Michael Albrecht Nauck

Aims: The impact of tirzepatide and dulaglutide on major adverse cardiovascular events (MACE) and heart failure (HF) outcomes according to HF status is unknown. Methods and results: Patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease were treated with tirzepatide up to 15 mg or dulaglutide 1.5 mg weekly (average 4 years). The incidence of MACE-3 [cardiovascular (CV) death, myocardial infarction (MI), stroke], MACE-4 (CV death, MI, stroke, coronary revascularization) and composite of all-cause or CV death and hospitalization or urgent visits for HF were analysed in patients with and without a history of HF. A history of HF (20.3%) was associated with more coronary artery disease and prior MI. Incidences of event categories were higher in the HF group. The hazard ratio (HR) for all-cause death or hospitalization or urgent visits for HF on tirzepatide vs. dulaglutide was 0.83 [95% confidence interval (CI) 0.70–0.99] in patients with HF and 0.88 (95%CI 0.78–1.00) without HF. The HR for CV death or hospitalization or urgent visits for HF was 0.85 (95%CI 0.70–1.03) and 0.96 (95%CI 0.83–1.12), for MACE-3 0.90 (95%CI 0.76–1.08) and 0.93 (95%CI 0.83–1.04), and for MACE-4 0.81 (95%CI 0.69–0.95) and 0.91 (95%CI 0.83–1.00) in patients with and without HF, respectively. The patient-reported outcomes of APPADL and EQ-5D-5L visual analogue scores improved and were higher on tirzepatide in both groups. Conclusion: With overall non-inferiority established, this exploratory analysis revealed lower rates of the composite of all-cause death or HF events, or MACE-4 among patients with T2D and HF treated with tirzepatide compared with dulaglutide.

OBJECTIVE: Selective glucagon-like protein 1 receptor (GLP-1R) agonists reduce body weight and improve cardiometabolic risk factors. However, whether dual GLP-1R and glucagon receptor (GCGR) agonism modifies these cardiometabolic effects remains unclear. Here, we assessed the effects of dual GLP-1R/GCGR agonists on cardiometabolic risk factors across randomized controlled trials. RESEARCH DESIGN AND METHODS: In this random-effects meta-analysis, Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, and Cochran Central Register of Controlled Trials (CENTRAL) were searched from database inception to 21 June 2026 for randomized controlled trials evaluating clinical efficacy of dual GLP-1R/GCGR agonists in adults with cardiometabolic disease with a treatment duration ≥12 weeks. The primary outcome was placebo-corrected change in body weight from baseline to end of treatment. Secondary outcomes were changes in waist circumference, atherogenic lipids (total cholesterol, LDL cholesterol, and triglycerides), glycated hemoglobin, and hemodynamic outcomes. Prespecified subgroup analyses evaluated effect modification by dose, treatment indication, and the use of an active comparator (selective GLP-1R agonists). RESULTS: A total of 6,593 records were identified, and 16 trials comprising 6,611 participants (47.3% male) were included. Dual GLP-1R/GCGR agonists significantly reduced body weight compared with placebo (−7.44% [95% CI −9.44, −5.43]; −7.27 kg [95% CI −9.28, −5.27]). Weight loss was accompanied by improvements across all cardiometabolic risk factors. Compared with selective GLP-1R agonists, dual GLP-1R/GCGR agonists were associated with a greater reduction in triglycerides (−0.28 mmol/L [95% CI −0.50, −0.06]). CONCLUSIONS: Dual GLP-1R/GCGR agonists consistently improved cardiometabolic risk factors across randomized clinical trials and may provide metabolic benefits beyond selective GLP-1R agonists. These findings support further evaluation in large-scale outcome studies.

Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists and tirzepatide, a dual GLP1R and glucose-dependent insulinotropic polypeptide receptor agonist, have become fundamental in managing type 2 diabetes mellitus (T2DM) and obesity due to their potent glycaemia-lowering and weight-lowering effects as well as their cardiovascular and renal benefits. However, data from the past 2 years suggest that real-world persistence on these drug classes is often suboptimal, with many people discontinuing these medications, even within their first year of therapy. Reasons for treatment discontinuation include, but are not limited to, gastrointestinal adverse effects, less-than-desired efficacy, high cost, and fear about uncommon or rare adverse effects. When treatment is discontinued, weight regain and the deterioration of multiple cardiometabolic risk factors are common. Repeated cycles of initiation, interruption and re-initiation of these drugs might induce body weight and HbA_1c fluctuations — two risk factors for cardiovascular and microvascular events. These phenomena, coupled with the re-development of overweight or obesity and poor glycaemic control when not on therapy, might increase the long-term risk of complications. The lack of anti-atherosclerotic and plaque-stabilizing effects of incretin-based medications might contribute to elevated cardiovascular risk, especially acutely following their discontinuation. However, at present, few data are available regarding the incidence of hard outcomes in people discontinuing such drugs. In this Review, we discuss common reasons for GLP1R agonist and tirzepatide discontinuation and examine available evidence related to potential cardiometabolic consequences. We also discuss long-term implications for T2DM care, weight management and, ultimately, cardiorenal disease prevention in patients with T2DM and/or overweight or obesity.

Incretin-based pharmacology has revolutionized the medical treatment of type 2 diabetes and obesity. The most effective drug to date is tirzepatide, a dual incretin receptor agonist that engages both the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). While the relative contributions of GIPR and GLP-1R actions to the clinical effects of tirzepatide have not been established, the potency of this agent has reignited interest in the clinical potential of GIPR agonism. Here, we discuss incretin biology as it relates to metabolic pharmacology and contextualize the mechanisms by which GIPR activity could contribute to the development of new and effective drugs. We explore current and future applications of GIPR agonists and antagonists, to underscore the potential that this signaling system could add to treatment of type 2 diabetes and obesity.

OBJECTIVE: In prespecified analyses, the treatment effect for MACE of tirzepatide compared with imputed placebo was estimated using SURPASS-CVOT and REWIND data. RESEARCH DESIGN AND METHODS: The indirect comparison with placebo was conducted for primary (MACE-3) and secondary outcomes of SURPASS-CVOT. The analysis included data from REWIND participants who would have been eligible for SURPASS-CVOT and all participants from SURPASS-CVOT. Propensity score estimation was used to adjust for differences in participant characteristics between studies. The indirect analysis of the treatment effect was derived by multiplying the hazard ratio (HR) for MACE-3 between tirzepatide and dulaglutide in SURPASS-CVOT by the HR for dulaglutide versus placebo in REWIND. Sensitivity analyses were performed using unadjusted analyses, including both the selected REWIND and the entire REWIND populations, and adjusted analysis in the entire REWIND population. Post hoc sensitivity analyses used data from a recent GLP-1RA meta-analysis that included REWIND. RESULTS: Analyses included 2,055 of 9,901 participants from REWIND and all 13,165 participants from SURPASS-CVOT. In indirect treatment effect comparisons, tirzepatide versus placebo was associated with lower MACE-3 (HR 0.72; 95% CI 0.55, 0.94), death from CV cause or heart failure events (HR 0.70; 95% CI 0.51, 0.96), and all-cause death (HR 0.61; 95% CI 0.45, 0.82). Sensitivity analyses, including nonadjusted or the entire REWIND cohort data or meta-analysis data for GLP-1RAs, were generally consistent. CONCLUSIONS: In this indirect prespecified exploratory comparison, tirzepatide compared with imputed placebo was associated with reduced CV outcomes and all-cause mortality in participants with type 2 diabetes and established atherosclerotic CV disease.

Plasma glucose and HbA _1c concentrations below the diagnostic threshold for diabetes have been achieved in people with type 2 diabetes (T2DM) in three clinical settings: with intensive weight‐management programs that induce > 10–15 kg bodyweight loss, following bariatric surgery, and during treatment with highly effective glucose‐ and weight‐lowering medications. The current consensus definition of T2DM remission excludes a status of absence of diabetes achieved with concomitant use of glucose‐ and weight‐lowering medications. However, since these treatments can safely achieve HbA _1c and plasma glucose concentrations lower than the ones currently used to define remission, we propose to consider a separate category of diabetes remission mainly achieved and maintained with pharmacological treatment. Our arguments are based on: (1) the similar endocrine mechanisms associated with bariatric surgery and use of GLP‐1 receptor agonists or GIP/GLP‐1 dual receptor agonists, (2) the lack of evidence that the effects of near‐normoglycemic states achieved with lifestyle, surgery or glucose‐ and weight‐lowering medications on long‐term complications differ and (3) the frequent use of these medications in conjunction with both lifestyle interventions and following bariatric surgery. With this proposal, we aim to invite further discussion towards expanding the current narrow definition of T2D remission to include remission during treatment with newer highly effective glucose‐ and weight‐lowering medications.

Aims/Hypothesis: Initial dose‐escalation has been shown to mitigate gastrointestinal adverse events in people treated with incretin‐based medications. We aimed to analyse dose‐response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP‐1 receptor agonists and the dual GIP/GLP‐1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials. Methods: Non‐linear regression analysis (curve fitting) was used to estimate the dose that would elicit nausea or vomiting in 50% of exposed subjects (ED ₅₀ ). We used the ratio of ED ₅₀ ies determined for Phase 1 and Phase 3 trials as an indicator of developing tolerance. Results: The development of tolerance for nausea and vomiting (indicated by a ratio of ED ₅₀ ies Phase 3/Phase 1) for semaglutide (both s.c. and oral) and for tirzepatide was significantly higher than 1. Comparing all approved incretin‐based medications, a higher ratio, indicating the development of more tolerance, was associated with (a) a longer drug escalation period and (b) a greater number of dose‐escalation steps. This ED ₅₀ ratio (Phase 3/Phase 1) was also significantly associated with effect sizes for intended therapeutic actions of incretin mimetics (reductions in HbA _1c and body weight). Conclusions/Interpretation: Taken together, optimised dose‐escalation regimens may lead to greater tolerance for nausea and vomiting, which allows to use of higher doses, which are associated with greater therapeutic effectiveness.