GLP-1 Receptor Agonists and Dual Incretin Agonism in Type 2 Diabetes and Obesity: A Narrative Review for Clinical Practice

Clinical Background and Unmet Needs

Type 2 diabetes mellitus (T2DM) affects over 500 million individuals globally and remains a leading driver of cardiovascular morbidity and mortality. Obesity—now recognized as a chronic, relapsing metabolic disease rather than merely a lifestyle consequence—is present in the majority of patients with T2DM and substantially amplifies cardiometabolic risk through dyslipidemia, hypertension, systemic inflammation, and direct cardiac remodeling. Traditional glucose-lowering agents frequently fail to simultaneously achieve durable glycemic control, meaningful weight reduction, and cardiovascular (CV) protection—three pillars now considered inseparable in contemporary diabetes and obesity management. This therapeutic gap has driven the development of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and, more recently, dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 receptor agonists, principally tirzepatide. Emerging indications—including heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD)—further underscore the pleiotropic clinical potential of this drug class.

Mechanisms of Action

GLP-1 RAs are incretin mimetics that act on GLP-1 receptors to stimulate glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, and promote satiety through central nervous system pathways. Their glucose-lowering effect is inherently self-limiting, conferring a favorable hypoglycemia profile relative to sulfonylureas or insulin.

Tirzepatide introduces a mechanistic advancement as a dual GIP/GLP-1 receptor agonist. Preclinical data demonstrate that tirzepatide binds GIP receptors with affinity equal to native GIP, while binding GLP-1 receptors with approximately five-fold lower affinity than native GLP-1. GIP receptor activation in adipose tissue and the central nervous system is thought to influence energy balance and adiposity, although the precise mechanisms contributing to weight reduction remain incompletely understood. Dual agonism appears to act synergistically, producing weight reduction significantly exceeding that achievable with GLP-1 monotherapy alone—a distinction with consequential clinical implications 45.

Key Clinical Evidence

Cardiovascular Outcomes in Type 2 Diabetes

Two pivotal semaglutide cardiovascular outcome trials (CVOTs) established the drug's CV safety and benefit profile. In SUSTAIN-6 (n=3,297), subcutaneous semaglutide reduced the primary endpoint of major adverse cardiovascular events (MACE—CV death, nonfatal myocardial infarction [MI], or nonfatal stroke) with a hazard ratio (HR) of 0.74 (95% CI: 0.58–0.95), including a significant reduction in nonfatal stroke (HR 0.61; 95% CI: 0.38–0.99). In PIONEER-6 (n=3,183), oral semaglutide achieved a numerically lower MACE rate (HR 0.79; 95% CI: 0.57–1.11), with nominally significant reductions in CV death (HR 0.49) and all-cause mortality (HR 0.51). A pooled post-hoc analysis yielded an overall MACE HR of 0.76 (95% CI: 0.62–0.92) 2. Across seven completed GLP-1 RA CVOTs reviewed by the American Heart Association, agents including liraglutide, subcutaneous semaglutide, albiglutide, dulaglutide, and efpeglenatide achieved statistically significant 12–27% relative MACE reductions in meta-analyses 9.

Cardiovascular Benefit Beyond Diabetes: SELECT Trial

The landmark SELECT trial (n=17,604) was the first to demonstrate that a GLP-1 RA reduces CV events in patients with established cardiovascular disease and obesity or overweight without diabetes. Over a mean follow-up of 39.8 months, semaglutide reduced MACE by 20% (HR 0.80; 95% CI: 0.72–0.90; p<0.001) versus placebo. Mean body weight fell by −9.39% with semaglutide versus −0.88% with placebo; 91% of semaglutide-treated patients achieved ≥5% weight loss. Systolic blood pressure (SBP) declined by −3.82 mm Hg and high-sensitivity C-reactive protein (hsCRP) by −39.12%, suggesting CV benefit mediated in part by anti-inflammatory and hemodynamic mechanisms beyond glucose lowering 3. This finding prompted the FDA to approve a new CV risk-reduction indication for Wegovy (semaglutide) in March 2024—the first weight-loss medication approved explicitly to prevent life-threatening cardiovascular events 18.

Renoprotection: FLOW Trial

The FLOW trial (n=3,533 patients with T2DM and CKD at 387 sites across 28 countries) established a dedicated renoprotective role for semaglutide, demonstrating significant slowing of kidney disease progression and a 24% reduction in cardiovascular mortality compared with placebo. This positions semaglutide as a dual cardiorenal agent in diabetic CKD 12131415.

Heart Failure with Preserved Ejection Fraction

Two trials evaluated incretin-based therapy in HFpEF. STEP-HFpEF (n=529; semaglutide 2.4 mg) showed a between-group improvement in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) of +7.8 points (p<0.001), 6-minute walk distance improvement of +20.3 m (p<0.001), and weight reduction of −13.3% versus −2.6% with placebo. Serious adverse events were lower with semaglutide (13.3% vs. 26.7%) 17. The SUMMIT trial (n=731; tirzepatide) demonstrated a 38% reduction in the composite of CV death or worsening heart failure (HR 0.62; 95% CI: 0.41–0.95; p=0.026), with KCCQ-CSS improvement of +6.9 points beyond placebo 16. Both trials support GLP-1/dual incretin agonism as emerging standard-of-care adjuncts in obese patients with HFpEF.

Weight Loss Efficacy: SURMOUNT Program and Head-to-Head Comparison

SURMOUNT-1 (n=2,539; tirzepatide in non-diabetic obesity) demonstrated dose-dependent weight reductions of 15.0%, 19.5%, and 20.9% for 5, 10, and 15 mg weekly doses respectively, versus 3.1% with placebo, accompanied by improvements in SBP (−7.2 mm Hg), triglycerides (−24.8%), HDL-C (+8.0%), and fasting insulin (−42.9%) 4. SURMOUNT-4 confirmed weight regain (+14.0%) upon discontinuation, reinforcing the chronic-disease treatment paradigm 11.

The SURMOUNT-5 direct head-to-head trial (n=751) demonstrated tirzepatide's superiority over semaglutide 2.4 mg at 72 weeks: −20.2% versus −13.7% weight reduction (difference −6.5 percentage points; p<0.001); 57% versus 27% achieving ≥20% weight loss; waist circumference reduction −18.4 cm versus −13.0 cm 5. The REALISE-DM real-world study in patients switching from liraglutide or dulaglutide to injectable semaglutide confirmed efficacy in GLP-1 RA-experienced patients, with HbA1c reductions of 0.65% and weight loss of 1.69 kg at 6 months; greatest benefit occurred in patients with baseline HbA1c ≥8.5% 1.

Guideline Recommendations

International guidelines have progressively repositioned GLP-1 RAs from second-line add-on agents to preferred or first-line options for patients with specific cardiometabolic profiles. The ADA 2025 Standards of Care recommend consideration of GLP-1 receptor agonists in patients with T2DM and established ASCVD or obesity, while SGLT-2 inhibitors remain the preferred evidence-based option for many patients with heart failure, particularly HFrEF, established atherosclerotic cardiovascular disease (ASCVD), or high CV risk without requiring prior metformin failure. The ADA/EASD 2022 consensus similarly endorses early initiation alongside SGLT-2 inhibitors (sodium-glucose cotransporter-2 inhibitors) for patients with CKD or HF. The ACC 2025 Concise Guidance positions GLP-1 RAs and tirzepatide as essential for obesity care, filling the efficacy gap between lifestyle intervention (~5% weight loss) and bariatric surgery (~25%). The AHA 2021 Scientific Statement classifies GLP-1 RAs with demonstrated CV benefit as preferred over insulin for patients with ASCVD requiring injectable therapy 6789.

Table 1. International Guideline Positioning of GLP-1 RAs and Tirzepatide (2021–2025)

Abbreviations: ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; ACC, American College of Cardiology; AHA, American Heart Association; T2DM, type 2 diabetes mellitus; ASCVD, atherosclerotic cardiovascular disease; HF, heart failure; CKD, chronic kidney disease; SGLT-2i, SGLT-2 inhibitor; MASLD, metabolic dysfunction-associated steatotic liver disease; BMI, body mass index (kg/m²).

Safety Profile

Across all trials, gastrointestinal events (GI)—nausea, vomiting, diarrhea, constipation—represent the predominant adverse effect, typically mild-to-moderate, most frequent during dose escalation, and manageable with a slow titration protocol (starting at 2.5 mg weekly for tirzepatide, escalating by 2.5 mg every 4 weeks). Discontinuation rates due to adverse events ranged from 4.3–7.1% for tirzepatide across the SURMOUNT program and were 6.1% versus 8.0% for semaglutide in the head-to-head trial 511. Tirzepatide carries a boxed warning and should not be used in patients with a personal or family history of medullary thyroid carcinoma or in patients with MEN2, consistent with current prescribing information. Rare serious events include pancreatitis. Renal protective effects have been observed in multiple trials, contrasting with isolated real-world reports of acute kidney injury in the context of severe dehydration from GI adverse effects.

Real-World Adherence and Implementation Challenges

Real-world data reveal a substantial gap between trial efficacy and clinical practice outcomes. Among 4,066 commercially insured non-diabetic adults initiating GLP-1 therapy in 2021, only 32.3% remained persistent at one year (using a 60-day gap definition) and mean proportion of days covered (PDC) was 51.0%, with only 27.2% achieving adequate adherence (PDC ≥80%). Weekly formulations demonstrated superior persistence: semaglutide (Ozempic) achieved 47.1% one-year persistence versus 19.2% for liraglutide (Saxenda). Drug switching occurred in 11.1% of patients. As of early 2025, the FDA confirmed resolution of the semaglutide and tirzepatide injection shortages, though localized disruptions persist 2022.

Table 2. Real-World GLP-1 RA Persistence and Adherence by Product (Non-Diabetic Adults, Commercial Insurance, n=4,066, 2021)

Abbreviations: PDC, proportion of days covered; CI, confidence interval; NR, not reported in retrieved materials. Adherence defined as PDC ≥80%; persistence defined as no gap ≥60 consecutive days. Data source: claims analysis of 16 commercial insurance plans 22.

Clinical Practice Implications and Unresolved Questions

Patient selection should integrate five clinical criteria: (1) presence of established ASCVD or high 10-year CV risk; (2) obesity (BMI ≥30 kg/m², or ≥27 kg/m² with weight-related comorbidities); (3) CKD or albuminuria; (4) HFpEF with obesity; and (5) inadequate glycemic or weight management on current therapy. Tirzepatide is favored when maximal weight loss is the priority; semaglutide offers more established long-term CV outcome data across diverse populations. Combination with SGLT-2 inhibitors is increasingly recommended for synergistic benefit in CKD and HF phenotypes 689.

Unresolved questions include the long-term cardiovascular outcome profile of tirzepatide across broader patient populations, although emerging cardiovascular outcomes data continue to accumulate; optimal sequencing and combination strategies with SGLT-2 inhibitors; cost-effectiveness and insurance access in lower-resourced settings; and the role of these agents in heart failure with reduced ejection fraction (HFrEF). Emerging evidence on oral semaglutide at 25 mg (OASIS 4 trial: −13.6% weight loss vs. −2.2% placebo at 64 weeks, with a 74% GI adverse event rate) expands non-injectable options but highlights tolerability as a limiting factor 21.

Conclusion

GLP-1 receptor agonists—particularly semaglutide—have accumulated robust evidence across T2DM, obesity, CKD, and HFpEF, representing a paradigm shift from single-target glucose lowering to comprehensive cardiometabolic protection. Tirzepatide, as a dual GIP/GLP-1 agonist, delivers superior weight reduction compared with semaglutide and demonstrates early HFpEF benefit. International guidelines from the ADA, EASD, ACC, AHA, and Chinese Diabetes Society consistently recommend early, proactive initiation in high-risk populations without requiring prior therapeutic failure. Real-world adherence remains critically suboptimal, underscoring the need for structured patient counseling, tolerability-guided titration, side-effect management, and sustained multidisciplinary follow-up to translate the substantial trial efficacy of this drug class into durable clinical benefit.