This article was written in collaboration with Dr. Timothy Garvey, Associate Director, Professor, Department of Nutrition Sciences, School of Health Professions, Senior Scientist, UAB Nutrition Obesity Research Center
In the last 15 years, the landscape of diabetes and obesity management has been significantly transformed by the advent of GLP-1 receptor agonists which are about to become the most successful drugs in the history of medicine, eclipsing drugs like insulin and statin. This article delves briefly into the historical development of key GLP-1 agonists, explores their mechanism of action, and their application in patients with heart disease who suffer from Type 2 Diabetes Mellitus (T2DM) and obesity, while also contemplating the future with emerging players like retatrudide, ushering into a new era of triple-G therapies.
Historical Development:
The journey of GLP-1 receptor agonists began in 2005 with the approval of exanatide (Byetta) which was administered twice a day. Liraglutide (Victoza and Saxenda) were approved in 2010 and 2014 respectively and can be administered daily. Over the subsequent years, the pharmaceutical landscape witnessed groundbreaking developments, with long-acting GLP-1 agonists that could be administered on a once-a-week basis. A long-acting form of exanatide (Bydureon) was approved in 2012, dulaglutide (Trulicity) in 2014, semaglutide (Ozempic for T2DM) in 2017, and the latest addition, tirzepatide (Mounjaro for T2DM) in 2022, all of which can be administered weekly by SC injections. Each milestone reflected an ongoing commitment to refining treatment options for patients grappling with the dual challenges of diabetes and obesity.
Mechanism of Action and effect on body weight:
GLP-1 receptor agonists or incretins, exert their therapeutic effects by mimicking the action of endogenous glucagon-like peptide-1. These agents stimulate insulin secretion, suppress glucagon release, and slow gastric emptying, collectively contributing to improved glycemic control with glucose-lowering without significant hypoglycemia. Beyond the pancreas, GLP-1 agonists also exert effects on the craving/reward center of the brain, influencing appetite regulation and satiety. This dual action makes incretins particularly promising in addressing the complex interplay between metabolism and neuroendocrine signaling and contributes to weight loss with the highest potency for tirzepatide, followed by semaglutide sc. and high-dose dulaglutide. GLP-1 receptors can be found in multiple organs including the heart and blood vessels contributing to increased glucose utilization, cardioprotection, vasodilatation, and increased cardiac output. At the kidney level, GLP-1 agonists can increase diuresis; in the immune system, they can cause a decrease in inflammation; in the liver, they can reduce steatosis or fatty liver, decrease VLDL, and reduce glucose production; in the adipose tissue, they increase lipolysis and increase glucose uptake.
Liraglutide 3 mg SC lowered the weight compared to baseline at 1 yr by approximately 6% in patients with obesity and without T2DM. Patients with obesity without DM tend to lose more weight than their T2DM comparators: In the STEP 5 study, semaglutide (Wegovy) 2.4 mg sc weekly, for patients with obesity without DM lost an average of 15% of their body weight. Compared to their baseline, at 68 weeks, 86% of participants had lost >5%of their body weight, 50% > 15%, and 30% had lost more than 20%. Of note, 14% had minimal to no response to semaglutide. In comparison, in the SUSTAIN 1-5 trials of patients with T2DM, semaglutide (Ozempic) 1 mg sc weekly induced weight loss of 5-6% on average from baseline. Patients with larger BMI tended to lose more weight.
Tirzepatide is a single molecule that activates the GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors. It enhances insulin secretion if the blood sugar is too high, suppresses glucagon and hepatic glucose, improves insulin sensitivity, slows gastric emptying, and suppresses appetite. GIP is responsible for nearly 2/3 of the incretin effects and contributes more to insulin secretion than GLP-1. Changes in body weight in T2DM were evaluated in the SURPASS clinical trials and tirzepatide at doses of 5, 10, and 15 mg reduced body weight by 7.8%, 10.8%, and 12.4% respectively. In the SURMOUNT clinical trials, tirzepatide was evaluated in patients with obesity without DM. At doses of 5, 10, and 15 mg, the average weight loss was 15%, 19.5%, and 20.9% respectively with patients losing between 35 and 52 lbs at the end of 72 weeks. Again, 14% were poor responders and had less than 5% loss.
Applications in Heart Disease patients with T2DM, and Obesity:
The cardiovascular benefits of GLP-1 agonists have garnered attention, with several studies demonstrating their efficacy in reducing major adverse cardiovascular events. Their use extends beyond glycemic control, making them valuable in patients with both heart disease and T2DM. Moreover, GLP-1 agonists have shown remarkable success in managing obesity, a prevalent concern in the diabetic population. The synergy between weight loss and glycemic control positions these agents as versatile tools in the battle against the intertwined epidemics of diabetes and obesity. Cardiovascular outcome (CVOT) benefits of GLP-1 and GIP/GLP-1 agonists in patients with T2DM have been discussed in our article: “Transforming diabetes care: a paradigm shift in treatment approaches”. In brief, a meta-analysis of CVOT trials with GLP-1 agonists reveals a 15% reduction in MACE, 15% reduction in CV death, 12% reduction of MI, and 19% reduction in stroke, 12% reduction in heart failure hospitalization and 22% reduction in renal failure (awaiting FLOW clinical trial).
STEP_HFpEF clinical study of patients with obesity and heart failure with preserved ejection fraction (HFpEF) demonstrated that semaglutide 2.4 mg once a week (Wygovy) produced an average of 10.7% body weight loss with an average gain of 7.8 points on the KCCQ (Kansas City Cardiomyopathy Questionaire) compared to placebo with a reduction of NT-proBNP. These results translate into larger reductions in symptoms and physical limitations with greater improvements in exercise function.
The SELECT trial studied the effect of semaglutide 2.4 mg (Wegovy) weekly in 17,604 patients with a BMI of >27, and pre-existing cardiovascular disease but without T2DM for a mean duration of 33 months. The composite risk of CV death, MI, or stroke was reduced by 20%. The mean weight loss was 9.4% resulting in changes in blood pressure, waist circumference, glycemic control, lipid levels, nephropathy, and C-reactive protein.
Side effects and how to deal with them:
GLP-1 receptor agonists are injected by pen fitted with a 32-gauge needle administered as a sc injection in the abdomen, outer thigh, or arm with minimal site injection discomfort. For the oral semaglutide (Rybelsus) patients are instructed to take the tablet with 1/2 glass of water in a fasting state and wait 30 minutes before drinking or eating. The most common side effects are GI and include nausea and diarrhea (up to 20% at higher doses), vomiting (10%) dyspepsia, and constipation (8%) abdominal pain (4%). To mitigate the side effects, a gradual and slow dose titration helps, eating smaller meals, limiting greasy or fatty foods, encouraging hydration, and bland foods, use of ginger or peppermint can help also. Also to preserve muscle mass, resistance training is encouraged ( with resistance bands or light weights), and eating an adequate protein intake throughout the day. In addition, short-term use of proton inhibitors can help when up-titrating the dose at the beginning.
Looking into the future:
There are multiple ongoing trials using semaglutide and tirzepatide currently: SOUL will look at the effect of semaglutide on CVOT in patients with T2DM with preexisting CV disease and/or CKD, SURPASS CVOT in T2DM will compare tirzepatide to liraglutide in high-risk patients with T2DM, SURMOUNT MMO will study tirzepatide on morbidity and mortality in patients with obesity. REDEFINE-3 will compare the combination of semaglutide 2.4 mg with 2.4 mg of cagrilintide (CagriSema) to a maximum dose of tirzepatide (Zepbound) in adults with obesity. Cagrilintide is a long-acting amylin analog potentiating the weight-loss effect of semaglutide. In a phase 2 trial of CangriSema, the combination treatment produced a 15.6% weight loss from baseline at week 32. SYNCHRONIZE-CVOT will study the effect of survodutide in patients with BMI >27 and with preexisting cardiovascular disease or CKD. Survotudide is a dual agonist that stimulates the GLP-1 and Glucagon receptors. Phase 2 studies revealed waist circumference reduction of up to 16 cm, weight reduction of up to 19.5 kg, and reduction of systolic and diastolic blood pressure.
Also exciting is the report of a phase 2 study of the first triple-hormone-receptor agonist, retatrutide for obesity. The dose-response of 1 mg, 4 mg, 8 mg, and 12 mg sc weekly of this GLP-1/GIP/Glucagon receptor agonist was evaluated in patients with BMI >27. At 48 weeks weight reduction of >5%, >10%, or >15% had occurred in 100%, 91%, and 75% of patients who received 8 mg. The average weight loss was 24.8% and a plateau had not been reached at the end of the study. As in prior GLP-1 agonist studies, GI side effects are most common and include nausea, vomiting, diarrhea, and constipation and occur in approximately half the patients during the first month of dose escalation. At high dose, transient sinus tachycardia was noted. Those symptoms are mitigated by using a smaller dose at initiation. A phase 3 clinical trial is planned for this year for patients with type 2 DM and BMI >27.
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