Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
Open accessAbstract
BACKGROUND: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).
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Claims the paper makes
10 of 24 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured
- Premisecitation
In the ELIXA trial, the GLP-1 receptor agonist lixisenatide did not show any cardiovascular benefit in patients with diabetes and a recent acute coronary syndrome.
“in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial,14 the GLP-1–receptor agonist lixisenatide, which is shorter-acting than and structurally dissimilar to liraglutide, did not show any cardiovascular benefit in patients with diabetes and a recent acute coronary syndrome.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] source
- Interpretationcitation
The pattern of cardiovascular benefits associated with liraglutide appears to differ from that with empagliflozin in the EMPA-REG OUTCOME trial.
“The pattern of cardiovascular benefits that were associated with liraglutide in our trial appears to differ from that with the sodium–glucose cotransporter 2 inhibitor empagliflozin in the previously reported EMPA-REG OUTCOME trial.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [12] source
- Premisecitation
In the EMPA-REG OUTCOME trial, the time to benefit emerged earlier than in the present trial.
“The time to benefit emerged earlier in that trial than in the present trial”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [12] source
The discussion on p. 9 says that reductions in cardiovascular and all-cause death occurred early in EMPA-REG OUTCOME and continued throughout the study. It does not compare the time to benefit with that of the citing authors’ present trial, so the ‘earlier than’ comparison is not supported by this source alone. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
At 36 months, diastolic blood pressure was 0.6 mm Hg higher in the liraglutide group than in the placebo group (95% CI, 0.2 to 1.0).
“the diastolic blood pressure was 0.6 mm Hg (95% CI, 0.2 to 1.0) higher in the liraglutide group”
Quote in the paperNot a substantial claim
- Findingown data
Medullary thyroid carcinoma occurred in no liraglutide patient and in one placebo patient.
“Medullary thyroid carcinoma occurred in no patient in the liraglutide group and in 1 in the placebo group.”
Quote in the paperNot a substantial claim - Findingown data
The incidence of the composite renal or retinal microvascular outcome was lower in the liraglutide group than in the placebo group, with a hazard ratio of 0.84 (95% CI, 0.73 to 0.97), P=0.02.
“The incidence of a composite outcome of renal or retinal microvascular events was lower in the liraglutide group than in the placebo group (hazard ratio, 0.84; 95% CI, 0.73 to 0.97; P = 0.02)”
Quote in the paperSubstantial claim - Findingown data
Mean serum amylase and lipase levels were higher in the liraglutide group than in the placebo group.
“The mean levels of serum amylase and lipase were higher in the liraglutide group than in the placebo group”
Quote in the paperNot a substantial claim - Findingown data
At 36 months, heart rate was 3.0 beats per minute higher in the liraglutide group than in the placebo group (95% CI, 2.5 to 3.4).
“the heart rate was 3.0 beats per minute (95% CI, 2.5 to 3.4) higher in the liraglutide group”
Quote in the paperNot a substantial claim - Findingown data
At 36 months, systolic blood pressure was 1.2 mm Hg lower in the liraglutide group than in the placebo group (95% CI, 1.9 to 0.5).
“the systolic blood pressure was 1.2 mm Hg (95% CI, 1.9 to 0.5) lower in the liraglutide group”
Quote in the paperNot a substantial claim - Findingown data
Acute pancreatitis occurred in 18 liraglutide patients and 23 placebo patients.
“Acute pancreatitis occurred in 18 patients in the liraglutide group and in 23 in the placebo group.”
Quote in the paperNot a substantial claim - Findingown data
The number needed to treat to prevent one death from any cause in 3 years was 98.
“The number of patients who would need to be treated to prevent one event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause.”
Quote in the paperNot a substantial claim - Findingown data
The number needed to treat to prevent one primary outcome event in 3 years was 66.
“The number of patients who would need to be treated to prevent one event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause.”
Quote in the paperNot a substantial claim - Findingown data
Adverse events leading to permanent discontinuation of the trial regimen were more common with liraglutide than with placebo.
“Adverse events leading to the permanent discontinuation of the trial regimen were more common with liraglutide than with placebo (Table 2).”
Quote in the paperNot a substantial claim - Findingown data
A sensitivity analysis of patients with an eGFR of less than 60 ml per minute per 1.73 m2 did not support a clinically meaningful interaction.
“A sensitivity analysis of data for patients with an eGFR of less than 60 ml per minute per 1.73 m2 did not support a clinically meaningful interaction”
Quote in the paperNot a substantial claim - Findingown data
Subgroup analyses suggested a possible greater benefit of liraglutide in patients with a history of cardiovascular disease.
“Subgroup analyses suggest a greater benefit of liraglutide with respect to the primary outcome in patients with an eGFR of less than 60 ml per minute per 1.73 m2 and possibly in patients with a history of cardiovascular disease.”
Quote in the paperNot a substantial claim - Findingown data
More liraglutide patients than placebo patients permanently discontinued the trial regimen owing to adverse events, with a difference of 2.2 percentage points.
“More patients in the liraglutide group than in the placebo group permanently discontinued the trial regimen owing to adverse events (difference, 2.2 percentage points).”
Quote in the paperNot a substantial claim - Findingown data
The rate ratio for confirmed hypoglycemia (plasma glucose <56 mg per deciliter) was 0.80 (95% CI, 0.74 to 0.88).
“Similarly, the rate ratio for confirmed hypoglycemia (plasma glucose level, <56 mg per deciliter [3.1 mmol per liter]) was 0.80 (95% CI, 0.74 to 0.88).”
Quote in the paperNot a substantial claim - Findingown data
Severe hypoglycemia occurred in 114 liraglutide patients and 153 placebo patients, with a rate ratio of 0.69 (95% CI, 0.51 to 0.93).
“Severe hypoglycemia occurred in 114 patients in the liraglutide group and in 153 in the placebo group (rate ratio, 0.69; 95% CI, 0.51 to 0.93).”
Quote in the paperNot a substantial claim - Findingown data
In type 2 diabetes patients at high cardiovascular risk, liraglutide added to standard care reduced the risk of the combined endpoint of cardiovascular death, nonfatal heart attack, or nonfatal stroke relative to placebo.
“The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority).”
- Also stated in: § DISCUSSION · plain
“In conclusion, among patients with type 2 diabetes who were at high risk for cardiovascular events while they were taking standard therapy, those in the liraglutide group had lower rates of cardiovascular events and death from any cause than did those in the placebo group.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
At 36 months, weight loss was 2.3 kg greater in the liraglutide group than in the placebo group (95% CI, 2.5 to 2.0).
“weight loss was 2.3 kg (95% CI, 2.5 to 2.0) higher in the liraglutide group”
Quote in the paperNot a substantial claim - Findingown data
Fewer liraglutide patients were treated with hypoglycemic medications (insulin, sulfonylurea, and glinides) during the trial than placebo patients.
“During the trial, fewer patients in the liraglutide group were treated with hypoglycemic medications (insulin, sulfonylurea, and glinides) than in the placebo group”
Quote in the paperNot a substantial claim - Findingown data
Retinopathy events occurred at a nonsignificantly higher rate in the liraglutide group than in the placebo group (0.6 vs. 0.5 events per 100 patient-years), with a hazard ratio of 1.15 (95% CI, 0.87 to 1.52), P=0.33.
“The incidence of retinopathy events was nonsignificantly higher in the liraglutide group than in the placebo group (0.6 vs. 0.5 events per 100 patient-years; hazard ratio, 1.15; 95% CI, 0.87 to 1.52; P = 0.33).”
Quote in the paperNot a substantial claim - Findingown data
Subgroup analyses suggested a greater benefit of liraglutide for the primary outcome in patients with an eGFR of less than 60 ml per minute per 1.73 m2 than in those with higher eGFR.
“Subgroup analyses suggest a greater benefit of liraglutide with respect to the primary outcome in patients with an eGFR of less than 60 ml per minute per 1.73 m2 and possibly in patients with a history of cardiovascular disease.”
Quote in the paperNot a substantial claim - Findingown data
At 36 months, the mean difference in glycated hemoglobin between the liraglutide and placebo groups was -0.40 percentage points (95% CI, -0.45 to -0.34).
“The prespecified analysis at 36 months showed a mean difference between the liraglutide group and the placebo group of −0.40 percentage points (95% CI, −0.45 to −0.34).”
Quote in the paperNot a substantial claim - Findingown data
No episodes of C-cell hyperplasia or medullary thyroid carcinoma were observed in liraglutide patients.
“In the present trial, no episodes of C-cell hyperplasia or medullary thyroid carcinoma were observed in patients in the liraglutide group.”
Quote in the paperNot a substantial claim - Findingown data
Fewer liraglutide patients added insulin during the trial than placebo patients.
“but fewer patients in the liraglutide group than in the placebo group added insulin during the trial.”
Quote in the paperNot a substantial claim - Findingown data
There were 1.5 episodes of pancreatitis per 1000 patient-years of observation in both regimens combined.
“There were 1.5 episodes of pancreatitis per 1000 patient-years of observation in both regimens combined”
Quote in the paperNot a substantial claim - Findingown data
There was a 31% lower rate of severe hypoglycemia in the liraglutide group than in the placebo group.
“There was a 31% lower rate of severe hypoglycemia and a 20% lower rate of the combination of severe and confirmed hypoglycemia (plasma glucose level, <56 mg per deciliter) in the liraglutide group than in the placebo group.”
Quote in the paperNot a substantial claim - Findingown data
There were numerically fewer acute or chronic pancreatitis events with liraglutide than with placebo.
“there were numerically fewer acute or chronic pancreatitis events with liraglutide than with placebo.”
Quote in the paperNot a substantial claim - Findingown data
There was a 20% lower rate of the combination of severe and confirmed hypoglycemia in the liraglutide group than in the placebo group.
“There was a 31% lower rate of severe hypoglycemia and a 20% lower rate of the combination of severe and confirmed hypoglycemia (plasma glucose level, <56 mg per deciliter) in the liraglutide group than in the placebo group.”
Quote in the paperNot a substantial claim - Study design and conductown data
Sensitivity analyses suggested that the findings were robust to baseline adjustment and alternative censoring.
“Sensitivity analyses suggested that our findings were robust to baseline adjustment and alternative censoring.”
Quote in the paperNot a substantial claim - Interpretationown data
The microvascular benefit with liraglutide was driven by lower rates of renal outcomes, such as new-onset persistent macroalbuminuria.
“The benefit with liraglutide was driven by lower rates of renal outcomes, such as new-onset persistent macro-albuminuria in particular.”
Quote in the paperSubstantial claim - Interpretationown data
With moderate differences in glycemic control between groups over a median 3.8 years of follow-up, the achievement of renal microvascular benefits is surprising.
“With moderate differences in glycemic control between the trial groups over a median 3.8 years of follow-up, the achievement of renal microvascular benefits is surprising.”
Quote in the paperNot a substantial claim - Interpretationown data
The higher rate of discontinuation due to adverse events in the liraglutide group appears to have been driven by gastrointestinal disorders.
“This result appears to have been driven by gastrointestinal disorders in the liraglutide group.”
Quote in the paperNot a substantial claim - Premisecitation
There is no consistent preclinical, pharmacovigilance, or epidemiologic evidence for an association between GLP-1 receptor agonists and pancreatitis or pancreatic cancer.
“There has been considerable interest in a potential association between the use of GLP-1–receptor agonists and pancreatitis and pancreatic cancer, although there is no consistent preclinical, pharmacovigilance, or epidemiologic evidence to date.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Study design and conductown data
Patients were randomly assigned in a 1:1 ratio to receive liraglutide or placebo.
“Patients with type 2 diabetes who were at high risk for cardiovascular disease were randomly assigned, in a 1:1 ratio, to receive liraglutide or placebo.”
Quote in the paperSubstantial claim - Premisecitation
Among rodents receiving liraglutide, higher rates of thyroid C-cell tumors and hyperplasia were observed than among control animals.
“Among rodents receiving liraglutide, higher rates of thyroid C-cell tumors and hyperplasia have been observed than were observed among control animals.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] source
- Interpretationown data
Because the trial recruited high-risk patients with a baseline glycated hemoglobin level of 7% or more, the observed benefits and risks may not apply to lower-risk patients.
“Also, because our trial recruited a population of patients who were at high risk for cardiovascular events and who had a baseline glycated hemoglobin level of 7% or more, the observed benefits and risks may not apply to patients at lower risk.”
Quote in the paperNot a substantial claim - Study design and conductown data
The demographic and clinical characteristics of the patients were similar in the two groups.
“The demographic and clinical characteristics of the patients were similar in the two groups”
Quote in the paperSubstantial claim - Study design and conductown data
A limitation is that patients were followed for only 3.5 to 5.0 years, so the safety and efficacy data are restricted to that time period.
“A limitation of our trial is that patients were followed for only 3.5 to 5.0 years, so the safety and efficacy data are restricted to that time period.”
Quote in the paperNot a substantial claim
- May combine two claims. 21
- Classified as probably not a substantial claim. 17
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationOther trials in high-risk type 2 diabetes patients showed similar glycemic control effects but without significant benefits for cardiovascular events or death.
“There are a number of other trials regarding cardiovascular outcomes in high-risk cohorts of patients with type 2 diabetes in which similar magnitude effects on glycemic control have been shown but without significant benefits with respect to rates of cardiovascular events or death.”
Quote in the paperSubstantial claim2 of 6 sources checked- cites [15] source
- cites [16] source
- cites [17] source
The Results (p. 1) report a small improvement in glycated hemoglobin with sitagliptin and no reduction in the primary cardiovascular outcome; Other Secondary Outcomes (p. 4) report no significant difference in deaths. The Discussion (p. 8) also says two other DPP-4 inhibitor trials found no reduction in major adverse cardiovascular events. It does not establish that those other trials had similar-magnitude glycemic effects or no mortality benefit. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [18] source
- cites [19] source
- cites [20] source
May combine two claims.
InterpretationcitationIn the EMPA-REG OUTCOME trial, the direction and magnitude of effects on the components of the primary composite outcome were heterogeneous, contrasting with the consistency of the effect in the present trial.
“the heterogeneity of the direction and magnitude of the effects on the components of the primary composite outcome in that trial contrasts with the consistency of the effect in the present trial.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [12] source
May combine two claims.
FindingcitationMore episodes of gallstone disease occurred with liraglutide, a finding that has been reported previously.
“There were more episodes of gallstone disease with liraglutide, a finding that has been reported previously.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] source
The Safety section reports more gallbladder-related adverse events with liraglutide than placebo (1.2% and 1.9% versus 0.5%). It does not identify those events specifically as gallstone disease or say that this particular finding had been reported previously. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationLiraglutide's efficacy in lowering glucose levels has been established, and it has been associated with slight reductions in weight and blood pressure.
“Its efficacy in lowering glucose levels has been established, and it has been associated with slight reductions in weight and blood pressure.6–8”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [6] source
The GLP-1RAs Glycaemic Efficacy section reports that liraglutide lowers fasting and postprandial glucose and HbA1c. The Non-glycaemic Effects section reports weight reductions with liraglutide, but it does not establish a blood-pressure reduction for liraglutide; it says a 52-week trial extension found no significant improvement in systolic blood pressure. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [7] source
- cites [8] Robinson LE, 2013, BMJ Open source
The Key messages and Results (Body weight; Blood pressure) support modest reductions in weight and systolic blood pressure with liraglutide and exenatide. The paper does not assess glucose-lowering efficacy; that part appears in titles in its References, but is not established by this analysis. Diastolic blood-pressure reductions were not statistically significant. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataAcute gallstone disease was more common with liraglutide than with placebo (145 vs. 90 patients), including severe events (40 vs. 31).
“Acute gallstone disease was more common with liraglutide than with placebo (in 145 vs. 90 patients), including severe events (in 40 vs. 31).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe combined primary endpoint occurred in 608 of 4668 liraglutide patients (13.0%) and 694 of 4672 placebo patients (14.9%), with a hazard ratio of 0.87 (95% CI, 0.78 to 0.97), P<0.001 for noninferiority and P=0.01 for superiority.
“The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataLeukemia occurred in fewer liraglutide patients than placebo patients (5 vs. 14).
“and also fewer patients with leukemia (5 vs. 14)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOverall rates of benign or malignant neoplasms were higher in the liraglutide group than in the placebo group, but the difference was not significant.
“The overall rates of benign or malignant neoplasms were higher in the liraglutide group than in the placebo group, but the difference was not significant”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNephropathy events occurred at a lower rate in the liraglutide group than in the placebo group (1.5 vs. 1.9 events per 100 patient-years), with a hazard ratio of 0.78 (95% CI, 0.67 to 0.92), P=0.003.
“a difference that was driven by a lower rate of nephropathy events in the liraglutide group (1.5 vs. 1.9 events per 100 patient-years of observation; hazard ratio, 0.78; 95% CI, 0.67 to 0.92; P = 0.003)”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataPancreatic cancer occurred in 13 liraglutide patients and 5 placebo patients, a difference that was not significant.
“There were 13 patients with pancreatic cancer in the liraglutide group and 5 in the placebo group.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenThe present trial had greater statistical power and included patients with a higher baseline glycated hemoglobin level than most previous studies.
“Our trial had greater statistical power and included patients with a higher baseline glycated hemoglobin level than did most previous studies.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCardiovascular death occurred in 219 liraglutide patients (4.7%) and 278 placebo patients (6.0%), with a hazard ratio of 0.78 (95% CI, 0.66 to 0.93), P=0.007.
“Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataProstate cancer occurred in fewer liraglutide patients than placebo patients (26 vs. 47).
“There were fewer patients with prostate cancer in the liraglutide group than in the placebo group (26 vs. 47)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe rate of nonfatal stroke was lower in the liraglutide group than in the placebo group, but the difference was not significant.
“The frequencies of nonfatal myocardial infarction and nonfatal stroke were lower in the liraglutide group than in the placebo group, although the differences were not significant”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe incidence of pancreatitis was lower in the liraglutide group than in the placebo group, but the difference was not significant.
“The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe rate of hospitalization for heart failure was lower in the liraglutide group than in the placebo group, but the difference was not significant.
“In the present trial, there were fewer hospitalizations for heart failure among patients in the liraglutide group than among those in the placebo group, although the difference was not significant.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataCalcitonin levels over time were similar in the two groups.
“Calcitonin levels over time were similar in the two groups (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe rate of nonfatal heart attack was lower in the liraglutide group than in the placebo group, but the difference was not significant.
“The frequencies of nonfatal myocardial infarction and nonfatal stroke were lower in the liraglutide group than in the placebo group, although the differences were not significant”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDeath from any cause occurred in 381 liraglutide patients (8.2%) and 447 placebo patients (9.6%), with a hazard ratio of 0.85 (95% CI, 0.74 to 0.97), P=0.02.
“The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P =0.02).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationHigher levels of lipase and amylase in the liraglutide group are similar to results in other studies.
“Higher levels of lipase and amylase were observed in the liraglutide group, a finding that is similar to results in other studies.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningNo obvious single explanation in terms of study designs or included populations is apparent to explain the divergent findings across the literature.
“However, no obvious single explanation in terms of either the study designs or the included populations is apparent to explain the divergent findings across this body of medical literature.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataVital status was known in 99.7% of patients, and 96.8% completed a final visit, died, or had a primary outcome.
“The vital status was known in 99.7% of the patients. A total of 96.8% of the patients completed a final visit, died, or had a primary outcome.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe mean percentage of time that patients received the trial regimen was 84% for liraglutide and 83% for placebo.
“The mean percentage of time that patients received the trial regimen was 84% for liraglutide and 83% for placebo.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAn independent data and safety monitoring committee performed ongoing safety surveillance and had access to all data in an unblinded fashion.
“An independent data and safety monitoring committee performed ongoing safety surveillance and had access to all the data in an unblinded fashion.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductreasoningRandomized trials of this type are not powered to determine the effect of drugs on cancer risk and can neither confirm nor exclude such a possibility.
“Randomized trials of this type, despite their size, are not powered to determine the effect of drugs on cancer risk and can therefore neither confirm nor exclude such a possibility.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationRegulatory authorities have mandated cardiovascular safety assessments of new diabetes treatments.
“Consequently, regulatory authorities have mandated cardiovascular safety assessments of new diabetes treatments.4,5”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4] Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. London: European Medicines Agency, 2012.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [5] Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: Department of Health and Human Services, 2008.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Study design and conductnone givenAll patients who underwent randomization were included in the primary and exploratory analyses.
“All the patients who underwent randomization were included in the primary and exploratory analyses”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataRandomization was stratified according to estimated glomerular filtration rate at screening.
“Randomization was stratified according to the estimated glomerular filtration rate (eGFR) at screening”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataThe trial was double-blind and placebo-controlled.
“In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningThe sample size was calculated as 8754 patients to observe at least 611 primary outcomes, with 90% power, a one-sided alpha level of 0.025, and an assumed annual primary-event rate of 1.8% in each group.
“Assuming a withdrawal rate of less than 10%, a minimum exposure to the trial regimen of 42 months, a null hypothesis hazard ratio of 1.30 or more, 90% power, and a one-sided alpha level of 0.025, we calculated that 8754 patients would need to undergo randomization if we were to observe at least 611 primary outcomes.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationConcern has been raised about the cardiovascular safety of antihyperglycemic therapies.
“Furthermore, concern has been raised about the cardiovascular safety of antihyperglycemic therapies.3”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Classified as probably not a substantial claim.
Study design and conductown dataPrimary and exploratory outcomes were adjudicated in a blinded fashion by an external, independent event-adjudication committee.
“all of which were adjudicated in a blinded fashion by an external, independent event-adjudication committee.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo adjustments were made for multiplicity of exploratory outcomes.
“Furthermore, no adjustments were made for multiplicity of exploratory outcomes.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The macrovascular benefits of glycemic control are less certain than its microvascular benefits.
“Although glycemic control is associated with reductions in the risk of microvascular complications, the macrovascular benefits of glycemic control are less certain.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Semaglutide reduced the risk of new or worsening nephropathy (a composite of persistent UACR >300 mg/g creatinine, doubling of serum creatinine, or ESKD) by 36%.
“and semaglutide reduced the risk of new or worsening nephropathy (a composite of persistent UACR >300 mg/g creatinine, doubling of serum creatinine, or ESKD) by 36% (each P < 0.01).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [95]
The Methods (Procedures; page unavailable) say this trial compared liraglutide with placebo, not semaglutide. The Results (Microvascular Outcomes; page unavailable) report a nephropathy hazard ratio of 0.78, corresponding to a 22% lower risk, not 36%. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredCompared with placebo, dulaglutide reduced the composite kidney outcome by 25%.
“dulaglutide reduced the composite kidney outcome (risk of ≥40% sustained decline in eGFR, kidney failure, or kidney-related death) by 25%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [104]
The Methods > Outcomes section defines a different renal outcome, and Results > Microvascular Outcomes reports a reduction in nephropathy events with liraglutide, not dulaglutide. Its reported hazard ratio is 0.78 (approximately a 22% reduction), not the claimed 25% reduction for the specified composite kidney outcome. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredCompared with placebo, canagliflozin reduced the risk of progression of albuminuria by 27% and the risk of reduction in eGFR, kidney failure, or death from kidney failure by 40%.
“canagliflozin reduced the risk of progression of albuminuria by 27% and the risk of reduction in eGFR, kidney failure, or death from kidney failure by 40%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [104]
The Methods (Procedures; page unavailable) state that participants were assigned to liraglutide or placebo, not canagliflozin. The Results (Microvascular Outcomes; page unavailable) report a nephropathy hazard ratio of 0.78 for liraglutide; they do not report the claimed 27% and 40% reductions for canagliflozin. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredACE inhibitors, ARBs, SGLT2is, GLP-1 RAs, and finerenone improve albuminuria and declining eGFR.
“Therapies shown to positively affect albuminuria and declining eGFR include ACE inhibitors, ARBs, SGLT2is, GLP-1 RAs, and the nonsteroidal mineralocorticoid antagonist finerenone.197,209,239,242,393,423–435”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [423]
The Results (Microvascular Outcomes; page unavailable) report fewer nephropathy events with liraglutide than with placebo, and the Discussion says the renal benefit was driven particularly by less new-onset macroalbuminuria. The paper studied one GLP-1 receptor agonist, not the other listed therapies; although its nephropathy outcome included an eGFR-related event, the cited passages do not establish an improvement in declining eGFR specifically. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGLP-1RAs improve glycemic control, promote weight loss and reduce major adverse cardiovascular events in high-risk patients with T2DM.
“GLP‐1 receptor agonists (GLP‐1RAs) improve glycemic control, promote weight loss and reduce major adverse cardiovascular events in high‐risk patients with T2DM [1, 2, 3]”
From Effects of <scp>GLP</scp> ‐1 Receptor Agonists and Dual <scp>GIP</scp> / <scp>GLP</scp> ‐1 Receptor Agonists on Inflammatory and Metabolic Biomarkers in Type 2 Diabetes: A Systematic Review and Meta‐Analysis (2026) · cites this paper as [2]
The Results sections on glycemic control and cardiovascular risk factors report lower glycated hemoglobin and greater weight loss with liraglutide; the Abstract Results report fewer major cardiovascular events in high-risk patients with type 2 diabetes. The claim extends those findings to GLP-1 receptor agonists as a class, whereas the Discussion notes that another agonist, lixisenatide, did not show cardiovascular benefit in its studied population. (LLM, conf=0.88)
Experimental — accuracy not yet measured
GLP-1RAs confer substantial benefits for individuals with atherosclerosis owing to their multifaceted impact on various aspects of cardiovascular health.
“GLP-1RAs confer substantial benefits for individuals with AS owing to their multifaceted impact on various aspects of cardiovascular health.39,40,446”
From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [446]
The Discussion reports lower risks of major cardiovascular events and cardiovascular death with liraglutide in this trial of patients with type 2 diabetes; it suggests, but does not establish, an effect on atherosclerotic disease progression. The claim extends those findings to GLP-1 receptor agonists as a class and to individuals with atherosclerosis generally. The Discussion also notes that another GLP-1 receptor agonist, lixisenatide, showed no cardiovascular benefit in a separate trial. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPatients with diabetes and high cardiovascular risk treated with liraglutide and semaglutide, but not exenatide, had lower risk of non-fatal myocardial infarction and stroke; dulaglutide reduced major adverse cardiovascular events.
“It was then found that patients with diabetes and high cardiovascular risk that were treated with liraglutide and semaglutide, but not exenatide, had a lower risk of non-fatal myocardial infarction and stroke [66, 70, 71] and another GLP-1R agonist, dulaglutide, reduced major adverse cardiovascular events [72].”
From Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes (2024) · cites this paper as [70]
The Methods and Results describe patients with type 2 diabetes at high cardiovascular risk receiving liraglutide or placebo. The Results report significantly fewer events for the composite outcome, but nonfatal myocardial infarction and nonfatal stroke were each only nonsignificantly lower with liraglutide. The semaglutide, exenatide, and dulaglutide claims have separate citations and are not assessed against this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe longest controlled trials of GLP-1 receptor agonist usage are 3-4 years, and the long-term effects beyond this time are not well-described.
“The longest controlled trials of GLP-1 receptor agonist usage are 3–4 years,12,13 and the long-term effects beyond this time are not well-described.”
From Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial (2024) · cites this paper as [12]
Results (Overview of Trial Conduct) reports median exposure of 3.5 years and median follow-up of 3.8 years. The Discussion says safety and efficacy data are restricted to the trial’s 3.5–5.0 years of follow-up, supporting uncertainty beyond the observed period. The paper does not establish that 3–4 years is the longest duration of any controlled GLP-1 receptor agonist trial. (LLM, conf=0.85)
Experimental — accuracy not yet measuredGLP-1 RA medications improve health outcomes in patients with type 2 diabetes mellitus.
“Glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications improve health outcomes in patients with type 2 diabetes mellitus (T2DM).”
From Differences in GLP-1 RA medication adherence across place-based variables in patients with diabetes living in Wisconsin (2025) · cites this paper as [3]
The Discussion reports improved cardiovascular, mortality, and microvascular outcomes with liraglutide versus placebo. But the Methods limit the trial to patients with type 2 diabetes who had cardiovascular disease or risk factors, and the Discussion notes that another GLP-1 receptor agonist, lixisenatide, did not show cardiovascular benefit. The result therefore does not establish the claim for GLP-1 receptor agonists as a class or for all patients with type 2 diabetes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe LEADER trial reported acute gallstone disease rates of 3.1% in the liraglutide group versus 1.9% in the placebo cohort (P<0.001).
“as initially evidenced by the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, which reported acute gallstone disease rates of 3.1% in the liraglutide group versus 1.9% in the placebo cohort (P<0.001) [33].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [33]
The Results (Safety and Adverse Events; page unavailable) report acute gallstone disease in 145 liraglutide patients versus 90 placebo patients. With the group sizes given in the Abstract Results, these correspond to 3.1% and 1.9%. Our copy does not report P<0.001 for gallstone disease, so that part of the claim is unsupported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLiraglutide is proven safe and effective in older adults with diabetes and obesity, with robust CVOT support.
“Proven safe and effective in older adults with diabetes and obesity, with robust CVOT support [34].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [34]
The Abstract Results and Discussion report fewer major cardiovascular events with liraglutide than placebo in patients with type 2 diabetes at high cardiovascular risk, supporting the CVOT portion of the claim. The Methods: Patients section includes people aged 50 or older, but the cited passages do not establish safety and efficacy specifically in older adults with obesity. The Results: Safety and Adverse Events section also reports more acute gallstone disease with liraglutide, making the unqualified claim that it is “proven safe” too strong. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLong-term trials like LEADER confirmed cardiovascular and renal safety for liraglutide in T2D, with no increased risk of pancreatitis or thyroid malignancy.
“Long-term trials like LEADER confirmed cardiovascular and renal safety for liraglutide in T2D, with no increased risk of pancreatitis or thyroid malignancy [34].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [34]
The Results (Microvascular Outcomes and Safety and Adverse Events; page unavailable) report fewer nephropathy events, fewer pancreatitis cases, and no medullary thyroid carcinoma cases in the liraglutide group; the cardiovascular Results also show fewer major cardiovascular events. But the Discussion (page unavailable) says the trial cannot confirm or exclude an effect on cancer risk. Thus the observed thyroid findings do not establish the claimed absence of increased thyroid-malignancy risk, and the findings are limited to the trial’s follow-up and high-risk T2D population. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGLP-1 agents enhance insulin secretion in pancreatic b-cell and showed many benefits in treating type 2 diabetes mellitus but are not a common choice for GDM.
“GLP-1 agents, including dipeptidyl peptidase-4 (DPP-4) inhibitor and glucagon-like peptide-1 receptor agonist (GLP-1 Ra), enhance insulin secretion in pancreatic b-cell and showed many benefits in treating diabetes mellitus type 2 but are not a common choice for GDM [117,118].”
From Gestational Diabetes Mellitus—Recent Literature Review (2022) · cites this paper as [118]
The introduction reports that liraglutide, a GLP-1 analogue, is approved for type 2 diabetes and lowers glucose; the Discussion reports cardiovascular and microvascular benefits in the trial. The paper does not establish benefits for DPP-4 inhibitors, explain enhanced pancreatic beta-cell insulin secretion, or address whether these agents are commonly used for gestational diabetes (GDM). (LLM, conf=0.88)
Experimental — accuracy not yet measuredLiraglutide reduced the risk of new or worsening nephropathy (a composite of persistent macroalbuminuria, doubling of serum creatinine, ESKD, or death from ESKD) by 22%.
“liraglutide reduced the risk of new or worsening nephropathy (a composite of persistent macroalbuminuria, doubling of serum creatinine, ESKD, or death from ESKD) by 22%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [95]
The Results (Microvascular Outcomes; page unavailable) report a nephropathy hazard ratio of 0.78 for liraglutide versus placebo, corresponding to a 22% lower risk. The Methods (Outcomes; page unavailable) define the composite similarly, but require an eGFR of 45 ml/min/1.73 m² or less alongside doubled serum creatinine and specify continuous renal-replacement therapy or death from renal disease, rather than simply ESKD or death from ESKD. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe evidence supporting the cardiovascular benefits of GLP-1 receptor agonists is more compelling, likely because of the higher pharmacological GLP-1 levels achieved by GLP-1 receptor agonists compared to the physiological levels with DPP-4 inhibitors.
“the evidence supporting the cardiovascular benefits of GLP-1RAs is more compelling, 95 likely because of the higher pharmacological GLP-1 levels achieved by GLP-1RAs compared to the physiological levels with DPP-4 inhibitors.127”
From The effect of <scp>GLP</scp> ‐1 receptor agonists on circulating inflammatory markers in type 2 diabetes patients: A systematic review and meta‐analysis (2025) · cites this paper as [95]
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 measuredNo 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).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [261]
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 measuredLarge clinical trials have shown benefits of newer glucose-lowering medications on cardiovascular and kidney outcomes in patients with CKD with type 2 diabetes.
“Large clinical trials have shown benefits of newer glucose-lowering medications on cardiovascular and kidney outcomes in patients with CKD with type 2 diabetes.5, 6, 7, 8, 9, 10, 11, 12, 13, 14”
From Disparities in SGLT2 Inhibitor or Glucagon-Like Peptide 1 Receptor Agonist Initiation Among Medicare-Insured Adults With CKD in the United States (2023) · cites this paper as [13]
The Discussion and Results report that liraglutide reduced cardiovascular events and nephropathy events in a trial of people with type 2 diabetes; the Methods confirm that patients with CKD could be enrolled. The cardiovascular subgroup analysis suggests benefit at lower eGFR, but the reported kidney-outcome benefit is for the trial population overall, not specifically for patients with CKD. This paper also tests one medication rather than establishing the claim for newer medications generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLarge clinical trials have shown benefits of newer glucose-lowering medications on cardiovascular and kidney outcomes in patients with CKD with type 2 diabetes.
“Large clinical trials have shown benefits of newer glucose-lowering medications on cardiovascular and kidney outcomes in patients with CKD with type 2 diabetes.5, 6, 7, 8, 9, 10, 11, 12, 13, 14”
From Disparities in SGLT2 Inhibitor or Glucagon-Like Peptide 1 Receptor Agonist Initiation Among Medicare-Insured Adults With CKD in the United States (2023) · cites this paper as [11]
The Results (Cardiovascular Outcomes and Microvascular Outcomes; page numbers unavailable) report cardiovascular benefit in the lower-eGFR subgroup and fewer nephropathy events with liraglutide overall. The trial included patients with CKD, but the reported kidney-outcome benefit is not established specifically for patients with CKD; this paper also tests one medication, not newer medications as a class. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFive large randomized clinical trials demonstrated cardiovascular benefits and kidney protective benefits of SGLT2i.
“Five large randomized clinical trials (the EMPA-REG OUTCOME, the Canagliflozin Cardiovascular Assessment Study [CANVAS], the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 [DECLARE–TIMI 58], CREDENCE, and DAPA-CKD) demonstrated cardiovascular benefits, and kidney protective benefits of SGLT2i.5, 6, 7, 8,11,12,34”
From Disparities in SGLT2 Inhibitor or Glucagon-Like Peptide 1 Receptor Agonist Initiation Among Medicare-Insured Adults With CKD in the United States (2023) · cites this paper as [11]
The Discussion mentions cardiovascular benefits in the EMPA-REG OUTCOME trial of the SGLT2 inhibitor empagliflozin. It does not report benefits from the other four named SGLT2-inhibitor trials or kidney protection from SGLT2 inhibitors; its reported renal benefit concerns liraglutide (Results, Microvascular Outcomes). (LLM, conf=0.87)
Experimental — accuracy not yet measuredSignificant benefits of SGLT2i were shown among the subgroup patients (aged ≥65 years) in the study of EMPAREG, CANVAS, DECLARE, and DAPA-CKD.
“However, significant benefits of SGLT2i were shown among the subgroup patients (aged greater than or equal to 65 years) in the study of EMPAREG, CANVAS, DECLARE, and DAPA-CKD.6, 7, 8,11,12,34”
From Disparities in SGLT2 Inhibitor or Glucagon-Like Peptide 1 Receptor Agonist Initiation Among Medicare-Insured Adults With CKD in the United States (2023) · cites this paper as [11]
The Discussion describes cardiovascular benefits in the EMPA-REG OUTCOME trial of the SGLT2 inhibitor empagliflozin. It does not report whether those benefits were significant among patients aged 65 or older, or address the claimed subgroup findings in CANVAS, DECLARE, or DAPA-CKD. No page number is available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredMajor cardiovascular trials in patients with T2DM, including the LEADER, SUSTAIN-6, HARMONY Outcomes and REWIND trials, have collectively demonstrated a significant reduction in cardiovascular death with GLP-1RA therapy, ranging from 12% to 26%.
“Major cardiovascular trials in patients with T2DM, including the LEADER, SUSTAIN-6, HARMONY Outcomes and REWIND trials, 22 -25 have collectively demonstrated a significant reduction in cardiovascular death with GLP-1RA therapy, ranging from 12% to 26%.”
From <scp>Glucagon‐like peptide‐1 receptor agonists</scp> improve biomarkers of inflammation and oxidative stress: A systematic review and meta‐analysis of randomised controlled trials (2021) · cites this paper as [22]
Experimental — accuracy not yet measuredLarge cardiovascular outcome trials have shown that GLP-1RAs reduce major adverse cardiovascular events and slow progression of kidney disease in high-risk patients.
“Large cardiovascular outcome trials have shown that GLP‐1RAs reduce major adverse cardiovascular events and slow progression of kidney disease in high‐risk patients [1, 2, 3].”
GLP-1 receptor agonists have demonstrated cardiovascular and renal benefits.
“Initially approved for T2D management, GLP-1 RAs have also demonstrated cardiovascular and renal benefits [5–7].”
From Triple Agonism Based Therapies for Obesity (2025) · cites this paper as [6]
Experimental — accuracy not yet measuredThe LEADER trial with liraglutide showed a numerically higher, though non-significant, rate of diabetic retinopathy events compared to placebo (HR 1.15; 95% CI 0.87 to 1.52).
“Similarly, the LEADER trial with liraglutide showed a numerically higher, though non-significant, rate of diabetic retinopathy events compared to placebo (HR, 1.15; 95% CI, 0.87 to 1.52) [33].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [33]
The LEADER trial reported 18 cases of suspected acute pancreatitis in 4668 participants randomized to liraglutide versus 23 in 4672 with placebo.
“the LEADER trial comparing liraglutide and placebo in patients with T2D (18 cases in 4668 participants randomized to liraglutide treatment vs. 23 in 4672 with placebo treatment) (67).”
From The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications (2026) · cites this paper as [67]
Liraglutide 1.8 mg reduces MACE and cardiovascular mortality in type 2 diabetes.
“At 1.8 mg, it reduced MACE by 13% (primary outcome) and CV mortality by 22% in LEADER [34].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [34]
In the LEADER trial, a non-significant trend towards diabetic retinopathy was observed for liraglutide.
“in the LEADER trial, a non-significant trend towards DRP was observed for liraglutide”
From Safety of Semaglutide (2021) · cites this paper as [121]
In the LEADER trial, patients on liraglutide lost 2.3 kg more and were less likely (HR 0.87, 95% CI 0.78 to 0.97) to experience cardiovascular events than patients receiving placebo and standard of care.
“patients on liraglutide lost 2.3 kg more and were less likely (HR 0.87, 95% CI (0.78 to 0.97)) to experience cardiovascular events (13%) than patients receiving a placebo and standard of care (14.9%).”
GLP-1 receptor agonists (RAs) have also been shown to improve kidney outcomes.
“Glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) have also been shown to improve kidney outcomes (95-100).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [95]
The LEADER trial demonstrated that liraglutide reduced cardiovascular risk.
“Liraglutide was also demonstrated to reduce cardiovascular risk in the LEADER trial.9”
From Tirzepatide: Clinical review of the twincretin injectable (2023) · cites this paper as [9]
Certain GLP-1 receptor agonists are superior to placebo in reducing the risk of MACE.
“Similarly, previously mentioned clinical trials have demonstrated superiority of certain GLP-1 receptor agonists to placebo in reducing the risk of MACE.[7][8][9]”
From Tirzepatide: Clinical review of the twincretin injectable (2023) · cites this paper as [9]
Several medications in the SGLT-2 inhibitor and GLP-1 receptor agonist drug classes have been demonstrated to have cardiovascular and renal benefits for patients.
“As previously discussed, several medications in the SGLT-2 inhibitor and GLP-1 receptor agonist drug classes have been demonstrated to have cardiovascular and renal benefits for patients.[7][8][9][37][38][39]”
From Tirzepatide: Clinical review of the twincretin injectable (2023) · cites this paper as [9]
Recently, trials evaluating empagliflozin and liraglutide have shown improved cardiovascular outcomes in patients with type 2 diabetes who were at high risk for cardiovascular events.
“Recently, trials evaluating a sodium-glucose cotransporter 2 inhibitor (empagliflozin) and a glucagon-like peptide 1 (GLP-1) analogue (liraglutide) have shown improved cardiovascular outcomes in patients with type 2 diabetes who were at high risk for cardiovascular events.2,3”
From Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (2016) · cites this paper as [3]
To date, two antihyperglycemic agents have been shown to reduce the rate of cardiovascular events in patients with type 2 diabetes at high cardiovascular risk.
“To date, two antihyperglycemic agents have been shown to reduce the rate of cardiovascular events in patients with type 2 diabetes at high cardiovascular risk.2,3”
From Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (2016) · cites this paper as [3]
GLP-1 RAs have been shown to improve kidney outcomes.
“GLP-1 RAs have also been shown to improve kidney outcomes (104-109).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [104]
Compared with placebo, liraglutide reduced the risk of new or worsening nephropathy by 22%.
“liraglutide reduced the risk of new or worsening nephropathy (a composite of persistent macroalbuminuria, doubling of serum creatinine, kidney failure, or death from kidney failure) by 22%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [104]
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).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [261]
In LEADER, after a median follow-up of 3.8 years, the primary composite outcome of MI, stroke, or cardiovascular death occurred in fewer liraglutide-treated participants (13.0%) than placebo participants (14.9%) (HR 0.87 [95% CI 0.78-0.97]; P < 0.001 for noninferiority; P = 0.01 for superiority).
“After a median follow-up of 3.8 years, LEADER showed that the primary composite outcome (MI, stroke, or cardiovascular death) occurred in fewer participants in the treatment group (13.0%) than in the placebo group (14.9%) (HR 0.87 [95% CI 0.78-0.97];P < 0.001 for noninferiority; P = 0.01 for superiority).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [261]
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).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [261]
Results of trials with GLP-1 RAs liraglutide, semaglutide, albiglutide, efpeglenatide, and dulaglutide have all shown evidence of a reduction in major atherosclerotic cardiovascular outcomes (MI, stroke, or cardiovascular death).
“Results of trials with the GLP-1 RAs liraglutide (once daily) and semaglutide, albiglutide, efpeglenatide, and dulaglutide (once weekly) have all shown evidence of a reduction in major atherosclerotic cardiovascular outcomes (MI, stroke, or cardiovascular death) (251–256).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [251]
The clinical trials that may have impacted our results were CANVAS, EMPA-REG OUTCOME, SUSTAIN-6, and LEADER, all of which demonstrated significant cardiovascular and kidney benefits of SGLT-2i and GLP-1RA.
“The clinical trials that may have impacted our results were the CANVAS (canagliflozin, published 2017), EMPA-REG OUTCOME (empagliflozin, 2015), the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial (semaglutide, 2016), and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEAD”
From Disparities in SGLT2 Inhibitor or Glucagon-Like Peptide 1 Receptor Agonist Initiation Among Medicare-Insured Adults With CKD in the United States (2023) · cites this paper as [13]
The clinical trials that may have impacted our results were CANVAS, EMPA-REG OUTCOME, SUSTAIN-6, and LEADER, all of which demonstrated significant cardiovascular and kidney benefits of SGLT-2i and GLP-1RA.
“The clinical trials that may have impacted our results were the CANVAS (canagliflozin, published 2017), EMPA-REG OUTCOME (empagliflozin, 2015), the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial (semaglutide, 2016), and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEAD”
From Disparities in SGLT2 Inhibitor or Glucagon-Like Peptide 1 Receptor Agonist Initiation Among Medicare-Insured Adults With CKD in the United States (2023) · cites this paper as [11]
Large cardiovascular outcome trials and kidney outcome trials of SGLT2 inhibitors have shown robust and consistent reductions in heart failure hospitalization risk in people with type 2 diabetes.
“Multiple large CVOTs and kidney outcome trials of SGLT2is have demonstrated robust and consistent reductions in the risk of hospitalization for HF in persons with T2D.239,423,425,426,648”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [423]
The Discussion reports fewer heart-failure hospitalizations with liraglutide than with placebo, but says the difference was not significant. A search for SGLT2 inhibitors and kidney outcome trials found no passage in our copy addressing whether those trials consistently reduced heart-failure hospitalization risk. (LLM, conf=0.75)
Experimental — accuracy not yet measuredBased on the CREDENCE trial, canagliflozin reduces the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic nephropathy with albuminuria.
“Based on the CREDENCE trial,423 the FDA has given canagliflozin an indication to reduce the risk of end-stage kidney disease, doubling of serum creatinine, CV death, and hospitalization for HF in adults with T2D and diabetic nephropathy with albuminuria.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [423]
The Methods (Trial Design and Oversight) describe a trial of liraglutide versus placebo, and the Discussion reports outcomes for liraglutide. Searches for CREDENCE, canagliflozin, and the stated FDA indication found no passage addressing that claim; findings about a different drug do not contradict it. (LLM, conf=0.78)
Experimental — accuracy not yet measuredSGLT2 inhibitors continue to provide renal protective benefit at low eGFR (e.g., <45 mL/min/1.73 m2) even though their antihyperglycemic effect may diminish.
“Although the antihyperglycemic effect can be diminished with decreasing eGFR, studies have shown that SGLT2is continue to exert their renal protective benefit for those with low eGFRs (eg, <45 mL/min/1.73 m2).423”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [423]
The Methods (Procedures; page unavailable) identify liraglutide, not an SGLT2 inhibitor, as the trial treatment. The Discussion mentions empagliflozin only in a comparison of cardiovascular benefits; a search for SGLT2 renal protection at low eGFR and diminishing antihyperglycemic effect found no passage addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCompared with placebo, empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to UACR >300 mg/g creatinine, doubling of serum creatinine, ESKD, or death from ESKD) by 39%.
“Specifically, compared with placebo, empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to UACR >300 mg/g creatinine, doubling of serum creatinine, ESKD, or death from ESKD) by 39%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [95]
The Results (Microvascular Outcomes; page unavailable) report a reduction in nephropathy events with liraglutide, not empagliflozin. The Discussion mentions empagliflozin only in a comparison of cardiovascular outcomes. Searches for empagliflozin nephropathy and the claimed 39% reduction found no passage addressing that result. (LLM, conf=0.76)
Experimental — accuracy not yet measuredEmpagliflozin reduced the risk of doubling of serum creatinine accompanied by eGFR ≤45 mL/min/1.73m2 by 44%.
“and the risk of doubling of serum creatinine accompanied by eGFR #45 mL/min/1.73m 2 by 44%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [95]
The Methods > Outcomes passage defines doubling of serum creatinine with eGFR ≤45 mL/min/1.73 m² as part of this liraglutide trial’s nephropathy outcome. Results > Microvascular Outcomes reports a composite nephropathy benefit for liraglutide, not a 44% reduction in that specific outcome with empagliflozin. A search for empagliflozin renal outcomes found no passage reporting the claimed result. (LLM, conf=0.78)
Experimental — accuracy not yet measuredCanagliflozin reduced the risk of progression of albuminuria by 27%.
“canagliflozin reduced the risk of progression of albuminuria by 27%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [95]
The Results (Microvascular Outcomes; page not provided) report fewer nephropathy events with liraglutide than with placebo. A search for canagliflozin and a 27% reduction in albuminuria progression found no passage addressing that claim. The liraglutide finding does not establish or contradict a canagliflozin effect. (LLM, conf=0.78)
Experimental — accuracy not yet measuredCanagliflozin reduced the risk of reduction in eGFR, ESKD, or death from ESKD by 40%.
“and the risk of reduction in eGFR, ESKD, or death from ESKD by 40%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [95]
The Results (Microvascular Outcomes; page not provided) report fewer nephropathy events with liraglutide than with placebo, with a hazard ratio of 0.78. A search for canagliflozin and the claimed 40% reduction found no passage in our copy addressing that drug or that result; the liraglutide finding does not establish or contradict the claim about canagliflozin. (LLM, conf=0.78)
Experimental — accuracy not yet measuredCompared with placebo, empagliflozin reduced the risk of incident or worsening nephropathy by 39% and the risk of doubling of serum creatinine accompanied by eGFR ≤45 mL/min/1.73m2 by 44%.
“empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to UACR >300 mg/g creatinine, doubling of serum creatinine, kidney failure, or death from kidney failure) by 39% and the risk of doubling of serum creatinine accompanied by eGFR ≤45 mL/ min/1.73m 2 by 44%”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [104]
The Results (Microvascular Outcomes; page unavailable) report renal outcomes for liraglutide, not empagliflozin. The Discussion mentions empagliflozin only in a comparison of cardiovascular outcomes; a search for its nephropathy and creatinine results found neither the claimed 39% nor 44% reduction in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredPrior studies have reported substantial benefits of GLP-1 receptor agonists in reducing cardiovascular disease risk and promoting weight loss.
“Prior studies have reported substantial benefits of GLP-1 agonists in reducing cardiovascular disease (CVD) risk and promoting weight loss.1,2”
From GLP-1 receptor agonist discontinuation among patients with obesity and/or type 2 diabetes (2024) · cites this paper as [1]
The quality of evidence was assessed using the GRADE approach.
“The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. 33”
From Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials (2025) · cites this paper as [33]
Several cardiovascular outcomes trials have demonstrated that certain anti-diabetic treatments are associated with a lower risk of cardiovascular disease.
“Following these regulatory requirements, several cardiovascular outcomes trials (CVOT) have been completed, which demonstrate that certain anti-diabetic treatments are associated with a lower risk of CVD [17–20].”
From Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017 (2018) · cites this paper as [18]
Newer antidiabetic drugs have been shown to lower the risk of cardiovascular disease in type 2 diabetes patients.
“Newer antidiabetic drugs have been shown to lower the risk of CVD in T2DM patients [17–20]; however, these drugs are often intended to be used as second- to third-line treatments and many years may pass before patients can benefit.”
From Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017 (2018) · cites this paper as [18]
GLP-1 receptor agonists prevent the onset of macroalbuminuria.
“Emerging data support the efficacy of GLP-1RAs, in reducing the incidence of major adverse cardiovascular events (MACEs), preventing the onset of macroalbuminuria and slowing the progression of renal damage toward ESRD [5, 6]”
From GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art (2022) · cites this paper as [6]
GLP-1 receptor agonists reduce the incidence of major adverse cardiovascular events.
“Emerging data support the efficacy of GLP-1RAs, in reducing the incidence of major adverse cardiovascular events (MACEs), preventing the onset of macroalbuminuria and slowing the progression of renal damage toward ESRD [5, 6]”
From GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art (2022) · cites this paper as [6]
GLP-1 receptor agonists slow the progression of renal damage toward end-stage renal disease.
“Emerging data support the efficacy of GLP-1RAs, in reducing the incidence of major adverse cardiovascular events (MACEs), preventing the onset of macroalbuminuria and slowing the progression of renal damage toward ESRD [5, 6]”
From GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art (2022) · cites this paper as [6]
In the LEADER trial, eGFR decline was slower in the liraglutide group, most evident in patients with moderate or severe chronic kidney disease.
“The eGFR decline was slower in the liraglutide group; this effect was most evident in subcategories of patients with moderate (eGFR 30–59 mL/min/1.73 m2) or severe (eGFR <30 mL/min/1.73 m2) CKD.”
From GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art (2022) · cites this paper as [6]
In the LEADER trial, no significant differences were observed between liraglutide and placebo for renal hard endpoints.
“Regarding the renal composite outcome, in the liraglutide group the incidence of nephropathy was 22% lower than in placebo with a favourable impact especially on macroalbuminuria, while no significant differences were observed about renal hard endpoints.”
From GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art (2022) · cites this paper as [6]
In the LEADER trial, liraglutide reduced the incidence of nephropathy by 22% compared with placebo, with a favourable impact especially on macroalbuminuria.
“Regarding the renal composite outcome, in the liraglutide group the incidence of nephropathy was 22% lower than in placebo with a favourable impact especially on macroalbuminuria, while no significant differences were observed about renal hard endpoints.”
From GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art (2022) · cites this paper as [6]
GLP1-RA have been shown to reduce MACE in patients with T2D with A1c elevation >6.5%, who were at high cardiovascular risk or had established CVD.
“GLP1-RA have been shown to reduce MACE in patients with T2D with A1c elevation >6.5%, who were at high cardiovascular risk or had established CVD (Table 1) [37], [38], [39], [40], [41].”
From Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: a review of their kidney and heart protection (2023) · cites this paper as [37]
Obesity medications have, to date, not been shown to reduce cardiovascular events.
“Given the additional beneficial effects of GLP-1 RAs and SGLT2 inhibitors on CV outcomes in T2DM (Section 5.3), these agents should be the preferred glucose-lowering medication in overweight and obese patients with CVD and T2DM, as obesity medications have, to date, not shown to reduce CV events.[70][71][72]”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [70]
Most GLP-1 receptor agonists had a neutral effect on risk of heart failure hospitalization in placebo-controlled randomized controlled trials assessing cardiovascular safety of glucose-lowering medications in patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, despite increasing heart rate by 3-5 b.p.m.
“Most GLP-1 RAs had a neutral effect on risk of HF hospitalization in the placebo-controlled RCTs assessing CV safety of glucose-lowering medications in patients with T2DM with or at high risk of ASCVD, despite increasing heart rate by 3-5 b.p.m. 70,72,158- 163,544”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [70]
GLP-1 receptor agonists (lixisenatide, liraglutide, semaglutide, exenatide ER, dulaglutide, efpeglenatide) have a neutral effect on the risk of heart failure hospitalization.
“GLP-1 RAs (lixisenatide, liraglutide, semaglutide, exenatide ER, dulaglutide, efpeglenatide) have a neutral effect on the risk of HF hospitalization, and should be considered for glucose-lowering treatment in patients with T2DM at risk of or with HF. 70,158-164,545 IIa A”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [70]
Liraglutide reduced major adverse cardiovascular events in LEADER, at least in the lower doses used for type 2 diabetes.
“liraglutide, which reduced MACEs in the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), at least in the lower doses used for T2DM”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [17]
Several cardiovascular outcomes trials demonstrated that drugs lowering HbA1c to similar levels had different effects on cardiovascular outcomes.
“several cardiovascular outcomes trials (CVOTs) demonstrated that drugs that lowered HbA1c to similar levels had different effects on cardiovascular outcomes”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [17]
In LEADER, liraglutide led to a 13% relative risk reduction in major adverse cardiovascular events (13.0% versus 14.9%) in 9340 patients with overt or at high risk for cardiovascular disease.
“liraglutide led to a 13% RRR in MACEs (13.0% versus 14.9%)”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [17]
In LEADER, liraglutide led to a 22% relative risk reduction in cardiovascular death (4.7% versus 6.0%).
“and a 22% RRR in cardiovascular death (4.7% versus 6.0%)”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [17]
In LEADER, after a median follow-up of 3.8 years, liraglutide reduced the primary composite outcome of myocardial infarction, stroke, or cardiovascular death compared with placebo (13.0% versus 14.9%; HR 0.87, 95% CI 0.78-0.97; P<0.001 for noninferiority; P=0.01 for superiority).
“After a median follow-up of 3.8 years, LEADER showed that the primary composite outcome (MI, stroke, or cardiovascular death) occurred in fewer participants in the treatment group (13.0%) when compared with the placebo group (14.9%) (HR 0.87 [95% CI 0.78 -0.97]; P < 0.001 for noninferiority; P = 0.01 for superiority).”
From 10. Cardiovascular Disease and Risk Management: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [203]
In LEADER, liraglutide significantly reduced cardiovascular deaths compared with placebo (4.7% versus 6.0%; HR 0.78, 95% CI 0.66-0.93; P=0.007).
“Deaths from cardiovascular causes were signi fi cantly 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) (203).”
From 10. Cardiovascular Disease and Risk Management: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [203]
Cardiovascular outcomes trials of the GLP-1 receptor agonists lixisenatide, liraglutide, semaglutide, exenatide once-weekly, albiglutide, and dulaglutide have not identified increased heart failure hospitalization risk compared with placebo.
“No increased risk of heart failure hospitalization has been identi fi ed in the cardiovascular outcomes trials of the GLP-1 receptor agonists lixisenatide, liraglutide, semaglutide, exenatide once-weekly, albiglutide, or dulaglutide compared with placebo ( Table 10.3 B ) (203,204,207 -209).”
From 10. Cardiovascular Disease and Risk Management: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [203]
Numerous large randomized controlled trials report statistically significant reductions in cardiovascular events for four FDA-approved GLP-1 receptor agonists: liraglutide, albiglutide, semaglutide, and dulaglutide.
“and four FDA-approved GLP-1 receptor agonists (liraglutide, albiglutide [although that agent was removed from the market for business reasons], semaglutide [lower risk of cardiovascular events in a moderate-sized clinical trial but one not powered as a cardiovascular outcomes trial], and dulaglutide).”
From 10. Cardiovascular Disease and Risk Management: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [203]
GLP-1 analogues appear to decrease the risk of cardiovascular pathology in patients according to some studies, and preliminary data suggest they do so to a greater degree than other oral glucose-lowering drugs.
“Additionally, GLP-1 analogues also appear to decrease the risk of cardiovascular pathology in patients, according to some studies, and preliminary data suggest they do so to a greater degree than other oral glucose-lowering drugs.262,275–277”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [276]
Glucagon-like peptide-1 receptor agonists are currently the most effective drugs for lowering weight.
“Glucagon-like peptide-1 receptor agonists (GLP1-RAs) are the currently most efficacious weight lowering drugs.”
The safety profile of liraglutide and semaglutide is well documented, with gastrointestinal side effects that are usually transient and mild to moderate.
“The efficacy and safety profile of the GLP1-RAs liraglutide and semaglutide are well-documented, with an average body weight loss of up to 15%, usually transient mild to moderate gastrointestinal side effects, and cardiorenal benefits [6–8].”
Liraglutide improves cardiovascular outcomes in patients with type 2 diabetes.
“The LEADER study in high-risk patients with T2D reported that the GLP-1 RA liraglutide improved CVD outcomes (20).”
From Effect of liraglutide on atrial natriuretic peptide, adrenomedullin, and copeptin in PCOS (2018) · cites this paper as [20]
The LEADER study demonstrated improvement in CVD outcomes despite an increase in heart rate of 3 bpm.
“The LEADER study demonstrated improvement in CVD outcomes despite an increase in the heart rate of 3 bpm (20).”
From Effect of liraglutide on atrial natriuretic peptide, adrenomedullin, and copeptin in PCOS (2018) · cites this paper as [20]
Compared with other anti-obesity drugs, liraglutide does not contribute to the incidence of CVD in obese patients with T2DM.
“Compared with other anti-obesity drugs, one of the main benefits of liraglutide is that it does not contribute to the incidence of CVD in obese patients with T2DM [64].”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [64]
A longer duration of 8-15 years after strict glycemic control is necessary for the suppression of ASCVD risk.
“However, a longer duration of 8–15 years after strict glycemic control is necessary for the suppression of ASCVD risk797, 798).”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [798]
Possible mechanisms of action on the cardiovascular system of GLP-1RAs include anti-inflammatory, antiatherosclerotic, vasodilatory, and other hemodynamic effects, and life-long exposure of GLP-1 is associated with prevention of HF.
“Possible mechanisms of action on the cardiovascular system of GLP-1RAs include anti-inflammatory, antiatherosclerotic, vasodilatory, and other hemodynamic effects, and life-long exposure of GLP-1 is associated with prevention of HF.22, 23, 24”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [23]
GLP-1 receptor agonists provide weight loss and cardiovascular protective effects.
“In addition to providing control of diabetes mellitus, GLP-1 receptor agonists have shown to provide weight loss and cardiovascular protective effects [12–15].”
From Effects of Semaglutide Versus Dulaglutide on Epicardial Fat Thickness in Subjects with Type 2 Diabetes and Obesity (2020) · cites this paper as [13]
GLP-1 receptor agonists as a class reduced major adverse cardiovascular events.
“Clinical trials found that GLP-1 receptor agonists as a class reduced major adverse cardiovascular events [12–15].”
From Effects of Semaglutide Versus Dulaglutide on Epicardial Fat Thickness in Subjects with Type 2 Diabetes and Obesity (2020) · cites this paper as [13]
GLP-1RAs are associated with substantial weight loss of 1.5 to 4.3 kg in trials with follow-up of 1.3 to 5.4 years.
“In addition, GLP-1RAs have a favorable safety profile and have been associated with substantial weight loss.4,6,7,9”
From Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review (2020) · cites this paper as [6]
GLP-1RA therapy has a favorable safety profile.
“GLP-1RA therapy has a favorable safety profile.”
From Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review (2020) · cites this paper as [6]
GLP-1RAs reduce cardiovascular events in at-risk individuals with type 2 diabetes.
“Recent randomized clinical trials have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce cardiovascular events in at-risk individuals with type 2 diabetes.”
From Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review (2020) · cites this paper as [6]
Randomized clinical trials of albiglutide, dulaglutide, liraglutide, and injectable semaglutide have reported favorable cardiovascular outcomes.
“To date, randomized clinical trials of albiglutide, dulaglutide, liraglutide, and injectable semaglutide have reported favorable cardiovascular outcomes.”
From Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review (2020) · cites this paper as [6]
Not all DPP4 inhibitors are associated with higher rates of HF.
“Not all DPP4 inhibitors are associated with higher rates of HF (Table 8).16 -24,184-186”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [22]
In large placebo-controlled trials in patients with T2DM and CV disease or at high risk of CV disease, GLP-1 receptor agonists had a neutral effect on the risk for HF hospitalization.
“In these trials, GLP-1 receptor agonists had a neutral effect on the risk for HF hospitalization.”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [22]
In the LEADER trial, SBP was significantly lower in the liraglutide group.
“SBP was also significantly lower in the liraglutide group.”
From The Vasculature in Prediabetes (2018) · cites this paper as [209]
In the LEADER trial, patients in the liraglutide group lost 2.3 kg more than the placebo group.
“Patients in the liraglutide group lost 2.3 kg more than the placebo treatment group.”
From The Vasculature in Prediabetes (2018) · cites this paper as [209]
Long-acting GLP-1 agonists reduce mortality in patients with T2DM.
“Importantly, long-acting GLP-1 agonists reduce mortality in patients with T2DM.”
From The Vasculature in Prediabetes (2018) · cites this paper as [209]
In the LEADER trial, liraglutide 1.8 mg/d reduced the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with T2DM and high cardiovascular risk compared to placebo (from 14.9% to 13%, HR 0.87, 95% CI 0.78-0.97, P=0.01).
“In the Liraglutide Effect and Action in Diabetes of Cardiovascular Outcomes Results (LEADER) trial, liraglutide 1.8 mg/d reduced the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with T2DM and high cardiovascular risk compared to placebo (from 14.9% to 13%, HR 0.87, 95% CI 0.78-0.97, P=0.01).209”
From The Vasculature in Prediabetes (2018) · cites this paper as [209]
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“There are some benefits with respect to macrovascular complications, but this is dependent on the profile of individual drug classes and even appears to be different for agents within the same class.88 The role of BP lowering to improve prognosis in T2D has been established since the UK Prospective Diabetes Study (UKP…”
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“Numbers in symbols identify the clinical trials: 1: REWIND (dulaglutide) [98], 4: LEADER (liraglutide) [96], 5: EXCSEL (once-weekly exeDECLARE-TIMI-58 (dapagliflozin) [121], 9: CANVAS program (canagliflozin) [122]; 10: es Association); 11: EXAMINE (alogliptin) [123], 12 CARMELINA (linagliptin) [124], 13:”
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“Glucagon-like peptide 1 receptor antagonists reduce the accumulation of epicardial adipose tissue (186,187), but importantly, they do not ameliorate its anti-inflammatory properties or its secretion of proinflammatory adipokines (188,189); accordingly, these drugs have not reduced the incidence of serious heart failur…”
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“Interestingly, in the SUSTAIN-6 and LEADER trials, the GLP-1 agonists semaglutide and liraglutide, respectively, reduced the incidence of nephropathy [60, 64]—these benefits were not observed with the exendin-4 based lixisenatide and exenatide in their respective CV outcome trials [65, 66].”
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- Authors
- Marso, S. P., Daniels, G. H., Brown-Frandsen, K., Kristensen, P., Mann, J. F. E., Nauck, M. A., Nissen, S. E., Pocock, S., Poulter, N. R., Ravn, L. S., Steinberg, W. M., Stockner, M., Zinman, B., Bergenstal, R. M., & Buse, J. B.
- Affiliations
- Cleveland Clinic (US)
- Mount Sinai Hospital (CA)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-07-28
- Volume
- 375
- Issue
- 4
- Pages
- 311-322
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4985288
- OpenAlex
- W2425644022
- Cited by
- 7,629
- References
- 25
- Citations by year
- 2026: 834 · 2025: 809 · 2024: 643 · 2023: 602 · 2022: 639 · 2021: 745 · 2020: 845 · 2019: 769 · 2018: 814 · 2017: 675 · 2016: 244 · 2015: 1 · 2014: 3 · 2013: 2
- FWCI
- 837.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (acceptedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- Digital Collections portal (Koç University) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Celgene
- Massachusetts Medical Society
- Intarcia Therapeutics
- Orexigen Therapeutics
- ResMed
- Novo Nordisk
- Esperion Therapeutics
- National Institutes of Health (UL1TR001111, UL1TR002489)
- Relypsa
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- type 2 diabetes, cardiovascular outcomes, GLP-1 receptor agonists, myocardial infarction, stroke, cardiovascular mortality, heart failure hospitalization, pancreatitis, gastrointestinal adverse effects, non-inferiority, high cardiovascular risk patients, GLP-1 receptor antagonists
- MeSH terms
- Liraglutide, Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Gastrointestinal Diseases, Humans, Hypoglycemic Agents, Male, Middle Aged, Myocardial Infarction, Treatment Outcome, Stroke
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read under definition version 3 (extract-v3) on 2026-09-28.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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