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Empagliflozin/Linagliptin Combination with Metformin for Triple Therapy

Two pills provided greater glucose-lowering efficacy than three with low hypoglycemia risk.

For the majority of patients with type 2 diabetes, the recommended first-line pharmacotherapy consists of metformin, but most will ultimately require additional therapies to help sustain glycemic control. Upholding intensive glucose control early on in the disease process is imperative and may eventually lead to benefits that continue beyond the period of treatment. Consequently, when metformin fails to attain glycemic control, add-on combination therapy with additional anti-diabetes agents may be valuable.  Given their corresponding mechanisms of action, the administration of a once-daily combination of empagliflozin/linagliptin adjunct to metformin may offer certain treatment benefits compared with the addition of either empagliflozin or linagliptin individually as dual therapy.

Empagliflozin—a potent and selective sodium-glucose co-transporter 2 (SGLT2)—helps in decreasing renal glucose reabsorption, thus increasing urinary glucose elimination and reducing incidences of hyperglycemia in patients with type 2 diabetes. Since this mechanism is impartial to insulin, SGLT2 inhibition is accompanied with an overall lower risk of hypoglycemia with added benefits involving weight loss and reduction in blood pressure.

Linagliptin is a very potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4) and its use results in reduced blood glucose by inhibiting the breakdown of incretin peptides (such as GLP-1), rousing insulin release and inhibition of glucagon secretion. As DPP-4 inhibition leads to a glucose-dependent release of insulin, it is accompanied with a low risk of hypoglycemia. Particularly as an add-on therapy with metformin, dual therapy has proved for great glycemic control without weight gain and an overall lower risk of hypoglycemia.

This particular study aimed to describe the latest clinical evidence on the efficacy and safety profiles of the single-tablet combination of empagliflozin and linagliptin, as well as presenting a comparison of the single-tablet combination of dapagliflozin and saxagliptin. The researchers conducted a “non-systemic search” using PubMed and collected abstract databases from the American Diabetes Association (ADA) and the European Association of the Study of Diabetes (EASD) spanning the years 2012-2014. Alongside drug manufacturer’s websites, they also went through www.clinicaltrials.gov where they utilized key phrases, including linagliptin, empagliflozin, dapagliflozin and saxagliptin to collect the most relevant ongoing studies.  The content of the review focused on features of empagliflozin and linagliptin, their combinations, and the dapagliflozin/saxagliptin duo.

Dual therapy with empagliflozin/linagliptin single-tablet combination (STC) was researched in both drug-naïve patients and in those who were already on metformin. Based off the collected data of RCTs (averaging ≥52 weeks duration), after 24-weeks of treatment, the mean reduction in HbA1c with the single-tablet combination ranged from -1.08% to -1.24. The key primary and secondary end-points at 24 weeks with empagliflozin/linagliptin STCs included the measurement of Hba1C %, fasting plasma glucose (FPG) and body weight.

The dapagliflozin and saxagliptin combination was studied as well in patients who were already initiated on metformin therapy; the mean change in this study population from baseline in HbA1c was slightly higher (-1.47%). This difference may be a consequence partly caused by a slightly higher baseline HbA1c in the dapagliflozin and saxagliptin combination study population. In the drug-naïve patient population being treated with empagliflozin/linagliptin STC, there was a significant improvement in glycemic control (HbA1c and FPG) compared with all respective mono-treatments. In contrast, patients undergoing dual therapy (with metformin and the empagliflozin/linagliptin STC), the STC helped achieve glycemic control relative to all mono-treatments. Besides overall glycemic control, the empagliflozin/linagliptin STCs attained statistically noteworthy mean differences in body weight and blood pressure reduction, and proved to be well tolerated with overall reduced rates of hypoglycemic events. Adverse effects, including incidences of hypoglycemia, events consistent with UTIs and genital infections with the STCs occurred at similar rates compared with mono-treatments of the individual agents.

Based off the findings noted in this article, the empagliflozin/linagliptin STC as add-on therapy to metformin provided greater glucose-lowering efficacy than the individual components, with a low risk of hypoglycemia. Empagliflozin/linagliptin was well tolerated, with safety profiles comparable to the established safety profiles of empagliflozin and linagliptin individually. The results therefore advocate the immediate use of triple therapy in patients who have been unsuccessful on metformin alone, suggesting that this approach may provide advantages over the traditional staggered treatment regimens.

Practice Pearls:

  • The combination of empagliflozin/linagliptin STC as part of triple-therapy approach (alongside metformin) is a suitable strategy to achieve desired target HbA1c.
  • The empagliflozin/linagliptin combination decreased HbA1c by about 1.1% without causing hypoglycemia and aided in reducing body weight by 2.0 to 3.0 kg on average.
  • The safety profiles of the combination product were comparable to the established drugs individually.

Woo V. Empagliflozin/linagliptin single-tablet combination: first-in-class treatment option. International journal of clinical practice. 69(12):1427-37. 2015. [pubmed]  

 

Researched and prepared by Javeria Fayyaz, Doctor of Pharmacy Candidate LECOM College of Pharmacy, reviewed by Dave Joffe, BSPharm, CDE