Type 2 diabetes mellitus in adults

Vildagliptin

Vildagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It is approved in Europe as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, but it is not approved in the US as yet. Studies have shown that combination therapy with vildagliptin and metformin is superior to metformin alone in reducing hemoglobin A1c (HbA1c), with a similar safety profile.[360][361]

Efpeglenatide

Efpeglenatide is an investigational exendin-based glucagon-like peptide-1 (GLP-1) receptor agonist in phase 3 clinical trials for type 2 diabetes.[362] It is administered as a subcutaneous injection. The AMPLITUDE-M trial found that as monotherapy in patients with type 2 diabetes, once-weekly efpeglenatide significantly improved glycemic control and body weight compared with placebo, with a safety and tolerability profile similar to that of other GLP-1 receptor agonists.[363] Results from the AMPLITUDE-O study showed that it reduced the risk of cardiovascular (CV) events versus placebo in patients with type 2 diabetes and either a history of CV disease or current kidney disease plus ≥1 other CV risk factor.[364] Data suggest that this benefit may be dose-dependent.[365] The most common adverse events with efpeglenatide treatment were gastrointestinal.[364] An exploratory analysis of AMPLITUDE-O found that the beneficial effect of efpeglenatide on CV outcomes was independent of baseline SGLT2 inhibitor use.[366] Moreover, a post-hoc analysis of earlier phase 2 data showed that efpeglenatide may be able to prevent patients with prediabetes from developing type 2 diabetes.[367] Efpeglenatide has yet to be submitted for regulatory approval.

Retatrutide

Retatrutide is an investigational novel single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon (GCGR) receptors. It is administered as a subcutaneous injection. Retatrutide demonstrated clinically meaningful glucose- and weight-lowering efficacy in people with type 2 diabetes in a 12-week phase 1 study.[368] A phase 2 randomized controlled trial aimed to assess the safety and efficacy of retatrutide versus dulaglutide and placebo in individuals with type 2 diabetes.[369] The primary outcome of this study was mean change in HbA1c at 24 weeks, while a key secondary outcome included mean change in body weight at 36 weeks. Retatrutide resulted in significant reductions in glycemic control and body weight compared with dulaglutide and placebo. Furthermore, there were improvements in lipid profile and blood pressure. The majority of adverse effects were gastrointestinal and mild-to-moderate in nature with no reported deaths.[369] A phase 3 study is currently under way.[370]

Orforglipron

Orforglipron is an investigational oral nonpeptide GLP-1 receptor agonist that is in development for type 2 diabetes and obesity. A phase 2 study evaluated orforglipron at varying doses for the treatment of type 2 diabetes compared with placebo and dulaglutide.[371] Orforglipron achieved meaningful reductions in HbA1c and body weight at 26 weeks with an adverse events profile consistent with other GLP-1 receptor agonists. Mean reduction in HbA1c (from a mean baseline of 8.1%) with orforglipron at 26 weeks was up to 2.1%, compared with 0.4% with placebo and 1.1% with dulaglutide. Orforglipron also demonstrated weight reductions up to 10.1 kg in adults with type 2 diabetes (from a mean baseline of 100.3 kg) compared with 2.2 kg with placebo and 3.9 kg for dulaglutide. With orforglipron, 65% to 96% of participants achieved an HbA1c of less than 7.0% at 26 weeks versus 64% in the dulaglutide group and 24% in the placebo group. Similar to other GLP-1 receptor agonists, orforglipron produced improvements in the blood pressure and levels of circulating lipids.[371] Phase 3 trials are in progress.[372][373][374][375][376]

Cagrilintide/semaglutide

Cagrilintide/semaglutide, a fixed-dose subcutaneous combination of the GLP-1 receptor agonist semaglutide and the investigational long-acting amylin analog cagrilintide, has shown promise in type 2 diabetes. In one network meta-analysis, it was found to be the most effective GLP-1 receptor agonist for lowering body weight in adults with type 2 diabetes (mean loss 14.03 kg).[377] Cagrilintide/semaglutide has been evaluated in a 32-week, multicenter, double-blind phase 2 trial involving 92 adults with type 2 diabetes and a body mass index (BMI) ≥ 27 kg/m².[378] The trial randomized participants to cagrilintide/semaglutide, semaglutide alone, or cagrilintide alone, and found that cagrilintide/semaglutide achieved significant HbA1c reductions (greater than cagrilintide alone, noninferior to semaglutide) and substantial weight loss (mean 15.6%, superior to both individual components) with acceptable tolerability.[378] The phase 3 REDEFINE 2 trial demonstrated that cagrilintide/semaglutide significantly and effectively induced greater weight loss versus placebo in adults with type 2 diabetes and overweight or obesity. The ongoing phase 3 REDEFINE 3 trial is evaluating the CV safety and potential benefits of cagrilintide/semaglutide versus placebo in a high-risk population with established cardiovascular disease, many of whom also have type 2 diabetes.[379]

Colchicine

Colchicine is an anti-inflammatory drug that has been in use for many decades for indications such as gout. More recently, it has been approved for risk reduction in atherosclerotic cardiovascular disease (ASCVD). In one randomized, double-blinded, placebo-controlled trial of patients with type 2 diabetes and recent myocardial infarction (COLCOT; Colchicine Cardiovascular Outcomes Trial), colchicine led to a large reduction in CV events compared with placebo.[380] The COLCOT-T2D study is currently recruiting 10,000 patients in Canada with type 2 diabetes and no history of ASCVD; it will evaluate whether low-dose colchicine in addition to standard treatment is effective in reducing the risk of CV events in this population, with the aim of establishing whether colchicine could have a role in primary prevention of ASCVD in patients with type 2 diabetes.[381]

Mazdutide

An investigational synthetic peptide analog of mammalian oxyntomodulin that acts as a dual GLP-1 and GCGR agonist. It is administered as a subcutaneous injection. Mazdutide has shown promise for the treatment of type 2 diabetes and obesity in phase 1 trials.[382] In a phase 2 trial in Chinese patients with diabetes, treatment with mazdutide for 20 weeks resulted in significant improvement in glycemic control and weight loss compared with placebo. The drug appears to be safe with a similar adverse effect profile to GLP-1 receptor agonists (with gastrointestinal adverse effects most frequently reported).[383] Phase 3 trials are in progress.

Endoscopic bariatric procedures

Stand-alone, primary endoscopic bariatric procedures (e.g., intragastric balloons) for the management of obesity and certain obesity-associated comorbidities like type 2 diabetes have evolved in recent years, bridging the gap between intensive lifestyle modifications and invasive bariatric surgical procedures.[45] In general, endoscopic bariatric procedures appear to be slightly less efficacious than bariatric surgery, although they are potentially slightly safer, less-invasive, and more reversible.[45]

Automated insulin delivery (AID)/hybrid closed-loop insulin delivery

AID/hybrid closed-loop insulin delivery uses an integrated system of a continuous glucose monitor (CGM), an insulin pump, and a control algorithm that automatically modulates subcutaneous insulin delivery.[384] AID systems have been widely studied in patients with type 1 diabetes and found to be associated with improvements in HbA1c, time in range, hypoglycemia, and diabetes-related distress and quality of life in this population.[385] Evidence from a single-center, randomized crossover trial in adults with type 2 diabetes demonstrated improved glucose control with AID versus standard insulin, without increased hypoglycemia.[386] One larger single-arm trial evaluated the Omnipod® 5 AID system over 13 weeks in an ethnically diverse cohort of 305 adults with insulin-treated type 2 diabetes.[387] Patients experienced a significant reduction in mean HbA1c (0.8%) and increased time in range, with noninferior hypoglycemia rates compared with standard therapy.[387] One 13-week randomized controlled trial (2IQP) further confirmed these benefits, demonstrating greater HbA1c reduction (0.6%) and increased time in range (14%) with AID compared to CGM alone, with low hypoglycemia rates in both groups.[388] Consequently, several AID systems have now received approval in the US for use in type 2 diabetes, highlighting their growing role in managing this population.[299]

Once-weekly insulin formulations

Basal insulin therapy may be needed in patients with type 2 diabetes, but there can be reluctance to initiate treatment due to the burden of the daily treatment regimen on the patient. A once-weekly insulin regimen may help to overcome this reluctance and improve overall treatment concordance. Two once-weekly basal insulins are in clinical development: insulin icodec and basal insulin Fc (BIF; also known as insulin efsitora alfa). Insulin icodec is approved in some countries for the treatment of diabetes mellitus in adults, but it is not approved in the US as yet (the Food and Drug Administration [FDA] rejected its approval citing a manufacturing issue). BIF is still under clinical development. The safety and efficacy of once-weekly insulin icodec has been assessed in patients with type 2 diabetes (both insulin-naive and previously insulin-treated) in a series of phase 3a randomized controlled trials (RCTs; the ONWARDS trials). Overall, the trials suggest that once-weekly insulin icodec results in noninferior, and in some cases superior, glycemic control compared with the once-daily insulin analogs insulin degludec and insulin glargine, with a similarly low rate of hypoglycemia.[389][390][391][392][393][394] The safety and efficacy of once-weekly BIF versus once-daily insulin degludec in insulin-naive patients with type 2 diabetes previously treated with oral antihyperglycemic drugs was assessed in a phase 2 randomized open-label study. It concluded that BIF achieved excellent glycemic control similar to insulin degludec, with no concerning hypoglycemia or other safety findings.[395] A systematic review and meta-analysis reported that the once-weekly basal insulin analogs seem to be at least equally efficient in glycemic management and safe compared with once-daily injections in people with type 2 diabetes.[396] Another meta-analysis found that insulin icodec showed a better HbA1c reduction with a higher proportion of patients achieving HbA1c targets in comparison with once-daily basal insulin analogs.[397] Phase 4 RCTs are expected to shed further light on the effectiveness and safety of once-weekly insulin therapy over the long term.