Glycaemic efficacy and safety profile of Empagliflozin as add-on to linagliptin in a fixed-dose combination in type 2 diabetes

Treatment guidelines for type 2 diabetes mellitus (T2DM) recommend initiating pharmacotherapy with an oral antidiabetic drug (OAD) to reduce hyperglycaemia when diet and exercise are inadequate.

International guidelines recommend metformin as the first OAD, whereas Japanese guidelines recognize that other OADs may be more appropriate in Japanese patients. Irrespective of the first-line OAD, most patients eventually require an additional OAD with a complementary mechanism to maintain glycaemic control.

How DPP-4 inhibitors works?

DPP-4 inhibitors Linagliptin improve glycaemic control in Asian patients, possibly because Asian patients have reduced insulin secretion capacity, and are the most commonly prescribed OAD in Japan. Linagliptin is a potent and selective DPP-4 inhibitor, with demonstrated efficacy and safety.

Dipeptidyl peptidase-4 (DPP-4) inhibitors stimulate glucose-dependent insulin secretion via increased levels of active glucagon-like peptide-1 (GLP-1), resulting in lower glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG), with low risk of hypoglycaemia.

How SGLT2 inhibitor works?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors Empagliflozin reduce plasma glucose by blocking renal glucose reabsorption, thus increasing urinary glucose excretion. The SGLT2 inhibitor is efficacious as monotherapy and as add-on to other OADs.

In addition to reducing HbA1c and FPG, empagliflozin reduces body weight, systolic blood pressure (SBP) and the risk of cardiovascular mortality in high-risk patients with T2DM.


This multicenter, double-blind, phase III trial compared outcomes in 433 Japanese patients with type 2 diabetes (T2D) randomized to receive empagliflozin 10 mg plus linagliptin 5 mg fixed dose combination (FDC) with those receiving linagliptin 5 mg plus placebo.

Compared with linagliptin alone, empagliflozin/linagliptin FDC treatment resulted in statistically significant and clinically relevant reductions in HbA1c of 1.14% at 24 weeks and 1.22% at 52 weeks, as well as improvements in FPG, weight and SBP.

Both doses of empagliflozin/linagliptin FDC were well tolerated, with safety profiles consistent with the individual components and without new safety signals.

In the EMPA-REG OUTCOME study, empagliflozin had a significantly lower risk of cardiovascular mortality, of all-cause mortality and of hospitalization for heart failure than placebo.


These results suggest that switching from linagliptin monotherapy to empagliflozin/linagliptin FDC was well tolerated and resulted in clinically significant reductions in HbA1c, FPG, body weight and SBP in Japanese patients with T2DM.

Thus, an empagliflozin/linagliptin fixed-dose combination represents an attractive therapeutic option for these patients, with potentially additive cardio-renal benefits from empagliflozin as well as a formulation expected to improve adherence.

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This double-blind, randomized, placebo-controlled trial evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add-on to linagliptin (Lina) 5 mg (fixed-dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients.


The trial (40 sites; May 2015-March 2017) screened 433 adults (≥20 years) who were treatment-naive or on one oral antidiabetic drug for ≥12 weeks (discontinued at enrolment). Patients with HbA1c 7.5%-10.0% after ≥16 weeks on Lina (pre-enrolment or in 16-week, open-label period) and two weeks on placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once-daily Empa/Lina 10/5 (n=182) or Plc/Lina 10/5 (n=93) for 24 weeks. Patients with HbA1c ≥7.0% at Week 24 were up-titrated to Empa/Lina 25/5 (n=126) or its placebo (n=80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks.


Change from baseline in HbA1c was greater (P<.0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome; -0.93% vs 0.21%; adjusted mean difference, -1.14%) and Week 52 (-1.16% vs 0.06%; -1.22%). More patients with HbA1c <7.0% and greater decreases in fasting plasma glucose, body weight, and systolic blood pressure were seen with Empa/Lina than with Plc/Lina. Empa/Lina was well tolerated; adverse events more frequent with Empa/Lina were known empagliflozin-associated events (eg, increased urination, increased blood ketones). There were no adjudication-confirmed diabetic ketoacidosis events or lower limb amputations.


These results support the empagliflozin-linagliptin combination as a therapeutic option for Japanese patients with type 2 diabetes.

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