Potential for dipeptidyl peptidase-4 inhibitor and sodium glucose cotransporter 2 inhibitor single-pill combinations

Abstract

With prolonged duration of Type 2 diabetes mellitus, most patients need a combination of antihyperglycemic drugs to reach their target HbA1c. Evidence shows that single-pill combinations (SPCs) may increase patient satisfaction, adherence, and reduce overall health-care costs. Several SPCs containing metformin and another oral antidiabetic drug (OAD) are available on the market. Although well established in clinical practice, long-term durability and tolerability of traditional OADs can be inadequate. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium glucose cotransporter (SGLT) 2 inhibitors are two newer classes of OADs that are efficacious and are less likely to induce adverse effects such as gastrointestinal reactions, hypoglycemia and weight gain when compared with metformin, sulfonylureas, and thiazolidinediones. This article describes current efficacy and safety data of DPP-4/SGLT2 inhibitor combination therapy. Pharmacokinetics, mechanism-of-action based rationale for the combination and timing of the addition of a SPC to the treatment regimen are discussed.

Keywords:

• antidiabetic drugs
• combination therapy
• dipeptidyl peptidase-4 inhibitors
• sodium glucose cotransporter 2 inhibitors
• single-pill combination
• Type 2 diabetes

Financial & competing interests disclosure

The author D Singh-Franco has nothing to disclose. The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The author received no direct compensation related to the development of the manuscript. Medical writing was provided by R Narayan, of Envision Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Key issues

• In patients with T2DM who need oral combination therapy, current treatments include metformin with another antidiabetic drug (a sulfonylurea, a thiazolidinedione or a DPP-4 inhibitor). These established drug combinations are generally efficacious, but contain at least one agent that can cause undesirable side effects.

• DPP-4 inhibitors and SGLT2 inhibitors are newer glucose-lowering agents that demonstrated more favorable safety profiles than the traditional antidiabetic drugs because of the low inherent risks of hypoglycemia, weight gain, fluid retention and gastrointestinal reactions.

• Pharmacokinetic studies of DPP-4 inhibitors combined with SGLT2 inhibitors have shown no significant drug–drug interactions, thus, they can be co-administered without dose adjustment. The two drug classes have complementary mechanisms of action. SGLT2 inhibitors block re-absorption of glucose, resulting in increased urinary glucose excretion. DPP-4 inhibitors slow inactivation of GLP-1, resulting in increased insulin secretion with reduced glucagon levels.

• Recent short-term studies indicate that in patients with T2DM, SGLT2 inhibitors increased endogenous glucose production along with plasma glucagon concentration, possibly blunting the antihyperglycemic effects of the drugs. These observations suggest an intriguing hypothesis that a DPP-4 inhibitor co-administered with an SGLT2 inhibitor might reverse the stimulation of glucagon and endogenous glucose production, thereby enhancing the glycemic efficacy of the SGLT2 inhibitor.

• Clinical trials with DPP-4/SGLT2-inhibitor combinations have shown superior glycemic efficacy relative to placebo or the respective monotherapies. The combination added-on to other glucose-lowering agents for up to 24 weeks achieved 0.5–0.75% reductions in mean HbA1c relative to placebo. Compared with the respective mono-treatments, the combination treatments for 24 weeks reduced mean HbA1c by 0.14 to 0.59% when used with or without additional antihyperglycemic agents.

• DPP-4/SGLT2-inhibitor combination treatments up to 24 weeks elicited changes in mean body weight ranging from −1.9 to −2.78 kg relative to placebo. With both the empagliflozin (25 or 10 mg)/linagliptin 5 mg combinations, changes in mean body weight were clinically and statistically significant relative to linagliptin monotherapy (−1.2 to −2.3 kg), but not relative to empagliflozin monotherapies.

• Rates of overall AEs were higher with DPP-4/SGLT2-inhibitor combination than with placebo for treatments lasting up to 48 weeks; however, the rates were similar to those with respective mono-treatments. Hypoglycemia incidence rates with the combinations were low and comparable with placebo or active mono-treatments, except when insulin, sulfonylurea or meglitinide were used as background therapies.

• Dapagliflozin plus sitagliptin treatment for 48 weeks resulted in higher rates of signs, symptoms and events suggestive of genital infections than placebo (9.8 vs 0.4%), whereas rates of signs, symptoms and events suggestive of urinary tract infections were comparable between groups (6.7 vs 6.2%). The infections were not serious and responded to treatment.

• Low rates of documented hypoglycemia in clinical trials with DPP-4/SGLT2-inhibitor combinations, with added benefits of reduction in body weight and blood pressure with SGLT2 inhibitors make this combination an attractive option in overweight or obese patients and patients with increased risk of hypoglycemia.

• Over the next 5 years, results of the ongoing clinical trials with DPP-4/SGLT2-inhibitor combinations and of large cardiovascular outcome studies with both the drug classes along with real-world data should provide additional guidance with regard to their long-term safety and durability.

Notes