarction survivors, not primary prevention, and the Results explicitly report no reduction in CHD death in the diabetes group. No page number is available in our copy. (LLM, conf=0.90)

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• cites [104] 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 reports a significant reduction in major cardiovascular events among patients with diabetes and established CHD, supporting secondary prevention. It does not study primary prevention, and the reduction in CHD death in the diabetes subgroup was not statistically significant (P = 0.203). (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [105] 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

  The ASCOT-LLA results (Statistical methods; page unavailable) report a significant reduction in total cardiovascular events and procedures among participants with diabetes, including those without preexisting cardiovascular disease. But the reduction in the diabetic subgroup for the endpoint combining fatal CHD and nonfatal myocardial infarction was not statistically significant. The paper reports benefits in an earlier trial among diabetic patients both with and without established cardiovascular disease, but its own results do not establish significant secondary prevention or a reduction in CHD death. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [106] 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 [107] 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

Multiple clinical trials have demonstrated the beneficial effects of statin therapy on ASCVD outcomes in subjects with and without coronary heart disease (CHD).

“Multiple clinical trials have demonstrated the beneficial effects of statin therapy on ASCVD outcomes in subjects with and without coronary heart disease (CHD) (99,100).”

• cites [99] 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
• cites [100] 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

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 (94)(95)(96).”

• cites [94] 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 [95] 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. However, the claim generalizes this finding to lipid-profile monitoring during statin therapy more broadly and implies that monitoring increases these outcomes. The Discussion states that the observational design cannot establish a causal relationship. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [96] 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

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 (88).”

• cites [88] 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

  The Introduction and Methods (pages not specified in our copy) describe spironolactone as an effective add-on for resistant hypertension in patients already taking an ACE inhibitor or ARB, a calcium channel blocker, and a diuretic. The Discussion says almost 14% of participants had type 2 diabetes, but the cited passages do not establish efficacy specifically in that subgroup. PATHWAY-2 did not test eplerenone, so its effectiveness is not supported by this trial. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Inclisiran reduces LDL cholesterol by 49-52% in trials evaluating individuals with established cardiovascular disease or ASCVD risk equivalent.

“In addition to the monoclonal antibodies, an siRNA, inclisiran, which also targets PSCK9, has demonstrated the ability to reduce LDL cholesterol by 49-52% in trials evaluating individuals with established cardiovascular disease or ASCVD risk equivalent (129).”

• cites [129] Ray, 2020, Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol, N Engl J Med sourceSupported

MRAs reduce albuminuria in people with diabetic nephropathy.

“In addition, MRAs reduce albuminuria in people with diabetic nephropathy (89)(90)(91).”

• cites [89] Sato, 2003, Effectiveness of aldosterone blockade in patients with diabetic nephropathy, Hypertension sourcePartly supported

  The Results section reports significantly reduced urinary albumin excretion after spironolactone was added to ACE-inhibitor treatment. The finding was in 13 patients with diabetic nephropathy and aldosterone escape, so it does not establish the unqualified claim for MRAs generally or for people with diabetic nephropathy outside that subgroup. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [90] 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 [91] 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

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

“Lifestyle intervention, including weight loss in people with overweight or obesity (when appropriate) (19,92), increased physical activity, and medical nutrition therapy, allows some individuals to reduce ASCVD risk factors.”

• cites [19] 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 [92] 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

High-intensity versus moderate-intensity statin therapy reduces cardiovascular event rates in high-risk individuals with established cardiovascular disease 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 cardiovascular disease in randomized trials (99).”

• cites [99] 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 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.

“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) (164).”

• cites [164] 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 diabetes diagnoses with rosuvastatin than placebo (270 versus 216), supporting the direction of the increase. They do not report the claimed 1.5% and 1.2% participant risks. The Methods describe follow-up of up to five years, not five years for every participant. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In the AIM-HIGH trial, there was a possible increased risk of ischemic stroke in those on combination therapy with a statin and niacin.

“In fact, there was a possible increased risk of ischemic stroke in the AIM-HIGH trial (160)”

• cites [160] Boden, 2011, Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N Engl J Med sourceSupported

The addition of 4 g per day of a carboxylic acid formulation of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (n-3 carboxylic acid) to statin therapy in individuals with atherogenic dyslipidemia and high cardiovascular risk, 70% of whom had diabetes, did not reduce the risk of major adverse cardiovascular events compared with the inert comparator of corn oil.

“As an example, the addition of 4 g per day of a carboxylic acid formulation of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (n-3 carboxylic acid) to statin therapy in individuals with atherogenic dyslipidemia and high cardiovascular risk, 70% of whom had diabetes, did not reduce the risk of major adverse cardiovascular events compared with the inert comparator of”

• cites [154] Nicholls, 2020, Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial, JAMA sourceSupported

The CLEAR Outcomes trial found a reduction in four-point major adverse cardiovascular events by 13% compared with placebo for individuals with established ASCVD (70% of population) or at high risk for ASCVD (30% of population) and considered to be intolerant to statin therapy.

“The Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid or Placebo (CLEAR Outcomes) trial found a reduction in four-point major adverse cardiovascular events by 13% compared with placebo for individuals with established ASCVD (70% of population) or at high risk for ASCVD (30% of population) a”

• cites [141] Nissen, 2023, Bempedoic acid and cardiovascular outcomes in statin-intolerant patients, N Engl J Med sourceSupported

Prespecified subgroup analyses suggested heterogeneity in treatment effects with possible benefit for men with both a triglyceride level $204 mg/dL ($2.3 mmol/L) and an HDL cholesterol level #34 mg/dL (#0.9 mmol/L).

“Prespecified subgroup analyses suggested heterogeneity in treatment effects with possible benefit for men with both a triglyceride level $204 mg/dL ($2.3 mmol/L) and an HDL cholesterol level #34 mg/dL (#0.9 mmol/L) (159).”

• cites [159] Ginsberg, 2010, Effects of combination lipid therapy in type 2 diabetes mellitus, N Engl J Med sourcePartly supported

  The Results (Clinical Outcomes; page unavailable) report separate subgroup findings: apparent benefit for men and a nonsignificant suggestion of benefit for patients with triglycerides ≥204 mg/dL and HDL cholesterol ≤34 mg/dL. The Discussion says the sex-by-treatment interaction was not observed within the dyslipidemia subgroup. The paper therefore does not establish the claimed combined subgroup of men meeting both lipid thresholds. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Three large, randomized trials of statin versus placebo where specific cognitive tests were performed showed 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 (166-169).”

• cites [166] 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 [167] 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 [168] 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 [169] Yusuf, 2016, Cholesterol lowering in intermediate-risk persons without cardiovascular disease, N Engl J Med sourcePartly supported

  The Methods (p. 1) identify a large randomized comparison of rosuvastatin with placebo. The available Results (p. 1) report cardiovascular outcomes and other adverse events, but do not report specific cognitive tests or a comparison of cognitive results between groups (searched: cognitive, memory, dementia, neuropsychological tests). The paper therefore supports the trial description, not the cognitive-outcome claim. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Several lines of evidence argue against an association between lipid-lowering agents and adverse cognitive function, as detailed in a 2018 European Atherosclerosis Society Consensus Panel statement.

“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 (165).”

• cites [165] 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

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.

“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.”

• cites [159] Ginsberg, 2010, Effects of combination lipid therapy in type 2 diabetes mellitus, N Engl J Med sourceSupported

For individuals requiring primary prevention, the use of 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 (143).”

• cites [143] Nissen, 2023, Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients, JAMA sourceSupported

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.

“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 (142).”

• cites [142] 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

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 [174] 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 sourceSupported

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 (171,172).”

• cites [171] 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 evidence suggests no adverse cognitive effect, and the Discussion reports no increased cognitive decline in the trials it describes. But the Studies selection section says this review included observational cohort and case-control studies of Alzheimer’s disease or dementia risk—not a systematic review of randomized trials evaluating cognition generally. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [172] Richardson, 2013, Statins and cognitive function: a systematic review, Ann Intern Med sourceNot checked — no full text of the source

No change in cognitive function has been reported in studies with the addition of ezetimibe or PCSK9 inhibitors 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 (119) or PCSK9 inhibitors (121,170) to statin therapy, including among individuals treated to very low LDL cholesterol levels.”

• cites [119] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med sourceCould not verify

  The Lipid Data section reports that ezetimibe added to simvastatin lowered LDL cholesterol to a mean of 53.2 mg/dl at one year. The Discussion reports no significant differences in prespecified safety endpoints, but neither section reports a cognitive-function assessment or result. A search for cognition, memory, and neurocognitive outcomes found no passage supporting the claim attributed to this ezetimibe study. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [121] 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 adverse events between evolocumab and placebo, and the Lipid Data section shows that many evolocumab-treated patients reached very low LDL cholesterol levels. The paper does not report cognitive-function testing or establish the absence of cognitive changes specifically among patients who reached those levels. The ezetimibe finding has a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [170] Giugliano, 2017, Cognitive function in a randomized trial of evolocumab, N Engl J Med sourceSupported

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 [160] 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 in its studied patients. 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=0.91)

  Experimental — accuracy not yet measured
• cites [161] 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

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 (140).”

• cites [140] De Filippo, 2023, Safety and efficacy of bempedoic acid: a systematic review and meta-analysis of randomised controlled trials, Cardiovasc Diabetol sourceSupported

In ASPREE, for cardiovascular disease (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]).

“In ASPREE, which included 19,114 individuals, for cardiovascular disease (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 [181] McNeil, 2018, Effect of aspirin on cardiovascular events and bleeding in the healthy elderly, N Engl J Med sourceSupported

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 [180] 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

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 [205] 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 in the COMPASS analysis. Our copy does not report a major-bleeding result for VOYAGER PAD, so it supports only the COMPASS part of the claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [206] 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 [207] Bonaca, 2020, Rivaroxaban in peripheral artery disease after revascularization, N Engl J Med sourcePartly supported

  The Abstract and Discussion report significantly more ISTH major bleeding with rivaroxaban plus aspirin in VOYAGER PAD, but no significant difference in the trial’s principal TIMI major-bleeding outcome. The paper discusses COMPASS’s reduction in ischemic risk but does not report a COMPASS major-bleeding finding, so it supports only the VOYAGER PAD portion of the claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In the ADAPTABLE trial, there were no significant differences in cardiovascular events or major bleeding between individuals assigned to 81 mg and those assigned to 325 mg of aspirin daily.

“In the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness) trial of individuals with established cardiovascular disease, 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 of aspirin daily (191).”

• cites [191] Jones, 2021, Comparative effectiveness of aspirin dosing in cardiovascular disease, 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; 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% ; P = 0.0007).”

• cites [180] 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

The Antithrombotic Trialists' Collaboration meta-analysis of six large trials of aspirin for primary prevention in the general population found that 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 [178] Baigent, 2009, Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials, Lancet sourceSupported

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 (205,206).”

• cites [205] Bhatt, 2020, Role of combination antiplatelet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: insights from the COMPASS trial, Circulation sourceSupported
• cites [206] 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

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 (179,181).”

• cites [179] 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 participants with diabetes and no evident cardiovascular disease, aspirin’s benefits were largely counterbalanced by bleeding—not that risk exceeded benefit. The Participants section (p. 3) confirms the trial included only people with diabetes, and the cited passages do not establish the claimed balance specifically for people over 70 or for those without diabetes. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [181] McNeil, 2018, Effect of aspirin on cardiovascular events and bleeding in the healthy elderly, N Engl J Med sourcePartly supported

  The Abstract Conclusions report that, for primary prevention in older adults, aspirin increased major hemorrhage without significantly reducing cardiovascular disease. The Methods and Results include diabetes as a subgroup and report no evidence of a differential cardiovascular effect. The claim omits the trial’s important limitation to generally healthy people without established cardiovascular disease; it should not be extended to everyone over 70. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

In the COMPASS trial, 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 [205] Bhatt, 2020, Role of combination antiplatelet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: insights from the COMPASS trial, Circulation sourceSupported
• cites [206] 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

Combination dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is indicated after acute coronary syndromes and coronary revascularization with stenting.

“Combination dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is indicated after acute coronary syndromes and coronary revascularization with stenting (197).”

• cites [197] Levine, 2016, 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-elevation myocardia sourceSupported

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

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 (174).”

• cites [174] 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 sourceSupported

In the ASCEND trial, 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) with aspirin 100 mg daily versus placebo in people with diabetes but no evident cardiovascular disease.

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

Early aspirin discontinuation compared with continued dual antiplatelet therapy after coronary stenting may reduce the risk of bleeding without a corresponding increase in the risks of mortality and ischemic events, as shown in a prespecified analysis of people with diabetes enrolled in the TWILIGHT trial and a meta-analysis.

“However, early aspirin discontinuation compared with continued dual antiplatelet therapy after coronary stenting may reduce the risk of bleeding without a corresponding increase in the risks of mortality and ischemic events, as shown in a prespecified analysis of people with diabetes enrolled in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial”

• cites [203] Angiolillo, 2020, Ticagrelor with or without aspirin in high-risk patients with diabetes mellitus undergoing percutaneous coronary intervention, J Am Coll Cardiol sourceNot checked — no full text of the source
• cites [204] Wiebe, 2021, Early aspirin discontinuation after coronary stenting: a systematic review and meta-analysis, J Am Heart Assoc sourceSupported

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 (239,240).”

• cites [239] Beckman, 2019, Microvascular disease, peripheral artery disease, and amputation, Circulation sourceSupported
• cites [240] 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

A randomized observational 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 observational 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 (210).”

• cites [210] 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 sourcePartly supported

  The Abstract and Comment describe a randomized controlled trial and report that MPI screening did not significantly reduce cardiac events in asymptomatic patients with type 2 diabetes. The Methods excluded specified abnormal resting ECG findings, but did not require an entirely normal ECG. The claim's description of an observational trial and its unqualified 'normal ECGs' are therefore inaccurate. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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) (72,73,246).”

• cites [72] 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

  The Blood Pressure Control section recommends ACE inhibitors or ARBs for hypertension in patients with type 2 diabetes and coronary artery disease, and reports reduced kidney-disease progression in patients with albuminuria. It also describes cardiovascular benefit over 4.5 years. The claim extends these benefits to people with diabetes and CKD or hypertension generally, without the source’s albuminuria and coronary-disease qualifications. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [73] 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 [246] Braunwald, 2004, Angiotensin-converting-enzyme inhibition in stable coronary artery disease, N Engl J Med sourceNot checked — no full text of the source

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 (241,242), prospective, randomized studies addressing whether screening for PAD in people with diabetes improves longterm limb outcomes and cardiovascular event rates are limited.”

• cites [241] 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 1-year major adverse cardiovascular event rates after a positive PAD screen than after a negative screen (5.54% versus 3.60%). 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=0.84)

  Experimental — accuracy not yet measured
• cites [242] 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

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 (221,222).”

• cites [221] 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 [222] 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 reports fewer cardiac events after NT-proBNP-guided treatment in patients with type 2 diabetes who were free of cardiac disease. The Conclusions table also shows fewer heart-failure hospitalizations in the intensified group (1 versus 7), but the study did not establish that participants had asymptomatic heart failure or directly measure progression to symptomatic heart failure. The claim extends the findings beyond the population and outcome studied. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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 (222,227,228).”

• cites [222] 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 Study design and hospitalization tables (pp. 1365–72; precise page unavailable in our copy) describe a randomized trial in patients with type 2 diabetes and elevated NT-proBNP. They report fewer heart-failure hospitalizations with intensified treatment (1 versus 7), although the reported time-to-event comparison was not statistically significant (p=0.07). The paper does not report symptomatic heart failure or newly diagnosed left ventricular dysfunction as outcomes; it also represents one trial, not evidence of results from several trials by itself. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [227] Gaede, 2003, Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes, N Engl J Med sourcePartly supported

  The Results (statistical analysis; page unavailable) report that intensive multifactorial treatment reduced a composite cardiovascular outcome in one trial of patients with type 2 diabetes and microalbuminuria. The paper does not report selecting patients by elevated natriuretic peptides or reductions in symptomatic heart failure, heart-failure hospitalization, or newly diagnosed left ventricular dysfunction; it also does not itself establish a finding from several trials. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [228] 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

People with diabetes are at an 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 (216,217).”

• cites [216] McAllister, 2018, Incidence of hospitalization for heart failure and case-fatality among 3.25 million people with and without diabetes mellitus, Circulation sourceSupported
• cites [217] 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 will have silent ischemia on screening tests (212,213).”

• cites [212] 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 did not accurately identify many patients with abnormal tests, supporting the claim about initial screening. It also says the study addressed silent ischemia only at enrollment and that five-year follow-up results were still forthcoming; it does not support the claim about subsequent follow-up. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [213] Scognamiglio, 2006, Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus, J Am Coll Cardiol sourcePartly supported

  The Discussion (page not supplied) reports that risk factors did not significantly predict myocardial perfusion abnormalities in asymptomatic patients with type 2 diabetes, supporting the claim about initial screening. It does not establish that a risk factor-based approach fails during subsequent follow-up; the Discussion says the study’s five-year follow-up was still pending. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Up to two-thirds of people with asymptomatic PAD have been shown to have comorbid diabetes.

“Conversely, up to twothirds of people with asymptomatic PAD have been shown to have comorbid diabetes (236).”

• cites [236] Eason, 2005, Diabetes mellitus, smoking, and the risk for asymptomatic peripheral arterial disease: whom should we screen?, J Am Board Fam Pract 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 (223-225).”

• cites [223] 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 outcomes analysis finds baseline NT-proBNP prognostic for heart-failure hospitalization and the combined outcome of hospitalization or cardiovascular death. The paper does not establish the same findings for BNP measured separately, symptom progression, or heart-failure-related mortality specifically. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [224] 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 [225] 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 composite biomarker score, and the Results report that the score stratified incident heart-failure risk among participants with diabetes. The paper does not establish the same predictive claim for BNP alone or address symptom progression or heart-failure-related mortality; its stated primary outcome was incident heart failure. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In a large multinational cohort of 750,000 people with diabetes without established cardiovascular disease, 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 cardiovascular disease, heart failure and CKD were the most frequent first manifestations of cardiovascular or kidney disease (218).”

• cites [218] 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

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 (219,220).”

• cites [219] 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 Conclusions (p. 2) say heart failure is common among adults with type 2 diabetes, and the Results (p. 4) document incident heart-failure events in participants without prior heart failure. The paper does not classify participants by heart-failure stage or establish that people with diabetes are particularly likely, relative to others, to progress from stages A or B to C or D. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [220] Echouffo-Tcheugui, 2022, Diabetes and progression of heart failure: The Atherosclerosis Risk In Communities (ARIC) study, J Am Coll Cardiol sourceSupported

The risk for PAD in people with diabetes is higher than that in people without diabetes.

“The risk for PAD in people with diabetes is higher than that in people without diabetes (230-232).”

• cites [230] 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 [231] Leibson, 2004, Peripheral arterial disease, diabetes, and mortality, Diabetes Care sourceSupported
• cites [232] Murabito, 1997, Intermittent claudication. A risk profile from The Framingham Heart Study, Circulation sourceNot checked — no full text of the source

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

“However, lixisenatide and extended-release exenatide were not superior to placebo with respect to the primary end point of cardiovascular outcomes (265).”

• cites [265] Holman, 2017, Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

There was an increased risk of lower-limb amputation with canagliflozin (6.3 vs 3.4 participants per 1,000 person-years; HR 1.97 [95% CI 1.41-2.75]).

“Of note, there was an increased risk of lower-limb amputation with canagliflozin ( 6.3 vs. 3.4 participants per 1,000 person-years; HR 1.97 [95% CI 1.41-2.75]) (256).”

• cites [256] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med sourceSupported

In DECLARE-TIMI 58, dapagliflozin did not show a lower rate of major adverse cardiovascular events compared with placebo (8.8% vs 9.4%; HR 0.93 [95% CI 0.84-1.03]; P = 0.17).

“but did not show a lower rate of major adverse cardiovascular events compared with placebo (8.8% in the dapagliflozin group and 9.4% in the placebo group; HR 0.93 [95% CI 0.84-1.03];P = 0.17) (258).”

• cites [258] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

Further studies have shown renoprotective effects of dapagliflozin.

“Further studies have shown renoprotective effects of dapagliflozin (259).”

• cites [259] Heerspink, 2020, Dapagliflozin in patients with chronic kidney disease, N Engl J Med sourceSupported

Subsequent retrospective analyses from SOLVD and SAVE revealed that concomitant use of b-blockers was associated with decreased risk of progression to symptomatic heart failure.

“Subsequent retrospective analyses from both trials revealed that concomitant use of b-blockers was associated with decreased risk of progression to symptomatic heart failure (280,281).”

• cites [280] 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 [281] 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 sourcePartly supported

  The Results (section 2.2) and Discussion (section 3.1) report that beta-blocker use in the retrospective SAVE analysis was associated with a lower risk of developing severe heart failure. The Methods (section 1.2) define that endpoint as heart failure requiring hospitalization or clinical deterioration requiring open-label ACE inhibition; the paper does not establish a reduction in progression to symptomatic heart failure more generally. This source addresses SAVE, not SOLVD. (LLM, conf=0.84)

  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 (271-274) (Fig. 10.6).”

• cites [271] 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 not specified) report that physical activity, not smoking, and avoiding obesity were associated with lower incident heart-failure risk in older adults. The Methods define incident heart failure using symptoms and clinical findings, supporting the reference to symptomatic disease. But this observational study does not establish that early prevention strategies or treatment of associated risk factors reduce incidence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [272] Young, 2014, Effects of physical activity and sedentary time on the risk of heart failure, Circ Heart Fail sourcePartly supported

  The Results (page not provided) report fewer incident heart-failure diagnoses among men with higher physical activity, supporting the physical-activity aspect of prevention. The Clinical Perspective (page not provided) describes this as an association and says whether changing these behaviors affects risk remains for future study. The paper does not establish that early prevention strategies or treatment of associated risk factors reduce symptomatic heart failure. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [273] 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 not available) reports that greater adherence to a Mediterranean diet was associated with lower risk of developing heart failure in men. That supports the nutrition aspect of primary prevention, but this observational finding does not establish that interventions or treatment of risk factors reduce symptomatic heart failure. The paper does not report benefits from physical activity, weight management, or smoking cessation interventions. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [274] Levitan, 2009, Consistency with the DASH diet and incidence of heart failure, Arch Intern Med sourcePartly supported

  The Introduction (page not provided) discusses preventing heart failure through treatment and lifestyle interventions targeting risk factors, and the Abstract Conclusions report lower heart-failure rates among people whose diets were consistent with DASH. But the study reports an association, not that early prevention or risk-factor treatment reduces incident symptomatic heart failure; it also did not assess when prevention began. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In DECLARE-TIMI 58, there was no difference in cardiovascular death between dapagliflozin and placebo groups.

“No difference was seen in cardiovascular death between groups.”

• cites [258] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

LEADER was a randomized, double-blind trial assessing liraglutide versus placebo on cardiovascular outcomes in 9,340 people with type 2 diabetes at high risk for cardiovascular disease or with cardiovascular disease.

“The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was a randomized, double-blind trial that assessed the effect of liraglutide, a GLP-1 RA, versus placebo on cardiovascular outcomes in 9,340 people with type 2 diabetes at high risk for cardiovascular disease or with cardiovascular disease (261).”

• cites [261] Marso, 2016, Liraglutide and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

Results of trials with semaglutide, albiglutide, and dulaglutide were consistent with the LEADER trial.

“Results of trials with semaglutide, albiglutide, and dulaglutide, once-weekly GLP-1 RAs, were consistent with the LEADER trial (262-264).”

• cites [262] Husain, 2019, Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes, N Engl J Med sourceSupported
• cites [263] 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
• cites [264] 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

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

“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% (276).”

• cites [276] 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

In DECLARE-TIMI 58, dapagliflozin produced a lower rate of hospitalization for heart failure compared with placebo (HR 0.73 [95% CI 0.61-0.88]).

“which reflected a lower rate of hospitalization for heart failure (HR 0.73 [95% CI 0.61-0.88]).”

• cites [258] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

Emerging data suggest that use of both an SGLT2 inhibitor and a GLP-1 RA 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;”

• cites [270] Gerstein, 2021, Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes, N Engl J Med sourcePartly supported

  The Discussion (p. 7) reports that efpeglenatide reduced cardiovascular and renal events in high-risk patients with type 2 diabetes, and suggests those benefits occurred independently of baseline SGLT2 inhibitor use. This supports a possible benefit from combining the drugs, but the trial did not establish an additive cardiovascular and kidney benefit for the two drug classes generally. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Meta-analyses 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 (266,267).”

• cites [266] 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 [267] 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 establish comparable reductions in composite atherosclerotic major adverse cardiovascular events specifically among people with established ASCVD. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

“Similarly, in the SPRINT trial, intensive treatment of hypertension decreased the risk for development of incident heart failure by 36% (277).”

• cites [277] 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 Methods (Study Outcomes) say all ADHF events were incident heart-failure events, but define them as events requiring hospital or emergency-department treatment. The claim broadens that specific outcome to incident heart failure generally. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In DECLARE-TIMI 58, dapagliflozin produced a lower rate of cardiovascular death or hospitalization for heart failure compared with placebo (4.9% vs 5.8%; HR 0.83 [95% CI 0.73-0.95]; P = 0.005).

“A lower rate of cardiovascular death or hospitalization for heart failure was noted (4.9% vs. 5.8%; HR 0.83 [95% CI 0.73-0.95];P = 0.005)”

• cites [258] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

In LEADER, deaths from cardiovascular causes were significantly reduced in the liraglutide group (4.7%) compared with the placebo group (6.0%) (HR 0.78 [95% CI 0.66-0.93]; P = 0.007).

“Deaths from cardiovascular causes were significantly reduced in the liraglutide group (4.7%) compared with the placebo group (6.0%) (HR 0.78 [95% CI 0.66-0.93];P = 0.007) (261).”

• cites [261] Marso, 2016, Liraglutide and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

In DECLARE-TIMI 58, dapagliflozin met the prespecified criteria for noninferiority to placebo with respect to major adverse cardiovascular events.

“The Dapagliflozin Effect on Cardiovascular Events-Thrombosis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial met the prespecified criteria for noninferiority to placebo with respect to major adverse cardiovascular events”

• cites [258] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

Canagliflozin significantly reduced the composite outcome of cardiovascular death, MI, or stroke versus placebo (occurring in 26.9 vs 31.5 participants per 1,000 person-years; HR 0.86 [95% CI 0.75-0.97]).

“Similarly, canagliflozin significantly reduced the composite outcome of cardiovascular death, MI, or stroke versus placebo (occurring in 26.9 vs. 31.5participants per 1,000 person-years; HR 0.86 [95% CI 0.75-0.97]).”

• cites [256] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med sourceSupported

In the EMPA-REG OUTCOME trial, treatment with empagliflozin reduced the relative risk for hospitalization from heart failure by 35%.

“In the EMPA-REG OUTCOME trial, only 10% of study participants had a prior history of heart failure, and treatment with empagliflozin reduced the relative risk for hospitalization from heart failure by 35% (255).”

• Also stated in: § GLP-1 Receptor Agonist Trials · boosted

  “Briefly, in the EMPA-REG OUTCOME trial, the addition of empagliflozin to standard care led to a significant 35% reduction in hospitalization for heart failure compared with placebo (255).”

• cites [255] Zinman, 2015, Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes, N Engl J Med sourceSupported

In DECLARE-TIMI 58, there was a 27% reduction in hospitalization for heart failure with SGLT2 inhibitor use versus placebo.

“Similarly, in CANVAS and DECLARE-TIMI 58, there were 33% and 27% reductions, respectively, in hospitalization for heart failure with SGLT2 inhibitor use versus placebo (256,258).”

• cites [258] Wiviott, 2019, Dapagliflozin and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported

In the CREDENCE trial, canagliflozin showed a 31% reduction in the composite of cardiovascular death or hospitalization for heart failure in a population with CKD and albuminuria.

“Additional data from the CREDENCE trial with canagliflozin showed a 39% reduction in hospitalization for heart failure and a 31% reduction in the composite of cardiovascular death or hospitalization for heart failure, in a population with CKD and albuminuria (UACR >300-5,000 mg/g) (257).”

• cites [257] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, N Engl J Med sourceSupported

In the DAPA-HF trial, the effect of dapagliflozin on the primary outcome 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 (299).”

• cites [299] McMurray, 2019, Dapagliflozin in patients with heart failure and reduced ejection fraction, N Engl J Med sourceSupported

In the CREDENCE trial, canagliflozin showed a 39% reduction in hospitalization for heart failure in a population with CKD and albuminuria.

“Additional data from the CREDENCE trial with canagliflozin showed a 39% reduction in hospitalization for heart failure and a 31% reduction in the composite of cardiovascular death or hospitalization for heart failure, in a population with CKD and albuminuria (UACR >300-5,000 mg/g) (257).”

• cites [257] Perkovic, 2019, Canagliflozin and renal outcomes in type 2 diabetes and nephropathy, 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 sourceSupported

In the CANVAS Program, hospitalization from heart failure was reduced by 33% in people allocated to canagliflozin.

“In the CANVAS Program, hospitalization from heart failure was reduced by 33% in people allocated to canagliflozin, and only 14% of individuals enrolled had a prior history of heart failure (256).”

• Also stated in: § GLP-1 Receptor Agonist Trials · plain

  “Similarly, in CANVAS and DECLARE-TIMI 58, there were 33% and 27% reductions, respectively, in hospitalization for heart failure with SGLT2 inhibitor use versus placebo (256,258).”

• cites [256] Neal, 2017, Canagliflozin and cardiovascular and renal events in type 2 diabetes, N Engl J Med sourceSupported

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

In the DAPA-HF trial, dapagliflozin treatment had a lower risk of first worsening heart failure event (HR 0.70 [95% CI 0.59-0.83]) compared with placebo.

“lower risk of first worsening heart failure event (HR 0.70 [95% CI 0.59-0.83]),”

• cites [299] McMurray, 2019, Dapagliflozin in patients with heart failure and reduced ejection fraction, N Engl J Med sourceSupported
• cites [307] American Diabetes Association Professional Practice Committee, 2024, 10. Cardiovascular disease and risk management: Standards of Care in Diabetes—2024, Diabetes Care sourceNot checked — no full text of the source

In the DAPA-HF trial, dapagliflozin treatment had a lower risk of the primary outcome of worsening heart failure or cardiovascular death (HR 0.74 [95% CI 0.65-0.85]) compared with placebo.

“Dapagliflozin treatment had a lower risk of the primary outcome (HR 0.74 [95% CI 0.65-0.85]),”

• cites [299] McMurray, 2019, Dapagliflozin in patients with heart failure and reduced ejection fraction, N Engl J Med sourceSupported
• cites [307] American Diabetes Association Professional Practice Committee, 2024, 10. Cardiovascular disease and risk management: Standards of Care in Diabetes—2024, Diabetes Care sourceNot checked — no full text of the source

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 [248] Pitt, 2021, Cardiovascular events with finerenone in kidney disease and type 2 diabetes, N Engl J Med 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 (248).”

• cites [248] Pitt, 2021, Cardiovascular events with finerenone in kidney disease and type 2 diabetes, N Engl J Med sourceSupported

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) (293), Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) (294), and the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) (295)-did not find a significant increase in risk of heart failure hospitalization with D”

• cites [293] 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 [294] Green, 2015, Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported
• cites [295] 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

No increased risk of heart failure hospitalization has been identified in the cardiovascular outcomes trials of the GLP-1 RAs lixisenatide, liraglutide, semaglutide, exenatide once weekly, albiglutide, or dulaglutide compared with placebo.

“No increased risk of heart failure hospitalization has been identified in the cardiovascular outcomes trials of the GLP-1 RAs lixisenatide, liraglutide, semaglutide, exenatide once weekly, albiglutide, or dulaglutide compared with placebo (261,264,265,296,297).”

• cites [261] Marso, 2016, Liraglutide and cardiovascular outcomes in type 2 diabetes, N Engl J Med sourcePartly supported

  The Discussion reports fewer heart-failure hospitalizations with liraglutide than with placebo, although the difference was not significant. This supports the liraglutide portion of the sentence, but this paper does not establish the heart-failure hospitalization results for the other listed GLP-1 receptor agonists. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [264] 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 [265] Holman, 2017, Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes, N Engl J Med sourceSupported
• cites [296] Marso, 2016, Semaglutide and cardiovascular outcomes in patients with type 2 diabetes, N Engl J Med sourceSupported
• cites [297] Pfeffer, 2015, Lixisenatide in patients with type 2 diabetes and acute coronary syndrome, N Engl J Med sourceSupported

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

“Similar results were obtained in clinical trials with empagliflozin (303).”

• cites [303] Packer, 2020, Cardiovascular and renal outcomes with empagliflozin in heart failure, N Engl J Med 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 (302).”

• cites [302] Solomon, 2022, Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction, N Engl J Med sourceSupported

In the SOLOIST trial, the relatively small percentage of individuals with ejection fraction >50% (21%) and early termination limited the ability to determine the effects of sotagliflozin in HFpEF specifically.

“However, the relatively small percentage of such individuals enrolled (only 21% of participants had ejection fraction >50%) and the early termination of the trial limited the ability to determine the effects of sotagliflozin in HFpEF specifically (309).”

• cites [309] Bhatt, 2021, Sotagliflozin in patients with diabetes and recent worsening heart failure, N Engl J Med sourcePartly supported

  Statistical Analysis (p. 4) reports that 256 of 1,222 participants—about 21%—had an ejection fraction of ≥50%, not >50% as claimed. The Discussion (p. 10) says early termination and the small preserved-ejection-fraction subgroup made firm conclusions about treatment effects difficult. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

There are multiple proposed pathways through which SGLT inhibition results in ketosis, such as increased production due to reduction in insulin doses, increases in glucagon levels leading to increased lipolysis and ketone production, and decreased renal clearance of ketones.

“There are multiple proposed pathways through which SGLT inhibition results in ketosis (increased b-hydroxybutyrate and acetoacetate), such as increased production due to reduction in insulin doses, increases in glucagon levels leading to increased lipolysis and ketone production, and decreased renal clearance of ketones (310,311).”

• cites [310] Peters, 2016, Diabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes, Diabetes Care sourceNot checked — no full text of the source
• cites [311] Danne, 2019, International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors, Diabetes Care 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 (301,(304)(305)(306).”

• cites [301] Nassif, 2021, The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial, Nat Med sourcePartly supported

  The Discussion (page unavailable) reports that dapagliflozin improved symptoms, physical limitations, and exercise function over 12 weeks in patients with heart failure with preserved ejection fraction, supporting the functional-status portion. It does not establish improved clinical stability: the Exploratory clinical endpoints section reports the same number of heart-failure hospitalizations or urgent visits in both groups. The claim also generalizes this dapagliflozin finding to SGLT2 inhibitors and individuals with heart failure broadly. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [304] 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 Discussion reports that empagliflozin maintained clinical stability in patients with heart failure and reduced ejection fraction. The Results also report higher odds of improvement in NYHA functional class with empagliflozin. The citing sentence extends these findings to SGLT2 inhibitors and people with heart failure generally, without the drug and reduced-ejection-fraction qualifications of this trial. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [305] Voors, 2022, The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial, Nat Med sourcePartly supported

  The Discussion (page unavailable) reports fewer heart-failure events and improved symptoms and quality of life after empagliflozin initiation, supporting a clinical benefit. The Methods and Results (pages unavailable) use a total symptom score rather than a direct measure of functional status; patients had also been stabilized before treatment. The claim therefore extends the trial’s findings beyond what it measured and beyond its hospitalized acute-heart-failure population. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [306] Spertus, 2022, The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial, Nat Med sourceSupported

Weight loss improves symptoms of HFpEF.

“Conversely, weight loss improves symptoms of HFpEF (322).”

• cites [322] Mikhalkova, 2018, Bariatric surgery-induced cardiac and lipidomic changes in obesity-related heart failure with preserved ejection fraction, Obesity (Silver Spring) sourcePartly supported

  The Conclusion reports improved heart-failure symptoms after gastric bypass–induced weight loss in women with obesity-related HFpEF. The citing sentence omits those population and intervention limits, presenting the finding as applying to weight loss and HFpEF generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

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

• cites [323] Kosiborod, 2024, Semaglutide in patients with obesity-related heart failure and type 2 diabetes, N Engl J Med sourcePartly supported

  The Abstract reports that improved 6-minute walk distance was a confirmatory secondary result: the estimated difference versus placebo was 14.3 m. However, the source identifies its study as STEP-HFpEF DM, in patients with type 2 diabetes, rather than the STEP-HFpEF trial named in the claim. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Approximately 45% of people admitted for HFpEF have diabetes.

“Approximately 45% of people admitted for HFpEF have diabetes, and most people with HFpEF have obesity (320,321).”

• cites [320] 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 [321] 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 sourcePartly supported

  The Discussion (Clinical and Demographic Characteristics; page unavailable) mentions diabetes in the HFpEF cohort but gives no 45% figure for people admitted with HFpEF. The Results (Baseline Characteristics; page unavailable) report that 41.3% of the cohort had obesity, while more than 83% had either overweight or obesity; thus the paper does not establish that most had obesity. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In the SOLOIST trial, no evidence of heterogeneity of treatment effect by ejection fraction was noted.

“ultimately no evidence of heterogeneity of treatment effect by ejection fraction was noted.”

• cites [309] Bhatt, 2021, Sotagliflozin in patients with diabetes and recent worsening heart failure, N Engl J Med sourceSupported

In a pooled analysis from FIDELIO-DKD and FIGARO-DKD, treatment with finerenone reduced the composite of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

“Finally, in a pooled analysis from both FIDELIO-DKD and FIGARO-DKD, treatment with finerenone reduced the composite of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure was reduced (249).”

• cites [249] Agarwal, 2022, Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis, Eur Heart J sourceSupported

In the SOLOIST trial, sotagliflozin initiated during or shortly after hospitalization 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 SOLOIST trial, sotagliflozin initiated during or shortly after hospitalization in people with diabetes also reduced the risk for the primary end point of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (309).”

• cites [309] Bhatt, 2021, Sotagliflozin in patients with diabetes and recent worsening heart failure, N Engl J Med sourceSupported

In the STEP-HFpEF trial, mean body weight was reduced by 9.8% in the semaglutide group compared with 3.4% with placebo.

“and the mean body weight was reduced by 9.8% in the group assigned to semaglutide compared with 3.4% with placebo.”

• cites [323] Kosiborod, 2024, Semaglutide in patients with obesity-related heart failure and type 2 diabetes, N Engl J Med sourcePartly supported

  The Abstract reports mean body-weight changes of −9.8% with semaglutide and −3.4% with placebo, matching the quoted figures. It identifies the study as STEP-HFpEF DM, in patients with type 2 diabetes, rather than the STEP-HFpEF trial named in the claim. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In the STEP-HFpEF trial, after 1 year of treatment, the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score was 13.7 points with semaglutide and 6.4 points with placebo.

“After 1 year of treatment, the mean change in the score was 13.7 points with semaglutide and 6.4 points with placebo,”

• cites [323] Kosiborod, 2024, Semaglutide in patients with obesity-related heart failure and type 2 diabetes, N Engl J Med sourcePartly supported

  The Abstract reports the stated 52-week mean changes in the Kansas City Cardiomyopathy Questionnaire clinical summary score: 13.7 points with semaglutide and 6.4 with placebo. It identifies the study as STEP-HFpEF DM, however, not STEP-HFpEF; the claim omits that distinction. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In the SCORED trial, the primary end point of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure was reduced with sotagliflozin.

“The primary end point of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure was reduced with sotagliflozin.”

• cites [284] Bhatt, 2021, Sotagliflozin in patients with diabetes and chronic kidney disease, N Engl J Med sourceSupported

No randomized trials have been specifically designed to assess the impact of cardiovascular risk reduction strategies in people with type 1 diabetes.

“No randomized trials have been specifically designed to assess the impact of cardiovascular risk reduction strategies in people with type 1 diabetes.”

In people with diabetes in HOT, there was a significant 51% reduction in the treatment group with a goal diastolic blood pressure of <80 mmHg compared with a goal diastolic blood pressure of <90 mmHg.

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

• cites [42] 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

ADVANCE trial revealed that treatment with perindopril and indapamide to an achieved systolic blood pressure of $135 mmHg significantly decreased cardiovascular event rates compared with a placebo treatment with an achieved blood pressure of 140 mmHg.

“The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial revealed that treatment with perindopril and indapamide to an achieved systolic blood pressure of $135 mmHg significantly decreased cardiovascular event rates compared with a placebo treatment with an achieved blood pressure of 140 mmHg (41).”

• cites [41] 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

There has been no randomized controlled trial to specifically demonstrate a decreased incidence of cardiovascular events in people with diabetes by achieving a blood pressure <130/80 mmHg.

“The committee recognizes that there has been no randomized controlled trial to specifically demonstrate a decreased incidence of cardiovascular events in people with diabetes by achieving a blood pressure <130/80 mmHg.”

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

• cites [41] 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

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

• cites [12] Heidenreich, 2022, 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines, Circulation sourceNot checked — no full text of the source

There is an absence of high-quality data available to guide blood pressure goals in people with type 1 diabetes.

“Notably, there is an absence of high-quality data available to guide blood pressure goals in people with type 1 diabetes, but a similar blood pressure goal of <130/80 mmHg is recommended in people with type 1 diabetes.”

A mean achieved blood pressure <120/80 mmHg is associated with adverse events.

“As discussed below, treatment should be individualized, and treatment goals should not be set to achieve <120/80 mmHg, as a mean achieved blood pressure <120/80 mmHg is associated with adverse events.”

In STEP, 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).

“In this trial, 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 (hazard ratio [HR] 0.74 [95% CI 0.60-0.92];P = 0.007).”

• cites [37] 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

Most evidence supporting interventions to reduce cardiovascular risk in diabetes comes from trials of people with type 2 diabetes.

“Notably, most of the evidence supporting interventions to reduce cardiovascular risk in diabetes comes from trials of people with type 2 diabetes.”

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.”

Treatment with SGLT2 inhibitors and/or GLP-1 RAs that have demonstrated benefit is considered a fundamental element of risk reduction and the pharmacological strategy to improve cardiovascular and kidney outcomes in people with type 2 diabetes.

“Therefore, in addition to the management of hyperglycemia, hypertension, and hyperlipidemia, treatment with SGLT2 inhibitors and/or GLP-1 RAs that have demonstrated benefit is considered a fundamental element of risk reduction and the pharmacological strategy to improve cardiovascular and kidney outcomes in people with type 2 diabetes (Fig. 10.1).”

Multiple-drug therapy is often required to achieve blood pressure goals, particularly in the setting of CKD in people with diabetes.

“Multiple-drug therapy is often required to achieve blood pressure goals (Fig. 10.2), particularly in the setting of CKD in people with diabetes.”

An analysis of trials including people with type 2 diabetes and impaired glucose tolerance with achieved systolic blood pressures of <135 mmHg in the intensive group and <140 mmHg in the standard group revealed a 10% reduction in all-cause mortality and a 17% reduction in stroke.

“An analysis of trials including people with type 2 diabetes and impaired glucose tolerance with achieved systolic blood pressures of <135 mmHg in the intensive blood pressure treatment group and <140 mmHg in the standard treatment group revealed a 10% reduction in all-cause mortality and a 17% reduction in stroke (35).”

• cites [35] Bangalore, 2011, Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials, Circulation sourceNot checked — no full text of the source

Extrapolation of these studies suggests that people with diabetes may also be more likely to benefit from intensive blood pressure management when they have high absolute cardiovascular risk.

“Extrapolation of these studies suggests that people with diabetes may also be more likely to benefit from intensive blood pressure management when they have high absolute cardiovascular risk.”

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

“Single-pill antihypertensive combinations may improve medication taking in some individuals (66).”

• cites [66] Bangalore, 2007, Fixed-dose combinations improve medication compliance: a meta-analysis, Am J Med sourceNot checked — no full text of the source

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.

“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 (102).”

• cites [102] 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

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.

“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 (122).”

• cites [122] 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

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.

“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 (108).”

• cites [108] 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

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 (98).”

• cites [98] 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

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.

“The Cholesterol Treatment Trialists' Collaboration, involving 26 statin trials, of which 5 compared high-intensity versus moderateintensity 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 (108).”

• cites [108] 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

The 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 (109).”

• cites [109] 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

The 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 lipidlowering therapy has been uniform across most subgroups tested (100,108), including subgroups that varied with respect to age and other risk factors.”

• cites [100] 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
• cites [108] 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

The highly variable LDL cholesterol-lowering response seen with statins is poorly understood.

“In individuals, the highly variable LDL cholesterol-lowering response seen with statins is poorly understood (97).”

• cites [97] Chasman, 2004, Pharmacogenetic study of statin therapy and cholesterol reduction, JAMA sourceNot checked — no full text of the source

The evidence for the use of drugs that target these 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 (155).”

• cites [155] Singh, 2007, High-density lipoprotein as a therapeutic target: a systematic review, JAMA sourceNot checked — no full text of the source

Cardiovascular death was reduced by 20% (P = 0.03).

“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).”

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 (173).”

• cites [173] 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

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

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

The REDUCE-IT trial 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.

“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.”

Other studies suggest no impairment in aspirin response among people with diabetes.

“but other studies suggest no impairment in aspirin response among people with diabetes (194).”

• cites [194] Zaccardi, 2016, In vivo platelet activation and aspirin responsiveness in type 1 diabetes, Diabetes 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 [200] 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
• cites [201] Steg, 2019, Ticagrelor in patients with stable coronary disease and diabetes, N Engl J Med sourceNot checked — no full text of the source
• cites [202] 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

It appears that 75-162 mg/day is optimal for aspirin.

“It appears that 75-162 mg/day is optimal.”

• AssumptionRests on an assumption: Average daily dosages used in most clinical trials involving people with diabetes ranged from 50 to 650 mg but were mostly in the range of 100-325 mg/day.

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 (200).”

• cites [200] 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

Many alternate pathways for platelet activation exist that are independent of thromboxane A2 and thus are not sensitive to the effects of aspirin.

“Many alternate pathways for platelet activation exist that are independent of thromboxane A 2 and thus are not sensitive to the effects of aspirin (192).”

• cites [192] Davì, 2007, Platelet activation and atherothrombosis, N Engl J Med sourceNot checked — no full text of the source

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

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

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.

“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 (201,202).”

• cites [201] Steg, 2019, Ticagrelor in patients with stable coronary disease and diabetes, N Engl J Med sourceNot checked — no full text of the source
• cites [202] 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 other screening studies, 26% of people with diabetes have been shown to have PAD.

“Similarly, in other screening studies, 26% of people with diabetes have been shown to have PAD (234), and diabetes increased”

• cites [234] Lange, 2004, High prevalence of peripheral arterial disease and low treatment rates in elderly primary care patients with diabetes, Exp Clin Endocrinol Diabetes 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 (233).”

• cites [233] Hirsch, 2001, Peripheral arterial disease detection, awareness, and treatment in primary care, JAMA sourceNot checked — no full text of the source

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.

“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 (226).”

• cites [226] 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 2008, the U.S. Food and Drug Administration issued guidance for industry to perform cardiovascular outcomes trials for all new medications for the treatment of type 2 diabetes amid concerns of increased cardiovascular risk.

“In 2008, the U.S. Food and Drug Administration (FDA) issued guidance for industry to perform cardiovascular outcomes trials for all new medications for the treatment of type 2 diabetes amid concerns of increased cardiovascular risk (253).”

• cites [253] U.S. Food and Drug Administration . Guidance for industry. Diabetes mellitus— evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD, 2008. Accessed 27 August 2024. Available from https://www.federalregister.gov/documents/2008/12/19/E8–30086/guidance-for-industry-on-diabetes-mellitus-evaluating-cardiovascular-risk-in-new-antidiabeticNot matched

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

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 (211).”

• cites [211] 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

Clear cardiovascular benefit exists for ACE inhibitor or ARB therapy in people with diabetes.

“Clear cardiovascular benefit exists for ACE inhibitor or ARB therapy in people with diabetes.”

• cites [245] 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

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.”

Prospective, randomized studies addressing whether screening for PAD in people with diabetes improves long-term limb outcomes and cardiovascular event rates are limited.

“prospective, randomized studies addressing whether screening for PAD in people with diabetes improves longterm limb outcomes and cardiovascular event rates are limited.”

In VERTIS CV, the hazard ratio for hospitalization for heart failure with ertugliflozin versus placebo was 0.70 (95% CI 0.54-0.90).

“The HR for a secondary outcome of hospitalization for heart failure (ertugliflozin vs. placebo) was 0.70 [95% CI 0.54-0.90],”

• cites [260] Cannon, 2020, Cardiovascular outcomes with ertugliflozin in type 2 diabetes, N Engl J Med 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.

“up to 91% of all new heart failure development in the Framingham cohort occurred in people with a previous diagnosis of hypertension (275).”

• cites [275] Levy, 1996, The progression from hypertension to congestive heart failure, JAMA sourceNot checked — no full text of the source

In VERTIS CV, ertugliflozin was not superior to placebo for death from cardiovascular causes.

“death from cardiovascular causes;”

• cites [260] Cannon, 2020, Cardiovascular outcomes with ertugliflozin in type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source

In VERTIS CV, ertugliflozin was not superior to placebo for the key secondary outcome of death from cardiovascular causes or hospitalization for heart failure.

“However, ertugliflozin was not superior to placebo for the key secondary outcomes of death from cardiovascular causes or hospitalization for heart failure;”

• cites [260] Cannon, 2020, Cardiovascular outcomes with ertugliflozin in type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source

In VERTIS CV, ertugliflozin met the prespecified criteria for noninferiority to placebo for major adverse cardiovascular events (11.9% vs 11.9%; HR 0.97 [95% CI 0.85-1.11]; P < 0.001).

“The Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV) (260) met the prespecified criteria for noninferiority of ertugliflozin to placebo with respect to the primary outcome of major adverse cardiovascular events (11.9% in the pooled ertugliflozin group and 11.9% in the placebo group; HR 0.97 [95% CI 0.85-1.11];P < 0.001).”

• cites [260] Cannon, 2020, Cardiovascular outcomes with ertugliflozin in type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source

In the CAPRICORN study, treatment with carvedilol reduced heart failure hospitalization by 14%.

“and there was a 14% risk reduction for heart failure hospitalization.”

• cites [282] Dargie, 2001, Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial, Lancet 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.

“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% (279).”

• cites [279] 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 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% (278).”

• cites [278] 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 VERTIS CV, ertugliflozin was not superior to placebo for the composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level.

“or the composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level.”

• cites [260] Cannon, 2020, Cardiovascular outcomes with ertugliflozin in type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source

The vast majority of incident heart failure is preceded by hypertension.

“The vast majority of incident heart failure is preceded by hypertension;”

• cites [275] Levy, 1996, The progression from hypertension to congestive heart failure, JAMA sourceNot checked — no full text of the source

The VERTIS CV finding for hospitalization for heart failure is consistent with findings from other SGLT2 inhibitor cardiovascular outcomes trials.

“consistent with findings from other SGLT2 inhibitor cardiovascular outcomes trials.”

• cites [260] Cannon, 2020, Cardiovascular outcomes with ertugliflozin in type 2 diabetes, N Engl J Med sourceNot checked — no full text of the source

Current guideline-directed medical therapy for a history of MI and symptomatic stage C and D heart failure in people with diabetes is similar to that for people without diabetes.

“In general, current guideline-directed medical therapy for a history of MI and symptomatic stage C and D heart failure in people with diabetes is similar to that for people without diabetes.”

• cites [12] Heidenreich, 2022, 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines, Circulation sourceNot checked — no full text of the source

Data on the effects of glucose-lowering agents on heart failure outcomes have demonstrated that thiazolidinediones have a strong and consistent relationship with increased risk of heart failure.

“Data on the effects of glucose-lowering agents on heart failure outcomes have demonstrated that thiazolidinediones have a strong and consistent relationship with increased risk of heart failure (286-288).”

• cites [286] 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 [287] Singh, 2007, Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis, JAMA sourceNot checked — no full text of the source
• cites [288] 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

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

“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 (283).”

• cites [283] 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

No randomized trial of metformin therapy has been conducted in people with heart failure.

“however, no randomized trial of metformin therapy has been conducted in people with heart failure.”

Studies examining the relationship between DPP-4 inhibitors and heart failure have had mixed results.

“Studies examining the relationship between DPP-4 inhibitors and heart failure have had mixed results.”

In the SAVOR-TIMI 53 study, individuals treated with the DPP-4 inhibitor saxagliptin were more likely to be hospitalized for heart failure than those given placebo (3.5% vs 2.8%).

“The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study showed that individuals treated with the DPP-4 inhibitor saxagliptin were more likely to be hospitalized for heart failure than those given placebo (3.5% vs. 2.8%, respectively) (292).”

• cites [292] 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

SGLT2 inhibitors constitute a key treatment approach to reduce cardiovascular disease and heart failure outcomes in people with diabetes.

“SGLT2 inhibitors constitute a key treatment approach to reduce cardiovascular disease and heart failure outcomes in people with diabetes.”

Restrictions to use of metformin in people with medically treated heart failure were removed by the FDA in 2006.

“Restrictions to use of metformin in people with medically treated heart failure were removed by the FDA in 2006 (289).”

• cites [289] Inzucchi, 2007, Metformin in heart failure, Diabetes Care sourceNot checked — no full text of the source

Observational studies of people with type 2 diabetes and heart failure suggest that metformin users have better outcomes than individuals treated with other antihyperglycemic agents.

“Observational studies of people with type 2 diabetes and heart failure suggest that metformin users have better outcomes than individuals treated with other antihyperglycemic agents (290);”

• cites [290] Eurich, 2005, Improved clinical outcomes associated with metformin in patients with diabetes and heart failure, Diabetes Care sourceNot checked — no full text of the source

Sotagliflozin was recently approved by the FDA to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure in people with heart failure or type 2 diabetes, CKD, and other cardiovascular risk factors.

“Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, was recently approved by the FDA to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure in people with heart failure or type 2 diabetes, CKD, and other cardiovascular risk factors.”

One concern with expanded use of SGLT inhibition is the infrequent but serious risk of diabetic ketoacidosis, including the atypical presentation of euglycemic ketoacidosis.

“One concern with expanded use of SGLT inhibition is the infrequent but serious risk of diabetic ketoacidosis, including the atypical presentation of euglycemic ketoacidosis.”

These collective studies indicate that finerenone improves cardiovascular and renal outcomes in people with type 2 diabetes.

“These collective studies indicate that finerenone improves cardiovascular and renal outcomes in people with type 2 diabetes.”

Use of preventative processes may have contributed to the lower rates of ketoacidosis seen in some studies of SGLT inhibitors for adjunctive glycemic management in type 1 diabetes compared with those that did not include preventative strategies.

“Use of these processes may have contributed to the lower rates of ketoacidosis seen in some of the studies of these agents for adjunctive glycemic management in people with type 1 diabetes (314-316) compared with those that did not include preventative strategies (310,317).”

• cites [314] Rosenstock, 2018, Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials, Diabetes Care sourceNot checked — no full text of the source
• cites [315] Mathieu, 2018, Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-week results from a randomized controlled trial, Diabetes Care sourceNot checked — no full text of the source
• cites [316] Garg, 2017, Effects of sotagliflozin added to insulin in patients with type 1 diabetes, N Engl J Med sourceNot checked — no full text of the source
• cites [310] Peters, 2016, Diabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes, Diabetes Care sourceNot checked — no full text of the source
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Use of SGLT inhibitors increases susceptibility to diabetic ketoacidosis, particularly when other risk factors or situations occur.

“Thus, the use of SGLT inhibitors (whether for glycemic management or another indication) increases the susceptibility to diabetic ketoacidosis, particularly when other risk factors or situations occur (including, but not limited to, insulin pump malfunctions, significant reduction in insulin doses, and nutritional intake plans with prolonged periods of fasting or carbohydrate restriction).”