According to the American Diabetes Association’s (ADA) “Standards of Medical Care in Diabetes,” there is strong and dependable data showing that obesity management delays the progression of prediabetes to T2D and improves glycemic management while reducing the need for glucose-lowering medications in those with T2D.
As the incidence of obesity continuously increases throughout the country, the demand for new and more effective treatments increases as well. Proper management of excessive body weight is necessary to delay or prevent the development of obesity-related complications, including but not limited to type 2 diabetes (T2D), cardiovascular disease (CVD), and certain cancers.1
Obesity affects hundreds of millions of people worldwide and can be influenced by various behavioral and environmental factors and genetic predispositions. It’s a complex condition indicated in part by body mass index (BMI), which utilizes height and weight to estimate total body fat. In adults, a calculated BMI ≥30 signifies obesity, and a BMI ≥40 is indicative of severe obesity.1 Obesity is associated with significant stigma, leading to a negative psychological impact on one’s mental health.1 Using a patient-centered approach and communicating with nonjudgmental language may encourage collaboration between patients and providers and minimize treatment barriers.1
According to the American Diabetes Association’s (ADA) “Standards of Medical Care in Diabetes,” there is strong and dependable data showing that obesity management delays the progression of prediabetes to T2D and improves glycemic management while reducing the need for glucose-lowering medications in those with T2D.1
The treatment landscape for T2D and obesity is robust, with many drugs in the pipeline, some having novel double and triple mechanisms of action. This review summarizes and concentrates on data for currently approved incretin-based treatments and agents on the horizon for dual treatment of diabetes and obesity (diabesity). There are numerous agents in various stages of investigation specifically being studied only for the treatment of obesity, which is beyond the scope of this review.
For people who want to minimize weight gain or promote weight loss, the ADA supports the use of agents indicated for the treatment of T2D that have efficacy for weight loss as preferred drugs of choice.2 These include glucagon-like peptide 1 receptor agonists (GLP-1 RAs), dual gastric inhibitory peptide (GIP)/GLP-1 RAs, and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is).2 They preferentially place injectable semaglutide and tirzepatide as “very high” efficacy, with dulaglutide and liraglutide considered “high” efficacy and exenatide and SGLT2-Is as “intermediate” efficacy.2 Diet, exercise, and behavioral counseling are indicated in people with diabetes and overweight or obesity regardless of their BMI, and pharmacotherapy is recommended with a BMI >27.1 Successful treatment with pharmacotherapy is defined as >5% weight loss after 3 months of use.1
There are several agents that are approved by the Food and Drug Administration (FDA) for the treatment of obesity. They include phentermine, orlistat, phentermine/topiramate extended release (ER), naltrexone/bupropion ER, liraglutide 3 mg, and semaglutide 2.4 mg.1 Considered a medical device, an oral hydrogel (Plenity) is also an option for obesity management.1 Of this list, only liraglutide and semaglutide have a dual FDA indication for both obesity and T2D, and although not compared to the others, they appear to be the most effective of the currently approved agents.2 Most recently, significant attention has been brought to a recently approved GIP/GLP-1 RA tirzepatide in T2D for robust weight loss.3 It is currently being investigated for an obesity indication and has recently been granted a fast-track designation by the FDA.4 There are multiple agents currently in development and in various stages of study for T2D and obesity.
Interest in GLP-1RAs for obesity first peaked when injectable exenatide twice a day was approved for T2D in 2005 and weight loss was seen.5 Injectable liraglutide once a day was approved in 2010 for T2D6 and later approved and marketed for obesity under a different brand name and dosing in 2014.7 This was followed by the approval of injectable semaglutide once weekly in 2017 for diabetes,8 which was later approved and marketed with a different brand name and dosing for obesity in 20219 (see Table 1).
For people who want to minimize weight gain or promote weight loss, the ADA supports the use of agents indicated for the treatment of T2D that have efficacy for weight loss as preferred drugs of choice.
The growth of the obesity market has led to shortages of these agents, with prescribers utilizing the drugs marketed for diabetes for obesity instead, particularly when there have been shortages of the agents approved for obesity. Patients with T2D have had trouble filling prescriptions for GLP-1RA and GIP/GLP-1RA due to off-label use for obesity. Due to this usage, shortages of these agents have been reported, with manufacturers having difficulty meeting the demand.10
Agents currently FDA approved for T2D and being studied for obesity that are closest to approval are tirzepatide and oral semaglutide. Tirzepatide is aiming to obtain an additional indication after showing weight loss reductions of up to 22.5% in its phase 3 obesity trial (SURMOUNT-1).11 Another phase 3 trial (OASIS-1) studied semaglutide’s oral formulation for an obesity indication at a higher dose of 50 mg daily compared to its currently approved lower doses of 7 mg and 14 mg for T2D. This trial found weight loss reductions of up to 15.1%.12 In a phase 3b trial (PIONEER PLUS), the efficacy and safety of oral semaglutide at higher doses of 25 mg and 50 mg was compared to the currently approved 14 mg dose for T2D (Table 1).12-14 Although tirzepatide is the only “twincretin” currently on the market, the door is open for others with novel dual and triple mechanisms.
The mechanisms in development for T2D and obesity include a mix and match of agonists, analogs, and hormones, including but not limited to GIP, GLP-1RA, amylin, and glucagon (GCG; Table 2). Recently initiated in phase 3 trials (DREAMS-1,15 GLORY-116) is a novel combination GCG/GLP-1RA known as mazdutide. Expected to start phase 3 in early 2023 (REDEFINE-2) is a novel combination of cagrilintide/semaglutide, which is a double-mechanism amylin analog/GLP-1 RA.17,18 Also expected to start in 2023 is phase 3 of a novel triple-mechanism drug, retatrutide (LY3437943), and another oral GLP-1 RA, orforglipron (LY3502970).19 Retatrutide, also coined as “triple G” or “tri-agonist,” is a novel combination of GCG/GIP/GLP-1RA.19 Another combination in the pipeline is survodutide (BI 456906), which is a dual GCG/GLP-1RA that has concluded phase 2 T2D and obesity trials.20,33 Lastly, an oral GLP-1RA, danuglipron (PF-06882961), is being studied for twice daily dosing in phase 2 trials.21
Some of these pipeline agents have mechanisms that we are long familiar with, while some are quite novel. GLP-1 and GIP are endogenous incretins that act as metabolic regulators through their various actions on glucose and appetite management. GLP-1 and GIP regulate blood glucose and appetite through the postprandial stimulation of insulin, delay in gastric emptying, and the activation of satiety pathways in the brain.22 In T2D, the endogenous effect of these incretins is impaired, which contributes to poor glycemic management, lipid accumulation, and insulin resistance. Alone, GLP-1 may have more effect on appetite suppression and provide more glycemic control than GIP.22 In contrast, GIP has been linked to an increase in lipid metabolism, decrease in circulating triglycerides and free fatty acids, and increase in insulin sensitivity through its direct effect on adipose tissue.22
GLP-1 RAs have been the single-mechanism therapy FDA approved for T2D and overweight or obesity up until 2022. The approval of the first dual-mechanism GIP/GLP-1RA treatment for T2D has shown robust data, with the twincretin being more effective than an incretin alone in providing glycemic management and lowering body weight.3
Another novel combination mechanism being added into incretin therapy is GCG. In development is a novel dual-mechanism GCG/GLP-1RA15,16 and a triple-mechanism GCG/GIP/GLP-1RA.19 Many of the early efforts of incorporating GCG into therapies have focused on antagonizing the GCG receptor due to its ability to stimulate gluconeogenesis in the liver, thus causing hyperglycemia.22 These studies have since been halted due to undesirable hepatic effects, and the focus has shifted toward activating the GCG receptor.22
The approval of the first dualmechanism GIP/GLP-1RA treatment for T2D has shown robust data, with the twincretin being more effective than an incretin alone in providing glycemic management and lowering body weight.
Despite the significant burden of diabesity worldwide, there remains an unmet need for affordable and effective treatments without financial constraints for patients.
The distribution of GCG, GIP, and GLP-1 on tissues has led to some overlapping activities of these peptides, but most tissues have nonoverlapping receptor expression, leading to unique effects of each.22 Activating the GCG receptor has been shown to increase energy expenditure, thermogenesis, and insulin secretion. Additionally, GCG increases lipolysis, satiety, and glucose production.22 The GCG/GLP-1 and GCG/GIP/GLP-1 combinations incorporate the effects of each peptide to aid in T2D and obesity, while GLP-1 combats the increased glucose potential of GCG.
Lastly, a novel combination in development is an amylin analogue/GLP-1 RA. An amylin analog mimics endogenous amylin, which is a glucoregulatory hormone co-secreted by the pancreas with insulin in response to food intake. Amylin inhibits GCG secretion, suppressing the liver’s glucose output; slows gastric emptying; and acts centrally to decrease appetite. Unlike GCG, GIP, and GLP-1, amylin does not have any insulin secretory effects. While there is currently an amylin analog available on the market,23 the combination with GLP-1 is new.18
Safety and adverse effects with the use of the FDA-approved agents are of the utmost importance to providers and patients alike. Efficacy and safety of these approved drugs are well established, while there are ongoing trials for those drugs in various stages of development and the approval process. The safety and adverse effects of the pipeline agents have not been fully elucidated yet. Those agents with similar mechanisms of action and pharmacology will likely share similar safety warnings and adverse effects. Except for short-acting exenatide,5 all available GLP-1RAs6-9,14,24,25 and the dualmechanism GIP/GLP-1RA3 have a black box warning for thyroid C-cell tumors in rodents. Their use should be avoided in people with a personal or family history of medullary thyroid carcinoma and multiple endocrine neoplasia syndrome type 2. Other important warnings include but are not limited to pancreatitis, acute kidney injury, and acute gallbladder disease. Their use in severe gastrointestinal disease should be avoided. Dulaglutide, semaglutide, and tirzepatide may worsen retinopathy, and regular eye care should be stressed.3,8,9,14,24
Of the approved GLP-1RAs and GIP/GLP-1RA, the most predominant adverse effects are gastrointestinal related, including nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, and decreased appetite. Nausea and vomiting can be mitigated by eating smaller meals and starting at lower doses. Hypoglycemia has been reported but is more commonly associated with concomitant sulfonylurea and/or insulin use. Stopping them or decreasing their doses should be considered.3,5-9,14,24,25
Out-of-pocket costs for the currently approved therapies can be a barrier to their use when not covered by health insurance. According to prices listed on GoodRx, the out-of-pocket cost of the agents currently used specifically for diabetes with or without obesity range from an average cost of $1050 to $1200.38 Sometimes a savings card or coupon from the manufacturer can be applied to lower the price, but the cost may still be burdensome for patients. People with government insurance, such as Medicare, are not eligible to use copay savings cards. Despite the significant burden of diabesity worldwide, there remains an unmet need for affordable and effective treatments without financial constraints for patients.
Obesity and T2D are chronic and progressive diseases that are increasingly prevalent worldwide. Effective management of both is required to prevent the risk of developing numerous medical, physical, and psychosocial complications. Managing obesity can delay the progression of prediabetes into T2D and is also beneficial in treating T2D. Weight loss is found to improve glycemic control and reduce the need for glucose-lowering medications.
While the currently available treatments approved for both T2D and obesity are limited, several of the medications approved for only T2D are currently being investigated for an obesity indication, with many new entities on the horizon. The treatment pipeline for diabesity is robust and exciting, with novel double- and triple-mechanism drugs in various phases of development, some of which show promising results.
George Pavlakis, PharmD Candidate 2024, and Jennifer Goldman, PharmD, CDCES, BC-ADM, FCCP, are with the Massachusetts College of Pharmacy and Health Sciences in Boston, MA.
George Pavlakis declares that he has no conflict of interest. Jennifer D. Goldman declares the following conflicts: speakers bureau for Bayer, Boheringer Ingelheim, Lilly, NovoNordisk, Xeris, Abbott Diabetes
The authors declare having received no specific grant from a funding agency in the public, commercial, or not-for-profit sectors related to the content or development of this article.
Jennifer Goldman https://orcid.org/0000-0002-9617-3998
