Incretin-based therapies for the treatment of obesity-related diseases

Abstract

Obesity-related disability-adjusted life years (DALYs) are expected to increase by approximately 40% from 2020 to 2030. DALYs and mortality related to obesity are the consequence of multiple comorbidities such as cardiovascular (i.e., heart failure) and metabolic diseases (i.e. type 2 diabetes [T2D], metabolic dysfunction-associated steatotic liver disease [MASLD]). Lifestyle interventions represent the foundation of obesity treatment, yet an escalation to pharmacological and/or surgical interventions is often needed. Liraglutide, semaglutide and tirzepatide are incretin-based therapies currently approved by FDA for the management of obesity, while triple GIPR/GCGR/GLP-1R agonist retatrutide (LY3437943), the cagrilintide/semaglutide (CagriSema) 2.4 mg combination, high-dose oral semaglutide, and oral orforglipron are in advanced stages of development. Incretin-based therapies have been associated with a body weight (BW) reduction of ≥5% in at least half of patients in most randomized controlled trials (RCT) and real-world studies (RWS). Semaglutide and tirzepatide have also displayed a mean 60-69% 10-years relative risk reduction of T2D development. In line with evidence accrued in patients with T2D, incretin-based therapies produced a favorable effect on traditional cardiovascular risk factors, such as lipids and blood pressure, and even reduced the risk of major cardiovascular events and heart failure-related events in individuals with obesity, as recently demonstrated for the first time in the SELECT trial with semaglutide 2.4 mg once-weekly. Moreover, incretin-based therapies have also been proven beneficial on obesity-related comorbidities, such as knee osteoarthritis (KOA), obstructive sleep apnea (OSA) syndrome, and MASLD. Further research is needed to improve our understanding of their effects on obesity-related comorbidities and the underlying mechanism, whether involving direct effects on target tissues or mediated by improvement in BW, glucose levels and other CV risk factors.

Fig. 1. Proportion of participants with at least 5%, 10%, 15%, 20%, 25% body weight loss across dedicated randomized controlled trials with incretin-based anti-obesity medications.

In randomized controlled trials investigating multiple doses of the experimental medications, results obtained with the highest dose were reported. Standard errors are not shown for data retrieved from a single study. Liraglutide 3.0 mg was administered subcutaneously once daily (refs. ^–,–,); Semaglutide 2.4 mg (refs. ^–,–), Tirzepatide 15 mg (refs. ^–) and Retatrutide 12 mg (refs. ) were administered subcutaneously once-weekly; Semaglutide 50 mg (refs. ) and Orforglipron 45 mg (refs. .) were administered orally once daily.

Fig. 2. Proportion of participants with normoglycemia, prediabetes and type 2 diabetes at baseline and end of study in dedicated randomized controlled trials with incretin-based anti-obesity medications.

EOS data refer only to participants with baseline prediabetes. Baseline data for liraglutide 3.0 mg are from SCALE Obesity and Prediabetes (ref. ), EOS data are from SCALE Obesity and Prediabetes extension (ref. ). Data for semaglutide 2.4 mg are a mean of the results from STEP 1, 3, 4 (refs. ^–). Data for tirzepatide (ref. ) and retatrutide (ref. ) refer to pooled doses. Liraglutide 3.0 mg was administered subcutaneously once daily; Semaglutide 2.4 mg, Tirzepatide 15 mg and Retatrutide 12 mg were administered subcutaneously once-weekly; Semaglutide 50 mg was administered orally once daily. EOS end of study, Lira liraglutide, Sema semaglutide, T2D type 2 diabetes.

Fig. 3. Effect of incretin-based anti-obesity medications on lipid profile and blood pressure in dedicated randomized controlled trials.

a, b Depict the effect of incretin-based anti-obesity medications on lipid profile and blood pressure, respectively. Liraglutide 3.0 mg was administered subcutaneously once daily (refs. ^–,–,); Semaglutide 2.4 mg (refs. ^–,–), Tirzepatide (refs. ^–,) and Retatrutide were administered subcutaneously once-weekly (ref. ); Semaglutide 50 mg (ref. ) and Orforglipron (ref. ) were administered orally once daily. Data on the effect of Tirzepatide, Retatrutide and Orforglipron were reported for pooled doses. C cholesterol, DBP diastolic blood pressure, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Lira liraglutide, SBP systolic blood pressure, Sema semaglutide, TG triglycerides, TZP tirzepatide.

Fig. 4. Association of mean between-arm HbA1c difference and the risk of MACE and its components across CVOT trials with GLP-1 receptor agonists.

The association of mean between-arm HbA1c difference and MACE HR (a) (R² = 0.47, p < 0.05) is largely driven by reduction of stroke (b) (R² = 0.57, p < 0.05) rather than CV mortality (c) or MI (d) HR. CV cardiovascular, HR hazard ratio, MACE major adverse cardiovascular events, MI myocardial infarction.

Fig. 5. Effect of incretin-based therapies on obesity-related comorbidities.

Summary of the effects of incretin-based therapies on obesity-related comorbidities and their underlying mechanisms according to results of studies conducted in individuals with obesity regardless of the presence of diabetes. AE adverse event, AHI apnea-hypopnea index, BW body weight, CKD chronic kidney disease, CV cardiovascular, DBP diastolic blood pressure, ED erectile dysfunction, eGFR estimated glomerular filtration rate, GERD gastroesophageal reflux disease, HF heart failure, hHF hospitalization for heart failure, KCCQ Kansas City Cardiomyopathy Questionnaire, KOA knee osteoarthritis, LDL-c LDL cholesterol, MACE major adverse cardiovascular events, MASH metabolic dysfunction-associated steatohepatitis, MASLD metabolic dysfunction-associated steatotic liver disease, OSA obstructive sleep apnea, PCOS polycystic ovary syndrome, SBP systolic blood pressure, T2D type 2 diabetes, VAT visceral adipose tissue. Underlining identifies results from preclinical studies. Red circles, results applicable to most incretin-based therapies; blue circles, results applicable to liraglutide; green circles, results applicable to semaglutide; purple circles, results applicable to dulaglutide; yellow circles, results applicable to tirzepatide; filled circles indicate mostly BW loss-mediated benefits.