Diabetes prevention while treating obesity: STEP by STEP analysis of an apparently inSURMOUNTable problem

Obesity is the main driver of prediabetes and type 2 diabetes. Clinical trials with liraglutide SCALE obesity and prediabetes, semaglutide (STEP 1, 3, 4, 10, and SELECT) and tirzepatide (SURMOUNT-1 and tirzepatide for obesity treatment and diabetes prevention) demonstrate that antiobesity pharmacotherapy not only induces substantial weight loss but also markedly reduces progression to overt diabetes and promotes regression to normoglycemia. These findings support early, obesity-focused treatment strategies to alter the natural history of prediabetes: a common but frequently underdiagnosed and undertreated complication of obesity. Lifestyle remains a cornerstone of the treatment of this disease, but today therapies are available that can normalize blood sugar levels and reduce the risk of developing diabetes with greater efficacy in addition to lifestyle changes. In this article, we focus on the effect of treating obesity with GLP-1 RA and GLP-1/GIP RA for the prevention of type 2 diabetes. Semaglutide and tirzepatide are at the forefront for their effectiveness. Liraglutide remains a valid tool even if, on average, less effective. The choice of drug will depend on the degree of obesity and on the presence of comorbidities. Treating prediabetes is clinically relevant, not only to prevent or delay the onset of diabetes but also to reduce the cardiovascular complications of this insidious condition. Obesity is the leading risk factor for prediabetes, a highly prevalent and insidious condition that markedly increases the likelihood of developing type 2 diabetes and cardiovascular disease. While lifestyle modifications remain the foundation of prevention, pharmacological strategies targeting the incretin axis have emerged as powerful tools to reduce diabetes risk by addressing both excess weight and impaired glucose regulation. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and, more recently, dual GLP-1/GIP agonists have shown robust efficacy in promoting weight loss and improving glycemic outcomes in individuals with obesity and prediabetes. This manuscript reviews the clinical evidence for 3 key molecules. Liraglutide was first tested in the SCALE obesity and prediabetes trial, showing a 79% reduction in diabetes incidence over 3 years. Semaglutide demonstrated consistent benefits across the STEP 1, 3, 4, and 10 trials and in the large cardiovascular outcomes trial SELECT, with significant reversion to normoglycemia and reduced progression to diabetes. Tirzepatide, evaluated in SURMOUNT-1 and in the phase 3 study tirzepatide for obesity treatment and diabetes prevention trial, achieved profound and durable weight loss with an unprecedented reduction in diabetes onset. Recent real-world data further suggest a superior effect of tirzepatide compared with semaglutide in preventing type 2 diabetes. By synthesizing these findings, we aim to highlight the pivotal role of antiobesity pharmacotherapy in modifying the natural history of prediabetes and preventing type 2 diabetes in patients with obesity. Indeed, the title references the STEP and SURMOUNT clinical trial programs, which have been central in establishing the role of GLP-1 and GLP-1/GIP receptor agonists in obesity and prediabetes. At the same time, the wording recalls the concept of an “insurmountable problem,” highlighting how advances in obesity pharmacotherapy are making diabetes prevention a realistic and achievable goal. In 2009, Ralph De Fronzo during a memorable Banting Lecture1 subverted the then traditional pathogenetic paradigm of type 2 diabetes by proposing 8 actors responsible for the appearance of hyperglycemia (ominous octet). Among those responsible for hyperglycemia was the impairment of the “incretin effect”: at the same dose, glucose taken orally causes a greater insulinemic response than intravenous administration. This is due to 2 peptide hormones produced in the gastrointestinal tract: GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). The physiological manifestations of the incretin effect are insulin secretion, glucose sensitivity, release of GLP-1 and suppression of glucagon secretion. It has been demonstrated that the incretin effect is significantly reduced in diabetes mellitus and that the extent of this effect is inversely correlated not only to glucose tolerance but also to BMI independently. During oral glucose loading, type 2 diabetes is characterized by reduction in secretion of GLP-1 and a tendency toward increasing GIP concentrations. For this reason, the incretin defect was initially attributed to reduced GLP-1 secretion and possible resistance to the action of GIP at the beta-cell level. The hypothesis that type 2 diabetes is characterized by a defect in the insulin-secretory response to GIP has been observed in some studies in which the infusion of GIP induced release of insulin and reduction of blood glucose during clamp in healthy individuals but not in subjects suffering from type 2 diabetes. On the contrary, GLP-1 infusion was able to induce secretion of insulin even in patients with type 2 diabetes. Initial studies documented that reduced GLP-1 secretion and sensitivity are pathological features of type 2 diabetes; these are proportional to increasing BMI and decreased glucose tolerance, being most pronounced in patients with type 2 diabetes mellitus; GIP secretion was not decreased according to BMI or glucose tolerance. More recent studies, however, showed a reduction in insulin secretion in response to both GIP and GLP-1 in patients with type 2 diabetes.2 Liraglutide has been the first GLP-1 RA approved for the treatment of obesity. It has been tested for weight loss, diabetes prevention and has a series of publications on the properties and mechanisms for improvements of cardiometabolic risk markers and improvement of beta-cell function.3 Liraglutide, compared with semaglutide and tirzepatide, has some limitations: the effect on weight loss is smaller (in nondiabetic patients, on average 8.4% vs 15.4% of semaglutide and 20.9% of tirzepatide)3–5; the activity of liraglutide, furthermore, lasts for 18 hours and it must be administered daily whereas semaglutide and tirzepatide are used weekly. Liraglutide, nonetheless remains, so far, the most extensively tested GLP-1 RA and new studies continue to be published. The study SCALE Obesity Prediabetes6 was the first study of a GLP1-RA to investigate the possible protective effect on the development of diabetes in overweight or obese patients with prediabetes. 2254 overweight/obese patients with prediabetes were enrolled and randomized to receive liraglutide at a dose of 3 mg/day or placebo for 3 years. Liraglutide reduced the risk of developing diabetes by 79%, also promoting regression to normoglycemia in 66% of cases (vs 36% of the placebo group). Weight loss in the treated group was 6.1%, higher than that of the placebo group. The study was not designed to identify the mechanisms for such a protection and it is not possible to assess the individual contribution of weight loss per se compared with the direct effect of liraglutide. Generally, however, lifestyle intervention can reduce relative risk of diabetes by 40%–70%, enhance insulin sensitivity and β-cell function in individuals with prediabetes at high-risk of developing type 2 diabetes. The combination of the effect of liraglutide on weight loss, its direct effect on beta-cell function and its protective effects on beta-cells from oxidative stress, likely contributed, on top of lifestyle modifications, to the regression to normoglycemia and to the reduction of developing overt diabetes. Diabetes prevention with Semaglutide was evaluated in a prespecified analysis of SELECT study, in prespecified and post hoc analyzes of the STEP 13,4 studies and in randomized controlled trial STEP 10.7,8,9 The SELECT study (effect of semaglutide on regression and progression of glycemia in people with overweight or obesity but without diabetes in the SELECT Trial) is a multicenter, randomized, double-blind controlled study involving 17 604 subjects over 45 years of age with BMI ≥27 kg/m2 and with previous cardiovascular disease but without diabetes. Patients were randomized to receive semaglutide 2.4 mg weekly or placebo with a mean follow-up duration of 176 ± 40 weeks. The main outcomes were the percentage of patients who achieved normoglycemia (defined as HBA1c < 5.7%) or who progressed to diabetes (defined as HBA1c ≥ 6.5%). The results showed that semaglutide was able to both promote the return to normoglycemia and significantly reduce the progression to diabetes, compared with placebo. Specifically, 1.5% of treated subjects developed diabetes versus 6.9% in the placebo group (HR 0.27). The preventive effect was more pronounced in subjects with initial HbA1c values between 6% and 6.5% and with greater weight loss. According to an analysis by the authors, ∼35% of the observed benefit was related to weight loss, while the remainder was attributable to direct effects of the drug on insulin secretion and pancreatic beta-cell function. Even in patients treated with semaglutide, however, a progressive worsening of glycemic control over time was observed. Possible causes include pre-existing impairment of beta-cell function, early discontinuation of the drug in some participants, and a potential reduction in efficacy over time (tachyphylaxis). It should also be noted that, in SELECT, the diagnosis of diabetes was based on a single HbA1c value, a methodology that differs from current clinical guidelines. The STEP studies 1, 3, and 4, analyzed in “Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program,” were randomized, placebo-controlled phase 3 studies lasting 68 weeks. The analysis was prespecified in STEP 1 and 3 and post hoc in STEP 4. In the 3 studies, respectively 84,1% vs 47,8%, 89,5% vs 55%, and 89.8% vs 70,4% of patients were normoglycemic at 68 week. In STEP 1 0.5% vs 3% in STEP 3 0% vs 1% in STEP 4 0% vs 0.9% developed diabetes. In all 3 studies, semaglutide significantly reduced HbA1c, fasting plasma glucose, and insulin resistance (assessed by HOMA-IR). Progression to diabetes was virtually absent in the semaglutide group, unlike the placebo group, where it occurred in a low percentage. The STEP 3 study included an intensive behavioral intervention program, considered the gold standard in diabetes prevention. In this context, semaglutide demonstrated added value compared with behavioral intervention alone. However, in the STEP 1 and STEP 4 studies, where the lifestyle intervention was less intensive, the results were similar suggesting that adding semaglutide to a healthy lifestyle may offer benefits even without intensive behavioral support. Furthermore, in the STEP 4 study, patients randomized to placebo had followed a 20-week run-in period under treatment with semaglutide and in this study a higher percentage of subjects in the placebo group with prediabetes at week 0 were normoglycemic at week 68. This suggests a possible pathogenic mechanism of incretins in the prevention of diabetes. The most recent study STEP 10 (efficacy and safety of once-weekly semaglutide 2·4 mg vs placebo in people with obesity and prediabetes, STEP 10) was a randomized, double-blind, placebo-controlled, multicenter phase 3 trial.9 Participants were randomly assigned to receive semaglutide 2,4 mg or placebo. All participants received educational program on diet and physical activity. The primary aims of the trial were change in body weight (%) and proportion of participants that reverted to normoglycemia at 52 weeks. A greater proportion of participants reverted to normoglycemia with semaglutide (81% vs 14%). The conclusions were that, in addition to diet and exercise, semaglutide 2,4 mg was superior to placebo for weight loss and prevention of diabetes. Changes in body weight, glycemic status, and cardiometabolic parameters were assessed also in the 28-week off-treatment period following the 52-week phase. During the treatment suspension period (28 weeks), a recovery of part of the lost weight and a loss of glycemic benefits were observed, supporting the need for continuous treatment to maintain the results obtained. A confirmation comes from the study “Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension”10; it documents that, 1 year after discontinuing semaglutide 2.4 mg subcutaneously once a week and following a lifestyle intervention, participants regained two-thirds of their previously lost weight, with similar changes in cardiometabolic variables (deterioration of HBA1c values and glycemic status). Also, these results confirm the chronicity of obesity and suggest the need for continued treatment to maintain improvements in weight and health. Limitations of the studies include the post hoc design of some analyses, the inability to precisely distinguish the role of weight loss from that of the direct effect of the drug, and the lack of long-term evaluation after treatment discontinuation. Furthermore, in the case of STEP 10, the sample was relatively small and not very heterogeneous (predominantly white women), although previous data show no significant differences in efficacy between gender and ethnic groups. In conclusion, semaglutide 2.4 mg remains an effective treatment option for preventing diabetes among subjects with obesity and prediabetes, due to the combination of weight loss, improved insulin sensitivity, and direct effects on pancreatic cells. However, the benefits appear to depend on continued treatment, underscoring the importance of a long-term therapeutic approach. Diabetes prevention with tirzepatide was evaluated in the post hoc analysis of SURMONT 111 and in the phase 3 randomized controlled trial “tirzepatide for obesity treatment and diabetes prevention.” In SURMONT 1, the cardiometabolic disease staging risk engine was used to calculate the risk of type 2 diabetes at 10 years at baseline, 24 and 72 weeks among participants randomized to 5, 10, and 15 mg of tirzepatide vs placebo. The cardiometabolic disease staging risk engine is a risk classification system using clinical parameters relevant to the diagnosis of metabolic syndrome from the adult treatment panel III and the definition of prediabetes/diabetes using fasting glucose and 2-hour OGTT according American Diabetes Association. This calculator progresses through 5 stages: stage 0: no risk factor, stage 1: 1 or 2 risk factors for metabolic syndrome, stage 2: metabolic syndrome or prediabetes, stage 3: metabolic syndrome and prediabetes, stage 4: type 2 diabetes mellitus and/or cardiovascular disease. Mean risk score changes were compared between subjects on tirzepatide and placebo at baseline, 24 weeks, and 72 weeks. Using a validated risk calculator, cardiometabolic disease staging, treatment with tirzepatide for 24 weeks significantly reduced the 10-year risk of diabetes, regardless of initial glycemic status or BMI; this result was maintained for up to 72 weeks. The benefit was particularly evident in subjects with prediabetes, suggesting that the significant weight loss induced by the drug plays a key role in preventing the disease. The risk reduction was multifactorial, with improvements also observed in glycemic, lipid, and blood pressure parameters. A post hoc analysis of the SURMOUNT 1 study showed that tirzepatide improved not only insulin sensitivity, partly due to weight loss, but also pancreatic β-cell function, suggesting a direct effect of the drug. In the phase 3 randomized controlled trial “tirzepatide for obesity treatment and diabetes prevention,” 2539 participants with obesity (1032 also with prediabetes) were randomized 1:1:1:1 ratio to receive tirzepatide weekly at the dose of 5, 10, and 15 mg vs placebo. The duration of follow-up was 176 weeks followed by a 17-week treatment-free period. The study confirmed the efficacy of tirzepatide in significantly reducing body weight (up to 19.7% with 15 mg) and the incidence of diabetes. Fewer participants received diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs 13.3%). The preventive effect was found to be proportional to weight loss, but even subjects with weight losses of