DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Abstract

SUMMARYIntroduction : Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach.Area covered: An extensive literature search was performed to analyze the pharmacokinetics, pharmacodynamics and clinical experience of different gliptin-gliflozin combinations.Expert opinion: There is a strong rationale for combining a DPP-4i and a SGLT2i in patients with T2D because the two drugs exert different and complementary glucose-lowering effects.Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin.Combining the two pharmacological options is safe and does not induce hypoglycemia. The additional glucose-lowering effect is more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. Bioequivalence of the two compounds given as FDC tablets was demonstrated when compared with coadministration of the individual tablets. FDCs could simplify the antihyperglycaemic therapy and improve drug compliance. Article highlights box -Type 2 diabetes (T2D) often requires the combination of several medications with complementary actions to reach glucose control targets while limiting side effects -The combination of a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) is an attractive approach for the management of T2D. Keywords-Both saxagliptin plus dapagliflozin and linagliptin plus empagliflozin combined therapies have been tested as separate tablets (no clinically relevant pharmacokinetic drug-drug interactions) and as fixed-dose combination (FDC : bioequivalence studies).-DPP-4i -SGLT2i combined therapies are more efficacious than either monotherapy to control blood glucose, without worsening of the safety profile.-Initial DPP-4i -SGLT2i combination may be considered or one compound may the added to the other. However, which one should be used in first place remains an open question.

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

“…However, reductions in FPG and 2-h PPG were similar between treatment arms [49] . Indirect comparison with findings of the previous trial [48] may suggest that the addition of dapagliflozin on top of a dual therapy metformin plus saxagliptin results in a greater improvement in glucose control than the addition of saxagliptin on top of a dual therapy metformin plus dapagliflozin [30] .…”

“…The absence of plasma insulin increase with the addition of saxagliptin may probably be explained by the concomitant reduction in hyperglycaemia, mainly due to the amount of glucose lost in the urine. Several clinical studies have shown that the addition of a DPP-4 inhibitor to a background therapy with a SGLT2i results in only a modest HbA1c reduction, about half of that observed with the addition of a SGLT2i to a DPP-4i background therapy (see below and reference [30] ). The fact that the DPP-4i blunts the increase in glucagon seen with the SGLT2i might contribute to reduce the risk of euglycaemic ketoacidosis reported wit SGLT2i,…”

“…DPP-4i and SGLT2i exert their glucose-lowering effects via different and complementary mechanisms [30,31] . When one single pharmacological class does not reach glycated haemoglobin (HbA1c) target as monotherapy or even when added to metformin, a combination of a DPP-4i and a SGLT2i could be helpful in the management of patients with T2D [32][33][34][35] .…”

Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

“…There is considerable interest in the combined use of SGLT2 inhibitors with dipeptidyl peptidase‐4 (DPP‐4) inhibitors for effective glycaemic control without an increased potential for hypoglycaemia, weight gain or cardiovascular diseases 8, 9. Randomized studies have demonstrated the efficacy and safety of triple therapy using a SGLT2 inhibitor, a DPP‐4 inhibitor, and metformin in patients who have inadequately controlled T2DM 10, 11.…”

Pharmacological management of type 2 diabetes: what’s new in 2017?

“…[89,90] Dual therapy (initial combination or stepwise approach) is more effective than either monotherapy in patients treated with diet and exercise or already treated with metformin.…”