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GLP-1 receptor agonists and tirzepatide in cardiovascular disease

Incretin-based drugs as cardiovascular therapy, from receptor pharmacology and the outcome trials in diabetes, obesity, heart failure, kidney disease, and peripheral artery disease through agent choice, dosing, adverse effects, and periprocedural management.

Incretin biology and the GLP-1 receptor

The incretin effect is the larger insulin response to oral glucose than to an isoglycemic intravenous glucose infusion. Two gut hormones account for it. GLP-1 is secreted by enteroendocrine L cells of the distal ileum and colon in response to nutrients. GIP is secreted by K cells of the duodenum and proximal jejunum. Both stimulate insulin secretion in a glucose-dependent manner, which is why neither causes hypoglycemia on its own. GLP-1 also suppresses glucagon secretion, slows gastric emptying, and acts on hypothalamic and hindbrain centers to reduce appetite and food intake. GIP stimulates glucagon at low glucose concentrations and acts on adipose tissue and the central nervous system. In type 2 diabetes the insulinotropic response to GIP is blunted. The response to pharmacologic GLP-1 is largely preserved, which made the GLP-1 receptor the first therapeutic target.

Native GLP-1(7–37) has a plasma half-life of 1.5 to 2 minutes because dipeptidyl peptidase 4 (DPP-4) and neutral endopeptidase degrade it. Two drug strategies follow. DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) raise endogenous GLP-1 and GIP to physiologic concentrations; they lower glucose modestly, are weight-neutral, and were neutral for major adverse cardiovascular events in their outcome trials. GLP-1 receptor agonists resist DPP-4 and achieve pharmacologic receptor stimulation, which produces weight loss and the cardiovascular effects described on this page.

The GLP-1 receptor is a class B G protein–coupled receptor that signals mainly through Gαs, adenylyl cyclase, and cyclic adenosine monophosphate (cAMP), with downstream protein kinase A and exchange protein activated by cAMP. It is expressed on pancreatic beta cells, in the hypothalamus and brainstem, and in the stomach and intestine (most strongly in duodenal Brunner glands). It is also expressed in the smooth muscle of arteries and arterioles of the kidney and lung, including the preglomerular vasculature. In primate and human hearts, receptor protein is localized to myocytes of the sinoatrial node, which accounts for the direct chronotropic effect. GLP1R messenger RNA is present in all four human cardiac chambers, but the ventricular cell type that expresses the receptor protein has not been identified. The direct inotropic benefit suggested by early animal work did not translate into improvement in reduced ejection fraction. Receptor expression on monocytes and macrophages in experimental models provides a plausible substrate for anti-inflammatory and antiatherosclerotic effects.

GLP-1 receptor agonists produce a modest natriuresis, attributed in experimental studies to inhibition of the proximal tubular sodium–hydrogen exchanger 3; in primate kidney the receptor protein has been localized to vascular smooth muscle and not in tubular epithelium. The effect is acute and small, and it partly overlaps with the tubular actions of sodium-glucose cotransporter 2 (SGLT2) inhibitors. Glucagon receptor agonism, added in triple agonists such as retatrutide, increases energy expenditure and hepatic fat oxidation and has its own chronotropic effect.

Structure and pharmacokinetics of the individual agents

The agents differ in structure, homology to human GLP-1, half-life, and route. Human GLP-1–based agents (liraglutide, semaglutide, dulaglutide, albiglutide) consistently reduced cardiovascular events in their outcome trials, whereas exendin-4–based agents (exenatide, lixisenatide) were neutral; efpeglenatide, an exendin-based agent, was the exception and reduced events. The meta-analysis of the outcome trials found no significant heterogeneity by structural homology, so trial design, population, duration, and dose explain part of the difference. The agents with proven benefit are preferred when cardiovascular protection is the goal.

Long half-lives are achieved by three methods: fatty acid acylation with reversible albumin binding (liraglutide with a C16 chain, semaglutide with a C18 diacid, tirzepatide with a C20 diacid), fusion to a large carrier protein (dulaglutide to an immunoglobulin G4 Fc fragment, albiglutide to albumin), and extended-release formulation (exenatide in microspheres). Albumin binding or Fc fusion also limits renal clearance, so semaglutide, liraglutide, dulaglutide, and tirzepatide require no dose adjustment for kidney function.

Structure, half-life, route, and cardiovascular outcome trial for each incretin-based agent. Half-lives from the US prescribing information where stated. SNAC, sodium N-(8-[2-hydroxybenzoyl]amino) caprylate; HFpEF, heart failure with preserved ejection fraction. Lixisenatide and albiglutide are no longer marketed in the United States.

Tirzepatide. Tirzepatide is a single peptide that activates both the GIP and GLP-1 receptors. It is weighted toward GIP receptor activity, and its GLP-1 receptor signaling is biased toward cAMP generation with less receptor internalization than native GLP-1. The contribution of GIP agonism to its greater weight loss is still debated, because GIP receptor antagonism also lowers weight in development programs. At maximal doses tirzepatide produces about 20% weight loss in obesity without diabetes, compared with about 14% to 15% for semaglutide 2.4 mg, and head-to-head data confirm the difference.

Oral semaglutide. Semaglutide is absorbed in the stomach with the help of the coformulated enhancer SNAC, which raises local pH and protects the peptide from pepsin. Absolute bioavailability is only about 0.4% to 1% for the 3-, 7-, and 14-mg tablets (Rybelsus), and about 1% to 2% for a newer formulation of 1.5, 4, and 9 mg (marketed as Ozempic tablets). The two oral formulations are not interchangeable milligram for milligram. Each tablet is taken on an empty stomach on waking with no more than 4 ounces of water, and food, drink, and other oral drugs are deferred for at least 30 minutes. A 25-mg tablet (Wegovy tablets) is labeled for weight reduction and for reduction of cardiovascular events in established cardiovascular disease with overweight or obesity.

Orforglipron. Orforglipron is a nonpeptide small molecule that is taken once daily without food or water restrictions. In ATTAIN-1, 3,127 adults with obesity without diabetes lost 7.5%, 8.4%, and 11.2% of body weight at 72 weeks with 6, 12, and 36 mg, compared with 2.1% with placebo, and adverse events led to discontinuation in 5.3% to 10.3% versus 2.7%. It was approved by the US Food and Drug Administration (FDA) for chronic weight management in 2026 (Foundayo). The labeled tablet strengths differ from the trial doses: treatment starts at 0.8 mg daily and is escalated at intervals of at least 30 days to 2.5 mg and 5.5 mg. Further escalation proceeds to 9 mg, 14.5 mg, or a maximum of 17.2 mg according to response and tolerance. Its weight loss is smaller than that of injectable semaglutide 2.4 mg or tirzepatide, and its cardiovascular outcome data are pending.

Mechanisms of cardiovascular benefit

The cardiovascular benefit of GLP-1 receptor agonists is not explained by glucose lowering. In the diabetes outcome trials the hemoglobin A1c (HbA1c) difference from placebo was small (0.4 percentage points in LEADER at 36 months), and intensive glucose lowering with other drugs in earlier trials had not reduced macrovascular events to a comparable degree in a comparable time. The benefit appears within the first 1 to 2 years, is concentrated in atherosclerotic events, and occurs in patients with and without diabetes.

Mechanisms and magnitude of the cardiovascular effects of GLP-1 receptor agonists. MACE, major adverse cardiovascular events; VLDL, very-low-density lipoprotein; eGFR, estimated glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction.

Benefit beyond weight loss. A prespecified SELECT analysis examined how baseline adiposity and weight change related to events. Semaglutide reduced events consistently across all categories of baseline weight and waist circumference. Within the semaglutide group, weight loss in the first 20 weeks did not predict subsequent risk. Reduction in waist circumference was associated with lower risk, and an estimated one-third of the benefit was mediated through waist circumference reduction. The cardioprotective effect therefore does not depend on the amount of weight lost, and a patient who loses little weight on semaglutide is not a treatment failure from the cardiovascular perspective. The early separation of the event curves in SELECT, before maximal weight loss, supports the same conclusion.

Atherosclerotic events and heart failure respond differently. In the diabetes trials the benefit was concentrated in atherosclerotic events (myocardial infarction, stroke, cardiovascular death), with only a modest reduction in heart failure hospitalization. SGLT2 inhibitors show the reverse pattern: large reductions in heart failure hospitalization and kidney outcomes with smaller effects on atherosclerotic events. In obesity-related HFpEF, where adiposity drives plasma volume expansion, pericardial restraint, and inflammation, incretin-based weight loss does reduce heart failure events.

Cardiovascular outcome trials in type 2 diabetes

In 2008 the FDA required new glucose-lowering drugs to exclude an unacceptable increase in cardiovascular risk, typically by ruling out a hazard ratio of 1.3 for MACE. The resulting cardiovascular outcome trials were designed for noninferiority, and several then showed superiority. In each trial the primary outcome was 3-point MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), except ELIXA, which added hospitalization for unstable angina.

Cardiovascular outcome trials of incretin-based drugs in type 2 diabetes. MACE, cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (ELIXA added hospitalization for unstable angina). T2D, type 2 diabetes; ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease; CKD, chronic kidney disease; ASCVD, atherosclerotic cardiovascular disease; ER, extended release; CI, confidence interval.

ELIXA. Lixisenatide, a short-acting exendin-based agent, was tested in 6,068 patients within 180 days of an acute coronary syndrome. It was noninferior but not superior to placebo for the expanded MACE outcome, with no difference in heart failure hospitalization (hazard ratio 0.96) or death (hazard ratio 0.94). ELIXA established safety after acute coronary syndrome and showed that a short-acting exendin agent with modest weight effect did not reduce events over 2 years.

LEADER. Liraglutide 1.8 mg daily reduced 3-point MACE in 9,340 patients at high cardiovascular risk, most with established cardiovascular disease or chronic kidney disease. Cardiovascular death fell from 6.0% to 4.7% (hazard ratio 0.78; 95% CI 0.66 to 0.93) and all-cause death from 9.6% to 8.2% (hazard ratio 0.85; 95% CI 0.74 to 0.97). Nonfatal myocardial infarction, nonfatal stroke, and heart failure hospitalization (hazard ratio 0.87; 95% CI 0.73 to 1.05) were nonsignificantly lower. The nephropathy outcome, driven by less new macroalbuminuria, was reduced (hazard ratio 0.78). Heart rate was 3.0 beats/min higher, systolic blood pressure 1.2 mm Hg lower, and weight 2.3 kg lower with liraglutide at 36 months. Acute gallstone disease occurred in 3.1% versus 1.9%, and pancreatitis was not increased.

SUSTAIN-6. Weekly semaglutide was tested in a preapproval safety trial of 3,297 patients over 104 weeks. MACE was 26% lower (hazard ratio 0.74; 95% CI 0.58 to 0.95), driven by nonfatal stroke (1.6% versus 2.7%; hazard ratio 0.61) and a nonsignificant reduction in nonfatal myocardial infarction (hazard ratio 0.74). Cardiovascular death was similar. The trial was designed for noninferiority, so superiority was not formally tested. Diabetic retinopathy complications were more frequent (hazard ratio 1.76; 95% CI 1.11 to 2.78), a finding discussed below.

EXSCEL. Once-weekly exenatide was tested in the largest of the early trials, 14,752 patients, 73% with prior cardiovascular disease. MACE fell nonsignificantly (hazard ratio 0.91; 95% CI 0.83 to 1.00; P=0.06 for superiority). Proposed explanations for the absence of a significant reduction are high rates of early discontinuation and the exendin structure. Heart failure hospitalization, pancreatitis, and medullary thyroid carcinoma did not differ.

Harmony Outcomes. Albiglutide reduced MACE by 22% in 9,463 patients with established cardiovascular disease over a median 1.6 years, mostly through fewer myocardial infarctions. The drug had been withdrawn from the market for commercial reasons before the result was published, so the trial is cited as evidence for the class, not for a usable drug.

REWIND. Dulaglutide 1.5 mg weekly was tested in 9,901 patients aged 50 years or older, most of whom had cardiovascular risk factors without established cardiovascular disease, with a median HbA1c of 7.2%. Over a median 5.4 years, the longest follow-up of the series, MACE fell from 13.4% to 12.0% (hazard ratio 0.88; 95% CI 0.79 to 0.99), and the effect was consistent in patients with and without prior cardiovascular disease. Nonfatal stroke was the component most reduced. All-cause death was not significantly lower (hazard ratio 0.90). Gastrointestinal adverse events occurred in 47.4% versus 34.1%. REWIND is the basis for the dulaglutide indication that includes patients with multiple cardiovascular risk factors.

PIONEER 6 and SOUL. PIONEER 6 was a safety trial of oral semaglutide in 3,183 high-risk patients over a median 15.9 months. MACE was nonsignificantly lower (hazard ratio 0.79), with fewer cardiovascular deaths (0.9% versus 1.9%; hazard ratio 0.49) and deaths from any cause (1.4% versus 2.8%; hazard ratio 0.51), findings that the trial was not powered to test. SOUL then tested oral semaglutide up to 14 mg in 9,650 patients aged 50 years or older with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both. Over a mean follow-up of 47.5 months (median 49.5 months), MACE was 14% lower (12.0% versus 13.8%; hazard ratio 0.86; 95% CI 0.77 to 0.96). SOUL established that the oral formulation provides cardiovascular benefit similar to the injectable formulation and led to a labeled indication to reduce MACE in adults with type 2 diabetes at high risk.

AMPLITUDE-O. Efpeglenatide reduced MACE by 27% and a composite kidney outcome by 32% in 4,076 patients with type 2 diabetes and cardiovascular disease or an eGFR of 25 to 59.9 mL/min/1.73 m² with another risk factor. Randomization was stratified by SGLT2 inhibitor use, so AMPLITUDE-O contributed early evidence that benefit is additive to SGLT2 inhibition. Efpeglenatide was not marketed.

Pooled effects on death, stroke, myocardial infarction, and heart failure

A 2021 meta-analysis of eight placebo-controlled trials (60,080 patients: ELIXA, LEADER, SUSTAIN-6, EXSCEL, Harmony Outcomes, REWIND, PIONEER 6, AMPLITUDE-O) estimated the class effect in type 2 diabetes.

Pooled hazard ratios from a 2021 meta-analysis of eight placebo-controlled trials. Each MACE component (cardiovascular death, myocardial infarction, and stroke) was reduced. Severe hypoglycemia, retinopathy, pancreatitis, and pancreatic cancer were not increased in the pooled data.

There was no significant heterogeneity by structural homology to human GLP-1, dosing interval, baseline HbA1c, presence of cardiovascular disease, body mass index, age, or eGFR. Stroke reduction is one of the most consistent findings across individual trials (SUSTAIN-6, REWIND) and in pooled analyses, which distinguishes GLP-1 receptor agonists from SGLT2 inhibitors, whose trials showed no stroke reduction. The heart failure reduction is modest and smaller than with SGLT2 inhibitors. Later trials (SOUL, FLOW, SURPASS-CVOT) are consistent with these estimates. Atherosclerotic disease in diabetes as a whole, including glucose targets and other glucose-lowering classes, is covered in Diabetes and cardiovascular disease.

Tirzepatide versus dulaglutide: SURPASS-CVOT

SURPASS-CVOT was the first cardiovascular outcome trial of a dual incretin agonist and the first to use an active GLP-1 receptor agonist comparator with proven benefit. A placebo comparator was considered unethical in patients with established atherosclerotic disease. A total of 13,299 patients with type 2 diabetes and atherosclerotic cardiovascular disease (mean age 64 years, mean body mass index 32.6 kg/m², mean HbA1c 8.4%, mean diabetes duration 14.7 years) were randomized to tirzepatide up to 15 mg weekly or dulaglutide 1.5 mg weekly.

Over a median follow-up of about 4 years, MACE occurred in 12.2% with tirzepatide and 13.1% with dulaglutide (hazard ratio 0.92; 95.3% CI 0.83 to 1.01). Tirzepatide met noninferiority (margin 1.05; P=0.003) but not superiority (P=0.09). All-cause death was lower with tirzepatide (hazard ratio 0.84; 95% CI 0.75 to 0.94), a secondary result outside the multiplicity-controlled hierarchy. Weight, HbA1c, and eGFR decline favored tirzepatide. Gastrointestinal adverse events were more frequent with tirzepatide, and other adverse events were similar. In the 20% of patients with a history of heart failure, results were consistent with the overall trial, and heart failure endpoints did not differ between the drugs.

Because dulaglutide itself reduced MACE by 12% against placebo in REWIND, indirect comparison suggests that tirzepatide reduces events by roughly a fifth to a quarter against placebo. That estimate is inferential. In 2026 the FDA added a labeled indication for tirzepatide (Mounjaro) to reduce MACE in adults with type 2 diabetes at high risk, based on SURPASS-CVOT. SURMOUNT-MMO, a placebo-controlled outcome trial of tirzepatide in adults with obesity without diabetes that includes heart failure events in its primary composite, has not reported.

Semaglutide in overweight and obesity without diabetes: SELECT

SELECT tested whether a GLP-1 receptor agonist reduces atherosclerotic events in patients without diabetes, so that the effect could not be attributed to glucose lowering. The trial enrolled 17,604 patients aged 45 years or older with established cardiovascular disease (prior myocardial infarction, stroke, or symptomatic peripheral artery disease) and a body mass index of 27 kg/m² or more, without diabetes. Mean age was 61.6 years and mean body mass index 33.4 kg/m². Semaglutide was escalated over 16 weeks to 2.4 mg weekly.

SELECT, mean follow-up 39.8 months. Because cardiovascular death, the first confirmatory secondary outcome, did not reach significance, the remaining secondary outcomes were not formally tested for superiority and are interpreted as supportive.

The 20% reduction in MACE, driven mainly by myocardial infarction, was consistent across subgroups of age, sex, race, and baseline body mass index. The benefit is additive to contemporary secondary prevention: most patients were taking statins and antiplatelet therapy. The number of patients who discontinued for adverse events, mostly gastrointestinal, was twice that with placebo. SELECT led to the first FDA indication of a weight-management drug to reduce cardiovascular events, in adults with established cardiovascular disease and either obesity or overweight. The indication includes semaglutide injection (Wegovy), with a maintenance dose of 2.4 mg (or 1.7 mg if 2.4 mg is not tolerated), and the 25-mg Wegovy tablet.

SELECT does not address primary prevention in obesity without established cardiovascular disease, where evidence for event reduction is lacking. Eligibility and the wider management of obesity, including lifestyle therapy and metabolic surgery, are covered in Obesity, metabolic syndrome and cardiovascular disease.

Heart failure events in the diabetes and obesity outcome trials

Heart failure was a secondary outcome in all the diabetes trials. Hospitalization for heart failure was nonsignificantly lower in LEADER and neutral in ELIXA and EXSCEL, and the pooled reduction was 11%. In SELECT, 4,286 patients (24.3%) had investigator-reported heart failure at enrollment: 53% with preserved ejection fraction, 31% with reduced ejection fraction, and 16% unclassified. Semaglutide reduced MACE (hazard ratio 0.72; 95% CI 0.60 to 0.87) and the heart failure composite (hazard ratio 0.79; 95% CI 0.64 to 0.98) in these patients, with similar point estimates in both ejection fraction groups. In SOUL, 23.1% had heart failure at baseline. Oral semaglutide reduced the composite of heart failure hospitalization, urgent visit, or cardiovascular death in those with heart failure (hazard ratio 0.78; 95% CI 0.63 to 0.96), most clearly in preserved ejection fraction (hazard ratio 0.59). It did not reduce the composite in those without heart failure (hazard ratio 1.01). These subgroup analyses are hypothesis-generating, but they do not show harm in stable patients with heart failure who also have atherosclerotic disease.

GLP-1 receptor agonists in heart failure with reduced ejection fraction

Two dedicated randomized trials tested liraglutide in reduced ejection fraction, and neither showed benefit.

FIGHT. FIGHT enrolled 300 patients with a left ventricular ejection fraction (LVEF) of 40% or less (median 25%) and a recent heart failure hospitalization; 59% had type 2 diabetes. Liraglutide titrated to 1.8 mg daily for 180 days did not improve a hierarchical global rank score of death, heart failure rehospitalization, and change in N-terminal pro–B-type natriuretic peptide (NT-proBNP). Deaths were 12% with liraglutide and 11% with placebo (hazard ratio 1.10; 95% CI 0.57 to 2.14).

LIVE. In 241 clinically stable patients with an LVEF of 45% or less, with and without diabetes, liraglutide 1.8 mg daily for 24 weeks did not change LVEF (difference −0.8%; 95% CI −2.1% to 0.5%). Heart rate rose by 7 beats/min, and serious cardiac events occurred in 10% versus 3% (P=0.04).

GLP-1 receptor agonists are not heart failure therapy for reduced ejection fraction and are not used to improve ventricular function or symptoms. In stable patients with reduced ejection fraction who have another compelling indication (atherosclerotic disease, diabetes, or obesity), the SELECT and SOUL subgroup data provide reassurance. Treatment is acceptable once guideline-directed therapy is established and the patient is euvolemic. GLP-1 receptor agonists are avoided in advanced or decompensated heart failure with reduced ejection fraction. The chronotropic effect and the absence of benefit argue against use, and unintended weight loss may reflect cardiac cachexia. Foundational therapy for this population is covered in Heart failure with reduced ejection fraction. The 2025 American College of Cardiology (ACC) scientific statement on obesity in heart failure identifies the safety of anti-obesity medication in reduced ejection fraction as an unresolved question.

Semaglutide and tirzepatide in obesity-related HFpEF

Obesity is present in most patients with HFpEF in the United States, and in this phenotype adiposity contributes through plasma volume expansion, epicardial fat and pericardial restraint, systemic inflammation, and reduced skeletal muscle quality. Three trials tested incretin-based weight loss in this population. Diagnosis, phenotyping, and the remainder of HFpEF therapy are covered in Heart failure with preserved ejection fraction.

Randomized trials of semaglutide and tirzepatide in obesity-related heart failure with preserved ejection fraction. KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire clinical summary score (0 to 100; a 5-point change is clinically meaningful); BMI, body mass index in kg/m²; HF, heart failure; HR, hazard ratio.

STEP-HFpEF and STEP-HFpEF DM. Both trials had dual primary endpoints of health status and weight. Semaglutide also improved 6-minute walk distance (by 20.3 m without diabetes and 14.3 m with diabetes) and reduced C-reactive protein (by 43.5% versus 7.3% in STEP-HFpEF). Serious adverse events were less frequent with semaglutide (13.3% versus 26.7% in STEP-HFpEF; 17.7% versus 28.8% in STEP-HFpEF DM). In the pooled analysis of 1,145 patients, the health status benefit was larger in patients taking loop diuretics, and loop diuretic dose fell by 17% with semaglutide versus a 2.4% increase with placebo. Weight loss with semaglutide was smaller in patients with diabetes, as in other semaglutide programs.

SUMMIT. SUMMIT was the first incretin trial in HFpEF with a clinical event primary endpoint. Tirzepatide reduced cardiovascular death or worsening heart failure by 38%. The effect was driven entirely by worsening heart failure events (8.0% versus 14.2%; hazard ratio 0.54; 95% CI 0.34 to 0.85), defined as hospitalization, urgent intravenous therapy, or intensification of oral diuretics. Cardiovascular deaths were few and not reduced (2.2% versus 1.4%; hazard ratio 1.58; 95% CI 0.52 to 4.83). Adverse events, mainly gastrointestinal, led to discontinuation in 6.3% versus 1.4%. A prespecified analysis showed reductions in blood pressure, high-sensitivity C-reactive protein, troponin, and albuminuria, consistent with relief of circulatory volume overload and inflammation.

Regulatory status. The FDA requested a confirmatory trial before granting a heart failure indication to tirzepatide, and the supplemental application was withdrawn in 2025. Treatment of obesity-related HFpEF therefore rests on trial evidence, guideline and consensus recommendations, and the obesity indication. The 2026 ACC expert consensus decision pathway on HFpEF, which updates the 2023 pathway, defines optimal medical therapy as an SGLT2 inhibitor and a nonsteroidal mineralocorticoid receptor antagonist. In patients with HFpEF and a body mass index of 30 kg/m² or more, it states that semaglutide or tirzepatide may be prescribed to improve health status and exercise function and potentially to reduce worsening heart failure events. The 2023 pathway predated STEP-HFpEF, STEP-HFpEF DM, and SUMMIT. The American Diabetes Association (ADA) 2026 Standards of Care recommendations for adults with type 2 diabetes, obesity, and symptomatic HFpEF are listed in the guideline table below.

As weight falls, filling pressures and congestion usually improve, and loop diuretic requirements often decrease. Diuretic doses are reviewed at each dose escalation, because unchanged doses combined with reduced oral intake and gastrointestinal fluid loss can cause volume depletion and acute kidney injury. Antihypertensive doses are reviewed for the same reason.

Kidney outcomes

Before FLOW, kidney evidence came from secondary outcomes driven mainly by less new macroalbuminuria: LEADER (nephropathy hazard ratio 0.78), SUSTAIN-6, REWIND (composite kidney outcome hazard ratio 0.85 in an exploratory analysis), and AMPLITUDE-O (hazard ratio 0.68). Effects on hard kidney endpoints were uncertain.

FLOW. FLOW was the first dedicated kidney outcome trial of a GLP-1 receptor agonist. It enrolled 3,533 patients with type 2 diabetes and chronic kidney disease, defined as an eGFR of 50 to 75 mL/min/1.73 m² with a urine albumin-to-creatinine ratio above 300 and below 5,000 mg/g, or an eGFR of 25 to less than 50 with a ratio above 100 and below 5,000 mg/g. Patients received semaglutide 1.0 mg weekly or placebo. The trial was stopped early for efficacy at a median 3.4 years.

Primary and secondary outcomes of FLOW, semaglutide 1.0 mg weekly versus placebo. Serious adverse events were less frequent with semaglutide (49.6% versus 53.8%).

FLOW led to a labeled indication for semaglutide injection (Ozempic) to reduce the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes and chronic kidney disease. In SELECT, semaglutide 2.4 mg reduced a composite kidney outcome in patients without diabetes (1.8% versus 2.2%; hazard ratio 0.78). The eGFR benefit at 104 weeks was 0.75 mL/min/1.73 m² overall and 2.19 mL/min/1.73 m² in those with a baseline eGFR below 60. SOUL did not show a significant effect of oral semaglutide on its confirmatory kidney outcome. SURPASS-CVOT showed slower eGFR decline with tirzepatide than with dulaglutide.

GLP-1 receptor agonists do not cause the early hemodynamic dip in eGFR typical of SGLT2 inhibitors and renin-angiotensin system blockers. Acute kidney injury occurs with volume depletion from vomiting or diarrhea, especially with concurrent diuretics and renin-angiotensin system blockers. Semaglutide, liraglutide, dulaglutide, and tirzepatide need no dose adjustment for eGFR, including in kidney failure, although data in dialysis are limited. Exenatide is renally cleared and is avoided at low eGFR. The integration of kidney-protective therapy with SGLT2 inhibitors, renin-angiotensin system blockade, and finerenone is covered in Chronic kidney disease, dialysis and the heart.

Peripheral artery disease and the STRIDE trial

In SELECT, symptomatic peripheral artery disease was one of the qualifying conditions, and peripheral artery disease is part of the atherosclerotic burden in the diabetes outcome trials. STRIDE tested a functional outcome and enrolled 792 patients with type 2 diabetes and claudication (Fontaine stage IIa, able to walk more than 200 m) and an ankle-brachial index of 0.90 or less or a toe-brachial index of 0.70 or less. Semaglutide 1.0 mg weekly for 52 weeks increased maximum treadmill walking distance (median ratio to baseline 1.21 versus 1.08; estimated treatment ratio 1.13; 95% CI 1.06 to 1.21). Pain-free walking distance and quality of life also improved. The magnitude is modest, about a 13% relative improvement, and smaller than that of supervised exercise therapy, but it is an added benefit in a patient who already qualifies for a GLP-1 receptor agonist. Limb outcomes and the full management of the disease are covered in Peripheral artery disease.

Weight loss with semaglutide and tirzepatide in obesity

The magnitude of weight loss determines several cardiovascular effects (blood pressure, HFpEF symptoms, sleep apnea, and plasma volume) and is the basis of the obesity indications.

Mean weight change in randomized trials of incretin-based and related agents in obesity. Treatment-policy or treatment-regimen estimands (all randomized patients regardless of adherence). BMI in kg/m². Weight loss is smaller in patients with type 2 diabetes for every agent.

Eligibility. The labeled population for chronic weight management with semaglutide 2.4 mg, tirzepatide, and orforglipron is adults with a body mass index of 30 kg/m² or more, or 27 kg/m² or more with at least one weight-related condition, as an adjunct to a reduced-calorie diet and increased physical activity. The 2025 ACC concise clinical guidance on medical weight management identifies semaglutide and tirzepatide as the obesity medications of choice because of their highest efficacy and notes slightly greater weight loss with tirzepatide. It states that patients are not required to try and fail lifestyle changes before starting pharmacotherapy. Lifestyle intervention is offered together with drug therapy. Lower body mass index thresholds are used for Asian populations in several guidelines. Bariatric surgery produces larger and more durable average weight loss than current drug therapy, and the two are complementary.

Weight regain after discontinuation. Obesity is a chronic disease, and weight returns when treatment stops. In the STEP 1 extension, patients regained about two-thirds of the weight they had lost within a year of stopping, and cardiometabolic improvements reverted toward baseline. In SURMOUNT-4, patients switched to placebo regained 14% of body weight, whereas those who continued lost a further 5.5%. Cardiovascular protection is assumed to require continued therapy, because the outcome trials tested continuous treatment.

Lean mass. Dual-energy x-ray absorptiometry substudies of STEP 1 and SURMOUNT-1 found that fat mass fell proportionally more than lean mass, so body composition improved, but lean tissue accounted for roughly a quarter to two-fifths of total weight lost. Part of lean mass loss reflects organ and water mass, and the functional consequence in most patients is uncertain. Older adults, patients with sarcopenia, and those with heart failure are at greater risk of frailty. Resistance exercise and adequate protein intake are the recommended countermeasures, and weight loss targets are individualized.

Obstructive sleep apnea and steatohepatitis

Obstructive sleep apnea. In SURMOUNT-OSA, two trials in adults with moderate to severe obstructive sleep apnea and obesity (mean apnea-hypopnea index about 50 events/h, mean body mass index about 39 kg/m²) showed that tirzepatide at 10 or 15 mg reduced the apnea-hypopnea index by 20.0 events/h more than placebo in patients not using positive airway pressure and by 23.8 events/h more in those using it. Hypoxic burden, high-sensitivity C-reactive protein, and systolic blood pressure also improved. Tirzepatide (Zepbound) is labeled for moderate to severe obstructive sleep apnea in adults with obesity at a maintenance dose of 10 or 15 mg. Sleep apnea is a risk factor for hypertension and atrial fibrillation, which makes this indication relevant to cardiology.

Metabolic dysfunction–associated steatohepatitis (MASH). In the 72-week interim analysis of ESSENCE in 800 patients with biopsy-proven MASH and stage 2 or 3 fibrosis, semaglutide 2.4 mg resolved steatohepatitis without worsening fibrosis in 62.9% versus 34.3% and reduced fibrosis without worsening steatohepatitis in 36.8% versus 22.4%. Semaglutide injection (Wegovy) has accelerated approval for noncirrhotic MASH with moderate to advanced fibrosis. Metabolic liver disease is a cardiovascular-kidney-metabolic (CKM) risk factor and is associated with excess cardiovascular events.

Guideline and consensus recommendations

The American Heart Association (AHA) presidential advisory on CKM health frames the interplay of obesity, diabetes, chronic kidney disease, and cardiovascular disease as one syndrome staged from 0 to 4, with GLP-1 receptor agonists and SGLT2 inhibitors as core therapies chosen by phenotype across stages. Staging and the full stage-based approach are in Cardiovascular-kidney-metabolic syndrome.

Guideline and consensus recommendations on incretin-based therapy. ADA, American Diabetes Association; ACC, American College of Cardiology; ESC, European Society of Cardiology; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease.

US and European guidance agree on the main point: in type 2 diabetes with atherosclerotic disease, a GLP-1 receptor agonist with proven benefit is used for cardiovascular protection regardless of HbA1c or background metformin. The 2023 ESC guideline additionally recommends both drug classes in all patients with type 2 diabetes and atherosclerotic disease when tolerated, whereas US guidance frames the choice between the two classes, and their combination, by phenotype.

FDA-labeled cardiovascular, kidney, and related indications

FDA-labeled cardiovascular and kidney indications by product. From the current US prescribing information. Exenatide and lixisenatide have no cardiovascular indication. Coadministration of two GLP-1 receptor agonists, or of tirzepatide with a GLP-1 receptor agonist, is not recommended.

Choosing an agent by cardiovascular, kidney, and metabolic phenotype

The choice of agent follows the indication with outcome evidence, then the need for weight loss, the route the patient will accept, tolerance, and coverage. Glucose lowering is a secondary consideration.

Agent selection by clinical phenotype. ASCVD, atherosclerotic cardiovascular disease; RAS, renin-angiotensin system; PAD, peripheral artery disease; HFrEF, heart failure with reduced ejection fraction.

In a patient with type 2 diabetes, SGLT2 inhibition is prioritized when heart failure, pre–heart failure, or chronic kidney disease dominates the phenotype, and GLP-1–based therapy when atherosclerotic disease, obesity, severe hyperglycemia, or metabolic liver disease dominates. Many patients qualify for both. When weight loss is a main goal, tirzepatide or semaglutide 2.4 mg produces the largest effect. Starting therapy is not deferred until metformin is titrated or HbA1c is above target.

Dosing and titration of GLP-1 receptor agonists and tirzepatide

All agents are started at a low dose and escalated to limit nausea and vomiting. Escalation is slowed or a dose repeated for another 4 weeks when gastrointestinal effects limit tolerance.

Starting, escalation, and maintenance doses by product. From the current US prescribing information. The 0.25-mg semaglutide, 3-mg and 1.5-mg oral semaglutide, and 2.5-mg tirzepatide starting doses are for tolerance and are not maintenance doses.

Missed doses and re-initiation. For weekly semaglutide, a missed dose is taken if the next scheduled dose is more than 2 days away. When two or more consecutive weekly doses are missed, the label directs re-initiation of dose escalation at a lower dose, because restarting at full dose after a gap reproduces initiation-phase nausea and vomiting and increases gastric retention. The tirzepatide labels allow a missed dose within 4 days and give no re-initiation schedule; after a prolonged interruption, restarting at a lower dose follows the same principle.

Switching. Switching from oral to injectable semaglutide, between oral formulations, or from a GLP-1 receptor agonist to tirzepatide follows the conversion guidance in each label. A patient switched from semaglutide to tirzepatide does not need to restart at 2.5 mg if tolerance is established, but gastrointestinal effects commonly recur at higher doses.

Concurrent glucose-lowering drugs. Insulin and sulfonylurea doses are reduced when therapy starts in patients with good glycemic control, because the combination causes hypoglycemia. DPP-4 inhibitors are stopped, because they add nothing to a receptor agonist.

Combining GLP-1 receptor agonists with SGLT2 inhibitors

The two classes have complementary mechanisms and outcome profiles. GLP-1 receptor agonists reduce atherosclerotic events, stroke, weight, and albuminuria. SGLT2 inhibitors reduce heart failure hospitalization, cardiovascular death in heart failure, and progression of chronic kidney disease with or without diabetes. No outcome trial has randomized patients to the combination versus either drug alone. The evidence for additive benefit comes from consistent effects in trial subgroups taking the other class.

In AMPLITUDE-O, randomization was stratified by SGLT2 inhibitor use, and efpeglenatide's effect was consistent with and without it. In FLOW, 550 participants (15.6%) were taking an SGLT2 inhibitor at baseline. The primary kidney outcome hazard ratio was 1.07 (95% CI 0.69 to 1.67) in that subgroup and 0.73 in those not taking one, with no significant interaction (P=0.109), and the eGFR slope and MACE benefits were similar in both subgroups. The SGLT2 inhibitor subgroup was too small to exclude a smaller effect. In SUMMIT and the STEP-HFpEF program, a minority of patients took SGLT2 inhibitors, and benefits were seen on top of contemporary therapy.

The ADA Standards of Care recommend the combination for additive reduction in cardiovascular and kidney events in patients with type 2 diabetes and atherosclerotic disease or multiple risk factors (grade B). In obesity-related HFpEF and in diabetic kidney disease, both classes are commonly used together. Volume depletion is the main interaction. Natriuresis from SGLT2 inhibition, gastrointestinal fluid loss and reduced intake with incretin therapy, and loop diuretics together increase the risk of hypotension and acute kidney injury during dose escalation or intercurrent illness. Both drugs are held during acute illness with vomiting, poor intake, or dehydration. The SGLT2 inhibitor class is covered in SGLT2 inhibitors.

Gastrointestinal adverse effects

Nausea, vomiting, diarrhea, constipation, dyspepsia, abdominal pain, and eructation are the most frequent adverse effects of every agent. They are dose-dependent, most common during initiation and escalation, usually mild to moderate, and usually transient. In the semaglutide diabetes trials, gastrointestinal adverse reactions occurred in 32.7% with 0.5 mg, 36.4% with 1 mg, and 15.3% with placebo. In REWIND they occurred in 47.4% with dulaglutide versus 34.1% with placebo. They account for most treatment discontinuations. Discontinuation for adverse events of any kind reached 16.6% versus 8.2% in SELECT, and discontinuation for adverse events reached 6.3% versus 1.4% in SUMMIT.

Mitigation measures are slow titration, smaller meals, cessation of eating at satiety, avoidance of high-fat meals, and adequate fluid intake. Severe or persistent vomiting can cause dehydration and acute kidney injury. The labels state that semaglutide is not recommended in severe gastroparesis. Ileus and bowel obstruction have been reported after marketing. Gastroparesis or obstruction is evaluated when vomiting persists beyond the escalation phase, occurs with abdominal distension, or follows a stable maintenance period.

Pancreatitis and gallbladder disease

Acute pancreatitis. Pancreatitis was reported in early postmarketing experience and remains a labeled warning. In randomized outcome trials and their meta-analysis, the incidence was not significantly increased: 0.4% with liraglutide versus 0.5% with placebo in LEADER, with no difference in EXSCEL or ELIXA. Pancreatic cancer was not increased. Therapy is stopped if pancreatitis is suspected and is not restarted if it is confirmed. A history of pancreatitis is a relative contraindication; these patients were largely excluded from the trials, and other drugs are preferred when they serve the indication.

Gallbladder disease. Cholelithiasis and cholecystitis are increased. In LEADER, acute gallstone disease occurred in 3.1% versus 1.9% (P<0.001). The mechanism combines rapid weight loss, which increases biliary cholesterol saturation, and reduced gallbladder motility. The risk is higher with greater weight loss and higher doses. Right upper quadrant pain, fever, or jaundice leads to gallbladder imaging.

Thyroid C-cell tumors and contraindications

All long-acting GLP-1 receptor agonists and tirzepatide carry a boxed warning for thyroid C-cell tumors. In rodents, these drugs cause dose- and duration-dependent C-cell hyperplasia, adenomas, and medullary thyroid carcinoma at clinically relevant exposures. Rodent C cells express far more GLP-1 receptor than human C cells, and a causal relationship in humans has not been established. Medullary thyroid carcinoma was not increased in the outcome trials, but they were not long enough or large enough to exclude a small effect on a rare tumor.

Contraindications, cautions, and monitoring for incretin-based therapy. Routine calcitonin measurement and thyroid ultrasound are not recommended for screening. Thyroid nodules or neck masses found during treatment are evaluated in the usual way.

Diabetic retinopathy and ischemic optic neuropathy

Diabetic retinopathy. In SUSTAIN-6, retinopathy complications (vitreous hemorrhage, blindness, or need for intravitreal agents or photocoagulation) were more frequent with semaglutide (hazard ratio 1.76; 95% CI 1.11 to 2.78). Most events occurred in patients with preexisting retinopathy and a large, rapid fall in HbA1c. This is the early worsening phenomenon also seen with intensive insulin therapy, not a direct retinal toxicity. The retinopathy outcome in LEADER was not significantly increased (2.3% versus 2.0%), and the class meta-analysis found no increase. Patients with known retinopathy receive retinal examination before and during treatment, and rapid glucose lowering is avoided in proliferative disease until it is treated.

Nonarteritic anterior ischemic optic neuropathy (NAION). Observational studies have reported an association between semaglutide and NAION, a sudden, painless, usually unilateral loss of vision. In 2025 the European Medicines Agency's safety committee concluded that NAION is a very rare adverse effect of semaglutide, and European product information was updated. Semaglutide is stopped if NAION is confirmed. The absolute risk is very low. Sudden visual loss during treatment is evaluated urgently.

Hypoglycemia, kidney injury, and hypersensitivity

GLP-1 receptor agonists and tirzepatide cause hypoglycemia only rarely when used alone or with metformin or an SGLT2 inhibitor, because their insulin secretion is glucose-dependent. With insulin or a sulfonylurea, the risk of hypoglycemia, including severe events, increases, so doses of those drugs are reduced at initiation. Patients without diabetes taking semaglutide 2.4 mg or tirzepatide for weight management have a very low risk.

Acute kidney injury occurs mainly through volume depletion from vomiting, diarrhea, and poor intake, sometimes requiring dialysis, and is more frequent with diuretics and renin-angiotensin system blockers. Anaphylaxis and angioedema have been reported. Injection-site reactions are usually mild. Skin sensitivity and dysesthesia were more frequent with the 7.2-mg semaglutide dose.

Heart rate and arrhythmia

All GLP-1 receptor agonists and tirzepatide raise resting heart rate. The mean increase is 1 to 4 beats/min with semaglutide 2.4 mg and 1 to 3 beats/min with tirzepatide. Daily and short-acting agents produce a smaller sustained effect than long-acting agents, and the rise is larger in some individuals: in the semaglutide obesity trials, 26% of patients had a maximum increase of 20 beats/min or more at some visit, compared with 16% with placebo. In LEADER the increase was 3.0 beats/min, and in LIVE, with liraglutide in reduced ejection fraction, it was 7 beats/min.

The mechanism is direct activation of sinoatrial node GLP-1 receptors with a contribution from reduced vagal and increased sympathetic tone. In the outcome trials, the heart rate increase did not offset the reduction in events. It is undesirable in conditions in which a rapid rate is poorly tolerated: advanced HFrEF, severe aortic or mitral stenosis, hypertrophic cardiomyopathy with obstruction, and active ischemia. The labels recommend regular heart rate monitoring. A persistent, clinically significant rise is addressed by dose reduction or a beta-blocker when one is otherwise indicated.

Atrial fibrillation was not increased in the randomized outcome trials, and pooled analyses of randomized trials have not shown a consistent signal of increased atrial arrhythmia. Weight loss itself reduces atrial fibrillation burden in obese patients, and the effect of incretin-induced weight loss on atrial fibrillation outcomes is under study. QT prolongation has not been a clinically significant effect at therapeutic doses.

Aspiration risk and management before procedures

GLP-1 receptor agonists and tirzepatide delay gastric emptying, an effect that is greatest after initiation and dose escalation and that attenuates partly with continued use (tachyphylaxis). Residual gastric contents despite standard fasting, and pulmonary aspiration during general anesthesia or deep sedation, have been reported, and the US labels carry a warning to inform proceduralists of planned procedures. The absolute risk is low, and evidence on the optimal management strategy is limited.

American Society of Anesthesiologists (ASA) guidance, 2023. The ASA initially advised holding daily agents on the day of a procedure and weekly agents for 1 week before elective procedures, regardless of indication, dose, or procedure type, with delay of elective procedures in patients with gastrointestinal symptoms and full-stomach precautions when the drug was not held.

Multisociety guidance, 2024. A joint document from the American Gastroenterological Association, the American Society for Metabolic and Bariatric Surgery, the ASA, the International Society of Perioperative Care of Patients with Obesity, and the Society of American Gastrointestinal and Endoscopic Surgeons revised this approach. It is described by its authors as guidance, not an evidence-based guideline. The document sets out these principles:

• Risk of delayed gastric emptying and aspiration is assessed before the procedure, early enough to modify care. Risk is elevated in the escalation phase, at higher doses, with weekly formulations, with gastrointestinal symptoms (nausea, vomiting, abdominal pain, dyspepsia, constipation), and with conditions that independently delay gastric emptying, such as gastroparesis, bowel dysmotility, and Parkinson disease.
• Patients without elevated risk may continue the drug. Withholding the drug only because a patient has obesity, without such risk features, is discouraged as a form of bias.
• A liquid diet for at least 24 hours before the procedure, as used before colonoscopy and bariatric surgery, can be used in patients at elevated risk.
• When withholding is chosen after shared decision-making, the duration needed is unknown. The suggested approach follows the original ASA advice: hold daily formulations on the day of the procedure and weekly formulations for 1 week before.
• In patients with diabetes, withholding is balanced against the risk of perioperative hyperglycemia, and glucose management is planned with the prescribing clinician.
• All patients are assessed on the day of the procedure for symptoms of retained gastric contents. Point-of-care gastric ultrasound can assess gastric contents when concern exists. When retained contents are suspected or confirmed, the options are rapid sequence induction with tracheal intubation or postponement.

AHA/ACC perioperative guideline, 2024. The 2024 AHA/ACC guideline for perioperative cardiovascular management for noncardiac surgery notes that GLP-1 receptor agonists can cause clinically significant delayed gastric emptying and cites the 2023 ASA advice to hold weekly formulations for 1 week and daily formulations before elective surgery to reduce the risk of pulmonary aspiration. It identifies perioperative management of these drugs as an area that needs further research and does not assign a class of recommendation to a holding interval. This contrasts with SGLT2 inhibitors, which the guideline advises stopping 3 to 4 days before surgery to reduce the risk of ketoacidosis. Perioperative cardiac risk assessment is covered in Perioperative cardiovascular evaluation.

Perioperative management by clinical situation. Synthesized from the 2023 ASA guidance, the 2024 multisociety guidance, and the US prescribing information. The final plan is made with the anesthesia and procedural teams.

The same principles apply to cardiovascular procedures performed under deep sedation or general anesthesia: transesophageal echocardiography, electrical cardioversion, catheter ablation, transcatheter valve procedures, and device implantation. For transesophageal echocardiography, residual gastric contents are both an aspiration risk and a technical problem, and the escalation phase is the period of greatest concern. Procedures under minimal or moderate sedation with a protected airway follow institutional protocols. Interruption for an elective procedure does not abolish the cardiovascular benefit of a long-term drug. Avoidable interruption, however, leads to dose re-escalation and recurrence of gastrointestinal effects, which supports the risk-based approach.

Pregnancy, contraception, and lactation

Weight loss offers no benefit in pregnancy, and animal studies showed fetal harm at clinically relevant exposures. GLP-1 receptor agonists and tirzepatide are stopped when pregnancy is recognized. Because of its half-life of about 1 week, semaglutide is stopped at least 2 months before a planned pregnancy. Tirzepatide reduces the efficacy of oral hormonal contraceptives through delayed gastric emptying: patients using oral contraceptives switch to a nonoral method, or add a barrier method, for 4 weeks after initiation and for 4 weeks after each dose escalation. Nonoral hormonal contraceptives are not affected. Weight loss can restore ovulation in women with obesity and polycystic ovary syndrome, so unplanned pregnancy is a recognized consequence. Data in lactation are limited.

Neuropsychiatric effects and substance use

Early postmarketing reports led to warnings about suicidal ideation in the weight-management labels. After an analysis of 91 placebo-controlled trials enrolling 107,910 patients and a claims-based cohort study, the FDA found that the evidence did not support a causal association, and in 2026 the warning about suicidal behavior and ideation was removed from the labels of Wegovy, Zepbound, and Saxenda. The diabetes products never carried it. Depression and suicidal thinking are still assessed as in any patient with obesity, whose baseline risk is elevated.

GLP-1 receptor agonists act on mesolimbic reward pathways. In a phase 2 randomized trial of 48 adults with alcohol use disorder, low-dose semaglutide for 9 weeks reduced laboratory alcohol self-administration and craving. Observational data suggest lower alcohol and other substance use with treatment. These effects are under study and are not an indication.

Drug interactions and absorption of oral drugs

GLP-1 receptor agonists and tirzepatide are not metabolized by cytochrome P450 enzymes and have few pharmacokinetic interactions. Their main interaction is delayed gastric emptying, which can slow the absorption of oral drugs. The effect is largest after the first dose and after escalation. It is clinically relevant for oral contraceptives with tirzepatide (above) and for drugs with a narrow therapeutic index or a need for rapid onset. The international normalized ratio is monitored more often when a GLP-1 receptor agonist is started in a patient taking warfarin.

Oral semaglutide has specific constraints. It is taken alone with a small volume of water at least 30 minutes before other drugs. It increases exposure to levothyroxine, and thyroid function is monitored when the two are combined.

Access, cost, and compounded products

Cost and insurance coverage determine use in many patients, especially for weight management without diabetes, for which coverage is inconsistent and Medicare Part D has historically excluded drugs used for weight loss alone. A labeled cardiovascular indication (SELECT for semaglutide 2.4 mg) or obstructive sleep apnea indication (tirzepatide) changes coverage eligibility for some patients. Manufacturer direct-to-patient programs have lowered cash prices.

During the 2022 to 2025 shortages, compounding pharmacies produced copies of semaglutide and tirzepatide. Those products are not FDA approved, have no outcome data, vary in concentration and salt form, and have caused dosing errors and adverse events. After the FDA removed tirzepatide (2024) and semaglutide (2025) from its shortage list, the basis for mass compounding ended. Counterfeit pens have also been identified. Cardiovascular benefit applies to the approved products used in the outcome trials.

Next-generation incretin and related agents

Incretin-based and related agents in development or recently approved. Weight changes are mean percentage changes from baseline in adults without diabetes. Glucagon receptor agonism raises heart rate and energy expenditure, so cardiovascular safety of triple agonists is being tested in dedicated trials.

The trend is toward greater weight loss, oral administration, and combination with other satiety hormones. Whether greater weight loss produces proportionally greater cardiovascular benefit is unknown.

Observational evidence and its limits

Large claims-based and electronic health record studies, many designed as target trial emulations, have compared incretin-based drugs with DPP-4 inhibitors, sulfonylureas, and each other. They have reported associations with fewer cardiovascular events, less heart failure, and lower mortality. They have also identified uncommon adverse effects (NAION, gastrointestinal obstruction) that trials were too small to detect. Observational comparisons are limited by confounding by indication, healthy adherer effects, differences in access, and misclassification of outcomes. They generate hypotheses and safety signals; the randomized trials on this page are the basis for indications and recommendations. Persistence with therapy outside trials is lower than in trials, mostly because of gastrointestinal effects and cost, which reduces the benefit achieved in practice.

Older adults, chronic kidney disease, and other special populations

Older adults. The outcome trials enrolled many patients older than 65 years, and benefit was consistent by age. Older adults are more vulnerable to dehydration, sarcopenia, and malnutrition from reduced intake. Doses are escalated slowly, protein intake and resistance exercise are encouraged, and unintended weight loss beyond the target leads to dose reduction.

Type 1 diabetes. Incretin-based drugs are not approved for type 1 diabetes, and the outcome trials excluded it. Weight loss and modest insulin dose reductions are reported, but the risk of ketoacidosis with large insulin reductions requires specialist management.

Recent acute coronary syndrome or stroke. ELIXA established safety after acute coronary syndrome, and SELECT and SOUL included patients with prior myocardial infarction and stroke. Initiation during or soon after a hospitalization for acute coronary syndrome is safe once oral intake is reliable, although gastrointestinal effects can be confused with ischemic symptoms early after initiation.

Baseline assessment and monitoring during incretin-based therapy

Baseline assessment records weight, waist circumference, blood pressure, heart rate, HbA1c, kidney function, urine albumin-to-creatinine ratio in patients with diabetes or chronic kidney disease, and the doses of insulin, sulfonylureas, diuretics, and antihypertensive drugs. History establishes contraindications (medullary thyroid carcinoma, multiple endocrine neoplasia type 2, pancreatitis, gastroparesis, retinopathy) and pregnancy plans.

During escalation, follow-up addresses gastrointestinal tolerance, volume status, blood pressure and orthostatic symptoms, and glucose in patients taking insulin or sulfonylureas. At maintenance, weight trajectory, heart rate, kidney function, and lipid levels are reviewed. Weight loss changes the need for antihypertensive and diuretic therapy and sometimes for anticoagulant dosing by weight. Body weight and natriuretic peptide levels interact: as obesity resolves, natriuretic peptide levels rise toward their true value, so a rising level during substantial weight loss is interpreted in that context.

Sources of error in the use of GLP-1 receptor agonists and tirzepatide

• Selecting an incretin-based drug for a patient with type 2 diabetes and atherosclerotic disease only when HbA1c is above target: the cardiovascular indication is independent of glucose control and metformin use.
• Prescribing an exendin-based or short-acting agent when cardiovascular protection is the goal: lixisenatide and exenatide did not reduce events, and the labeled cardiovascular indications belong to liraglutide, dulaglutide, semaglutide, and tirzepatide.
• Using a GLP-1 receptor agonist to treat HFrEF, or starting one in advanced or decompensated HFrEF: FIGHT and LIVE showed no benefit, and LIVE showed more serious cardiac events.
• Reporting the SUMMIT result as a mortality benefit: the reduction was in worsening heart failure events, and cardiovascular deaths were few and not reduced.
• Reading SURPASS-CVOT as proof that tirzepatide is superior to dulaglutide for cardiovascular events: noninferiority was met, and superiority was not.
• Judging cardiovascular treatment success by the amount of weight lost: in SELECT, benefit was independent of weight loss.
• Leaving diuretic and antihypertensive doses unchanged during rapid weight loss, which leads to hypotension and acute kidney injury.
• Stopping every GLP-1 receptor agonist for a week before every procedure: current multisociety guidance continues therapy in patients without elevated risk and focuses precautions on the escalation phase, high doses, and symptoms.
• Restarting at the full maintenance dose after two or more missed weekly doses, which reproduces initiation-phase nausea and vomiting.
• Combining two GLP-1 receptor agonists, or tirzepatide with a GLP-1 receptor agonist, or continuing a DPP-4 inhibitor with a receptor agonist.
• Omitting contraceptive counseling with tirzepatide, which reduces oral contraceptive efficacy after initiation and each escalation.
• Attributing new visual loss to diabetes without evaluating for NAION, or rapidly lowering glucose in untreated proliferative retinopathy.

Prognosis and expected benefit

The absolute benefit depends on baseline risk. In LEADER, the number of patients with type 2 diabetes at high risk who needed to be treated for 3 years to prevent one MACE event was 66. In SELECT, the absolute MACE difference was 1.5 percentage points over about 3.3 years in patients with established cardiovascular disease without diabetes. In FLOW, patients with diabetic kidney disease had high event rates, and the absolute benefit for the kidney and cardiovascular composite was correspondingly larger. In obesity-related HFpEF, the health status improvement of about 7 points on the KCCQ-CSS is comparable to or larger than that of other HFpEF therapies. Tirzepatide reduced worsening heart failure events by almost half. Benefits persist only with continued treatment, because weight and cardiometabolic risk factors return toward baseline after discontinuation.

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