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.[334][335]

Finerenone

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist that has been shown in randomized trials to lower risks of cardiovascular (CV) events and chronic kidney disease (CKD) progression in patients with type 2 diabetes, CKD, and albuminuria.[336][337] In the FIDELIO-DKD trial, compared with placebo, finerenone was associated with lower rates of kidney failure, CKD progression, death from renal and CV causes, nonfatal myocardial infarction, stroke, and hospitalization for heart failure (HF).[336] In the FIGARO-DKD trial, finerenone was associated with lower rates of CV events and death from CV causes, but had no significant reduction in rates of renal failure, CKD progression, or death from renal causes.[337] These trials both included patients with type 2 diabetes and CKD who were already on a maximum tolerated dose of an ACE inhibitor or angiotensin-II receptor antagonist. Overall rates of adverse events were similar for finerenone and placebo, although patients taking finerenone were more likely to drop out of the trial due to hyperkalemia than those taking placebo. In FIDELITY, a pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies that included 13,026 participants, finerenone was associated with a reduction in composite CV risk in patients with CKD, type 2 diabetes, estimated glomerular filtration rate (eGFR) >25 mL/minute/1.73 m², and moderately to severely increased albuminuria.[338] The benefit was consistent across all age and sex subgroups.[339] Simulation analysis based on approximately 6.4 million treatment-eligible individuals estimated that over 1 year, finerenone may prevent 38,359 CV events, which includes the prevention of approximately 14,000 hospitalizations for HF.[340] One large network meta-analysis found that compared with standard treatments, adding finerenone probably reduces all-cause mortality, admission to hospital for HF, and end-stage kidney disease.[156] Based on these trials, the American Diabetes Association and the European Society of Cardiology both recommend finerenone in addition to an ACE inhibitor or an angiotensin-II receptor antagonist for patients with type 2 diabetes, CKD, and albuminuria, to improve CV outcomes and reduce the risk of CKD progression.[2][77] One study looked at combination treatment with finerenone, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and a glucagon-like peptide-1 (GLP-1) receptor agonist in patients with type 2 diabetes and at least moderately increased albuminuria. The combination was associated with a 35% reduction in risk of major adverse CV events (nonfatal myocardial infarction, nonfatal stroke, or CV death) compared with conventional treatment (renin-angiotensin system blockade and traditional risk factor control). There were also projected gains in survival free from hospitalized HF, CKD progression, CV death, and all-cause death, suggesting a possible role for combination therapy in the future.[341] Consistent with its mechanism of action, hyperkalemia is the most common adverse effect associated with finerenone. Other common adverse effects include hypotension, decreased eGFR, and pruritus. People with low eGFR, higher serum potassium levels, or previous episodes of hyperkalemia are at increased risk of developing hyperkalemia. Accordingly, finerenone should be used with caution and with more frequent monitoring in people with these characteristics.[342] Finerenone should not be initiated if eGFR is <25 mL/minute/1.73 m² and should be discontinued in people who have progressed to end-stage renal disease (eGFR <15 mL/minute/1.73 m²). It should not be initiated if serum potassium level is >5.0 mmol/L. The risk of hyperkalemia increases with concomitant drugs that can raise serum potassium and finerenone should not be administered with potassium-sparing diuretics or other mineralocorticoid antagonists.[342] There are no data on the use of finerenone in pregnant women, and women of childbearing potential should use effective contraception during treatment.[342]

Efpeglenatide

Efpeglenatide is an investigational exendin-based GLP-1 receptor agonist in phase 3 clinical trials for type 2 diabetes.[343] 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.[344] Results from the AMPLITUDE-O study showed that it reduced the risk of 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.[345] Data suggest that this benefit may be dose-dependent.[346] The most common adverse events with efpeglenatide treatment were gastrointestinal.[345] An exploratory analysis of AMPLITUDE-O found that the beneficial effect of efpeglenatide on CV outcomes was independent of baseline SGLT2 inhibitor use.[347] 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.[348] 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.[349] 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.[350] 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.[350] A phase 3 study is currently under way.[351]

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.[352] 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.[352] Phase 3 trials are in progress.[353][354][355][356][357]

Cagrilintide/semaglutide

A subcutaneous combination drug formulation containing semaglutide (a GLP-1 receptor agonist) and cagrilintide (an investigational long-acting amylin analog). In one network meta-analysis, cagrilintide/semaglutide 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).[358] The efficacy and safety of cagrilintide/semaglutide was assessed in a 32-week, multicenter, double-blind, phase 2 trial.[359] Adults with type 2 diabetes and a body mass index (BMI) ≥27 kg/m² on metformin, with or without an SGLT2 inhibitor, were randomly assigned to cagrilintide/semaglutide, semaglutide alone, or cagrilintide alone. The primary end point was change from baseline in HbA1c; secondary end points were body weight, fasting plasma glucose, continuous glucose monitoring (CGM) parameters, and safety. Treatment with cagrilintide/semaglutide resulted in clinically relevant improvements in glycemic control (including CGM parameters). The mean change in HbA1c with cagrilintide/semaglutide was greater versus cagrilintide alone, but not versus semaglutide alone. Treatment with cagrilintide/semaglutide resulted in significantly greater weight loss versus semaglutide alone and cagrilintide alone and was well tolerated. Adverse events were reported by 68% of participants in the cagrilintide/semaglutide group, 71% in the semaglutide alone group, and 80% in the cagrilintide alone group. Mild or moderate gastrointestinal adverse events were most common; no fatal adverse events were reported.[359] Longer and larger phase 3 studies are needed.

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.[360] 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.[361]

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.[362] In a phase 2 trial in Chinese patients with diabetes, treatment with mazdutide for 20 weeks showed 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).[363] 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.[32] 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.[32]

Automated insulin delivery/hybrid closed-loop insulin delivery

Automated insulin delivery/hybrid closed-loop insulin delivery uses an integrated system of a continuous glucose monitor, an insulin pump, and a control algorithm that automatically modulates subcutaneous insulin delivery.[364] A small number of short-term studies have demonstrated the benefits of automated insulin delivery in adults with type 2 diabetes; however, its value in this population is not fully understood and requires further investigation.[364] In one open-label, single-center, randomized crossover trial in adults with type 2 diabetes, automated insulin delivery improved glucose control without increasing hypoglycemia compared with standard insulin therapy, with the authors concluding that this may represent a safe and efficacious method to improve patient outcomes.[365] Automated insulin delivery systems have been studied more widely in patients with type 1 diabetes. The Association of British Clinical Diabetologists Closed-Loop Audit Program was designed to assess the real-world effectiveness and safety of hybrid closed-loop systems commercially available in the UK in an outpatient setting for patients with type 1 diabetes with an HbA1c of ≥8.5% (≥69 mmol/mol).[366] The study concluded that the use of hybrid closed-loop therapy is associated with improvements in HbA1c, time in range, hypoglycemia, and diabetes-related distress and quality of life in people with type 1 diabetes.

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. There are currently two once-weekly basal insulins in various stages of clinical development: insulin icodec and basal insulin Fc (BIF; also known as insulin efsitora alfa). Insulin icodec is approved in Europe for the treatment of diabetes mellitus in adults, but it is not approved in the US as yet (the Food and Drug Administration 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.[367][368][369][370][371][372] 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.[373] 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.[374] 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.[375] Phase 4 RCTs are expected to shed further light on the effectiveness and safety of once-weekly insulin therapy over the long term.