Abstract
Introduction
Obesity has been recognized as a major public health problem and associated with many comorbidities and complications such as diabetes, cardiovascular & renal diseases, metabolic dysfunction–associated steatotic liver diseases, and musculoskeletal problems. In our previous book chapters (ATTD Yearbook 2022 & 2023), we have highlighted increasing prevalence of overweight and obesity across the world.
Development of glucagon-like peptide-1 receptor analogs (GLP-1RA) and dual agonists for gastrointestinal polypeptide (GIP) receptor and GLP-1R has changed the landscape of diabetes and obesity management. In this book chapter, we refer both GLP-1RA and dual agonist molecules as a GLP-1RAs. These molecules are now the cornerstone for management of diabetes, obesity and associated cardiovascular, renal, and hepatic diseases. There has been number of clinical trials documenting efficacy and safety of these molecules for management of obesity and diabetes.
In this year’s book chapter, we have focused on highlighting some landmark outcome clinical trials with the use of GLP-1RAs for obesity treatment in people with and without diabetes that were published in the year 2023–2024. To develop this book chapter, we screened PubMed using the term “obesity and diabetes” [all field]. Only clinical trials in human and published between July 1, 2023, to June 30, 2024, in English language were reviewed. With this search strategy, we found 319 clinical trials. We selected six trials related to the effect of different GLP-1RAs in patients with obesity with or without diabetes.
Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes
Kosiborod MN1, Petrie MC2, Borlaug BA5, Butler J6,7, Davies MJ3, Hovingh GK8, Kitzman DW10, Møller DV8, Treppendahl MB8, Verma S11, Jensen TJ8, Liisberg K8, Lindegaard ML8, Abhayaratna W13, Ahmed FZ4, Ben-Gal T14, Chopra V15, Ezekowitz JA12, Fu M16, Ito H17, Lelonek M18, Melenovský V19, Merkely B20, Núñez J21,22, Perna E23, Schou M9, Senni M24, Sharma K25, van der Meer P26, Von Lewinski D27, Wolf D28, Shah SJ29; for the STEP-HFpEF DM Trial Committees and Investigators
1Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, MO; 2School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK; 3Diabetes Research Centre, University of Leicester, and the NIHR Leicester Biomedical Research Centre, Leicester, UK; 4Division of Cardiovascular Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, UK; 5Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN; 6Baylor Scott and White Research Institute, Dallas, TX; 7Department of Medicine, University of Mississippi, Jackson, MS; 8Novo Nordisk, Søborg, Demnark; 9Department of Cardiology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark; 10Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, NC; 11Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, Canada; 12University of Alberta, Edmonton, Canada; 13College of Health and Medicine, Australian National University, Canberra, ACT, Australia; 14Heart Failure Unit, Cardiology Department, Rabin Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 15Max Super Speciality Hospital, Saket, New Delhi, India; 16Section of Cardiology, Department of Medicine, Sahlgrenska University Hospital-Östra, Gothenburg, Sweden; 17Department of General Internal Medicine 3, Kawasaki Medical School, Okayama, Japan; 18Department of Noninvasive Cardiology, Medical University of Lodz, Lodz, Poland; 19Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 20Heart and Vascular Center, Semmelweis University, Budapest, Hungary; 21Hospital Clínico Universitario de Valencia, INCLIVA, Universidad de Valencia, Valencia, Spain; 22CIBER (Centro de Investigación Biomédica en Red) Cardiovascular, Valencia, Spain; 23Instituto de Cardiologia J.F. Cabral, Corrientes, Argentina; 24ASST (Azienda Socio Sanitaria Territoriale) Papa Giovanni XXIII, Bergamo, Italy; 25Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD; 26Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 27Medical University of Graz, Graz, Austria; 28Cardiology and Angiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, German; 29Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
N Engl J Med 2024; 390: 1394–1407
Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes.
We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.
A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P < 0.001), and the mean percentage change in body weight was −9.8% with semaglutide and −3.4% with placebo (estimated difference, −6.4 percentage points; 95% CI, −7.6 to −5.2; P < 0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P < 0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P < 0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group.
Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year.
Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity
Kosiborod MN1, Abildstrøm SZ2, Borlaug BA4, Butler J5,6, Rasmussen S2, Davies M7, Hovingh GK2, Kitzman DW10, Lindegaard ML2, Møller DV2, Shah SJ11, Treppendahl MB2, Verma S12, Abhayaratna W14, Ahmed FZ8, Chopra V15, Ezekowitz J13, Fu M16, Ito H17, Lelonek M18, Melenovsky V19, Merkely B20, Núñez J21,22, Perna E23, Schou M3, Senni M24, Sharma K25, Van der Meer P26, von Lewinski D27, Wolf D28, Petrie MC9; for the STEP-HFpEF Trial Committees and Investigators
1Department of Cardiovascular Disease, Saint Luke’s Mid America Heart Institute, University of Missouri–Kansas City School of Medicine, Kansas City, MO; 2Novo Nordisk, Søborg, Denmark; 3Department of Cardiology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark; 4Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN; 5Baylor Scott and White Research Institute, Dallas, TX; 6Department of Medicine, University of Mississippi, Jackson, MS; 7Diabetes Research Centre, University of Leicester, and National Institute for Health and Care Research Leicester Biomedical Research Centre, Leicester, UK; 8Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; 9School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK; 10Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, NC; 11Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; 12Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, Canada; 13University of Alberta, Edmonton, Canada; 14College of Health and Medicine, the Australian National University, Canberra, ACT, Australia; 15Max Super Specialty Hospital, New Delhi, India; 16Section of Cardiology, Department of Medicine, Sahlgrenska University Hospital-Ostra, Gothenburg, Sweden; 17Department of General Internal Medicine 3, Kawasaki Medical School, Okayama, Japan; 18Department of Noninvasive Cardiology, Medical University of Lodz, Lodz, Poland; 19Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 20Heart and Vascular Center, Semmelweis University, Budapest, Hungary; 21Hospital Clínico Universitario de Valencia, INCLIVA, Universidad de Valencia, Valencia, Spain; 22CIBER (Centro de Investigación Biomédica en Red) Cardiovascular, Valencia, Spain; 23Instituto de Cardiologia J.F. Cabral, Corrientes, Argentina; 24ASST (Azienda Sociosanitaria Territoriale) Papa Giovanni XXIII, Bergamo, Italy; 25John Hopkins Hospital, Baltimore, MD; 26Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 27Medical University of Graz, Graz, Austria; 28Cardiology and Angiology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
N Engl J Med 2023; 389: 1069–1084
Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction.
We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.
The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P < 0.001), and the mean percentage change in body weight was −13.3% with semaglutide and −2.6% with placebo (estimated difference, −10.7 percentage points; 95% CI, −11.9 to −9.4; P < 0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P < 0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P < 0.001). The mean percentage change in the CRP level was −43.5% with semaglutide and −7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P < 0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group.
In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo (Funded by Novo Nordisk; STEP-HFpEF.
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
Lincoff AM1, Brown-Frandsen K2, Colhoun HM3, Deanfield J4, Emerson SS5, Esbjerg S2, Hardt-Lindberg S2, Hovingh GK2,7, Kahn SE6, Kushner RF8, Lingvay I9, Oral TK2, Michelsen MM2, Plutzky J10, Tornøe CW2, Ryan DH11 for the SELECT Trial Investigators
1Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; 2Novo Nordisk, Søborg, Denmark; 3Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh UK; 4National Institute for Cardiovascular Outcomes Research, University College London, London, UK; 5Department of Biostatistics, University of Washington, Seattle, WA; 6Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA; 7Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; 8Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL; 9Department of Internal Medicine (Endocrinology Division) and Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX; 10Department of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 11Pennington Biomedical Research Center, Baton Rouge, LA
N Engl J Med 2023; 389: 2221–2232
Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown.
In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.
A total of 17,604 patients were enrolled; 8,803 were assigned to receive semaglutide and 8,801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2 ± 13.7 months, and the mean duration of follow-up was 39.8 ± 9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8,803 patients (6.5%) in the semaglutide group and in 701 of the 8,801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P < 0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1,461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P < 0.001).
In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months.
Continued Treatment with Tirzepatide for Maintenance of Weight Reduction in Adults with Obesity: The SURMOUNT-4 Randomized Clinical Trial
Aronne LJ1, Sattar N2, Horn DB3, Bays HE4, Wharton S5, Lin WY6, Ahmad NN7, Zhang S7, Liao R7, Bunck MC7, Jouravskaya I8, Murphy MA7; for the SURMOUNT-4 Investigators
1Comprehensive Weight Control Center, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York, NY; 2BHF Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK; 3University of Texas Center for Obesity Medicine and Metabolic Performance, Department of Surgery, University of Texas McGovern Medical School, Houston, TX; 4Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY; 5McMaster University, and Wharton Weight Management Clinic, York University, Toronto, Ontario, Canada; 6Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan; 7Eli Lilly and Company, Indianapolis, IN; Eli Lilly and Company, Moscow, Russia
JAMA 2024; 331: 38–48
The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.
The objective of this study was to assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction.
This phase 3, randomized withdrawal clinical trial conducted at 70 sites in four countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes.
Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks.
The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period.
Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs 14.0% with placebo (difference, −19.4% [95% CI, −21.2% to −17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo.
In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.
Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity
Wharton S1,2,3, Blevins T4, Connery L6, Rosenstock J5, Raha S7, Liu R7, Ma X7, Mather KJ7, Haupt A7, Robins D7, Pratt E7, Kazda C7, Konig M7; for the GZGI Investigators
1McMaster University, Toronto, Canada; 2York University, Toronto, Canada; 3Wharton Weight Management Clinic, Toronto, Canada; 4Texas Diabetes and Endocrinology, Austin, TX; 5Velocity Clinical Research at Medical City, Dallas, TX; 6Alliance for Multispecialty Research, Norman, OK; 7Eli Lilly, Indianapolis, IN
N Engl J Med 2023; 389: 877–888
Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity.
In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point).
A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from −8.6% to −12.6% across the orforglipron dose cohorts and was −2.0% in the placebo group. At week 36, the mean change ranged from −9.4% to −14.7% with orforglipron and was −2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class.
Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists.
Glucagon and GLP-1 Receptor Dual Agonist Survodutide for Obesity: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Phase 2 Trial
Roux CW1, Steen O2, Lucas KJ3, Startseva E4, Unseld A5, Hennige AM6
1Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland; 2LMC Diabetes and Endocrinology, Toronto, ON, Canada; 3Diabetes and Endocrinology Consultants, Morehead City, NC; 4Boehringer Ingelheim International GmbH, Ingelheim, Germany; 5Boehringer Ingelheim Pharma GmbH, Biberach an der Riß, Germany; 6Boehringer Ingelheim International GmbH, Biberach an der Riß, Germany
Lancet Diabetes Endocrinol 2024; 12: 162–173
Obesity is a widespread and chronic condition that requires long-term management; research into additional targets to improve treatment outcomes remains a priority. This study aimed to investigate the safety, tolerability, and efficacy of glucagon receptor-GLP-1 receptor dual agonist survodutide (BI 456906) in obesity management.
In this randomized, double-blind, placebo-controlled, dose-finding phase 2 trial conducted in 43 centers in 12 countries, we enrolled participants (aged 18–75 years, BMI ≥27 kg/m2, without diabetes) and randomly assigned them by interactive response technology (1:1:1:1:1; stratified by sex) to subcutaneous survodutide (0.6, 2.4, 3.6, or 4.8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance). The primary endpoint was the percentage change in bodyweight from baseline to week 46. Primary analysis included the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of trial medication and who had analyzable data for at least one efficacy endpoint) and was based on the dose assigned at randomization (planned treatment), including all data censored for COVID-19-related discontinuations; the sensitivity analysis was based on the actual dose received during maintenance phase (actual treatment) and included on-treatment data. Safety analysis included all participants who received at least one dose of study drug.
Between March 30, 2021, and November 11, 2021, we enrolled 387 participants; 386 (100%) participants were treated (0.6 mg, n = 77; 2.4 mg, n = 78; 3.6 mg, n = 77; 4.8 mg, n = 77; placebo n = 77) and 233 (60.4%) of 386 completed the 46-week treatment period (187 [61%] of 309 receiving survodutide; 46 [60%] of 77 receiving placebo). When analyzed according to planned treatment, mean (95% CI) changes in bodyweight from baseline to week 46 were −6.2% (−8.3 to −4.1; 0.6 mg); −12.5% (−14.5 to −10.5; 2.4 mg); −13.2% (−15.3 to −11.2; 3.6 mg); −14.9% (−16.9 to −13.0; 4.8 mg); −2.8% (−4.9 to −0.7; placebo). Adverse events occurred in 281 (91%) of 309 survodutide recipients and 58 (75%) of 77 placebo recipients; these were primarily gastrointestinal in 232 (75%) of 309 survodutide recipients and 32 (42%) of 77 placebo recipients.
All tested survodutide doses were tolerated and dose-dependently reduced bodyweight.
The GLP-1RAs were already demonstrated to improve glycemic outcomes and cause significant weight loss. Previous studies lifestyle interventions (PMID: 23796131) and other weight loss agents failed to demonstrate improvement in CV safety despite significant weight loss (https://www.ncbi.nlm.nih.gov/books/NBK581942/). Hence, demonstrating weight loss with cardiovascular (CV) safety was necessary for GLP-1RA agents. The manuscripts published in recent years clearly support the notion that the weight loss induced by GLP-1RA are accompanied by a broad benefit on the cardiovascular, renal, and hepatic systems, and these effects were observed in people with and without diabetes.
Clinical trials of GLP-1RAs demonstrated significant reduction in the progression of heart failure with reduced ejection fraction (HFrEF) in previous years. A recent study suggests that semaglutide, a GLP-1RA, is also effective in ameliorating the progression of heart failure with preserved ejection fraction (HFpEF) in patients with obesity, with (Article 1 of this book chapter) or without (Article 2) diabetes. Both trials had a similar design and included people with BMI > 30 with diagnosis of HFpEF. The primary endpoint was the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS). Secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. In both trials, clinically meaningful reduction of all these endpoints were observed, suggesting potentials of semaglutide in changing the trajectory of the disease by treating obesity and the associated, chronic inflammatory status.
The semaglutide has also proved effective in reducing the incidence of atherosclerosis-related endpoints in people with obesity without diabetes (Article 3). Semaglutide, both its injectable and oral formulations, had already demonstrated to reduce the incidence of major adverse cardiovascular events (MACE), a composite outcome including myocardial infarction, stroke, and cardiovascular mortality, in patients with type 2 diabetes. These results have now been extended to people without diabetes with a BMI>27 and history of CVD.
In the STEP-1 extension trial, 1 year after withdrawal of once-weekly semaglutide 2.4 mg, participants regained two-thirds of their prior weight loss, suggesting that obesity is a chronic disease and requires long-term therapy. This evidence now extends to tirzepatide, a GLP-1/GIP dual agonist. In individuals with obesity or overweight, discontinuation of tirzepatide therapy resulted in a significant regaining of previously lost weight. Conversely, the continuation of tirzepatide administration not only preserved the initial weight reduction but also enhanced it further (Article 4).
Most weekly GLP-1RA agents are injectable, which is not an acceptable form of drug delivery by many people with obesity/type 2 diabetes. At present only semaglutide has an approved in oral formulation, with similar glycemic efficacy and CV safety as of injectable semaglutide. A recent trial demonstrated that orforglipron, a once-daily oral nonpeptide GLP-1RA, is effective in reducing body weight (Article 4). If the weight benefit is paralleled by the CV benefit, oral GLP-1RA may represent an option for patients not willing to receive injectable therapies. Many other GLP-1RAs are currently under development. We presented here weight loss efficacy of a novel glucagon-GLP-1R agonist under development, Survodutide, in people with obesity without diabetes (Article 6). The efficacy and safety were comparable to other GLP-1RAs.
The effects of GLP-1RAs for diabetes, obesity, and its complications have completely taken the stage, with an ever-increasing interest and a goal of managing obesity as a risk factor for cardiovascular diseases and diabetes. The burden of the evidence prompted the prestigious journal, Science, to name GLP-1 RA the 2023 Breakthrough of the Year (https://www.science.org/content/article/breakthrough-of-the-year-2023#section_breakthrough).
Author Disclosure Statement
A.C. reports on being on Advisory Board, Consultancy, Lectures: Abbott, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Hikamr Pharma, Guidotti, Eli Lilly, MSD, Merck, Novo, Roche Diagnostics, Sanofi, Servier, SUN Pharma
“VNS” institution has received research grants from Alexion, Dexcom, Enable Bioscience, Breakthrough T1D and NIH. VNS has received honoraria from Sanofi, NovoNrodisk, Lilly, Dexcom, Insulet, Embecta, Ascensia Diabetes Care, Tandem Diabetes Care, Genomelink and Lumosfit for speaking, consulting or advising outside of this work. V.S. reports no relevant disclosure related to this book chapter.