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Clinical Review Report: Empagliflozin and Metformin Fixed-Dose Combination (Synjardy) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Sep.

Cover of Clinical Review Report: Empagliflozin and Metformin Fixed-Dose Combination (Synjardy)

Clinical Review Report: Empagliflozin and Metformin Fixed-Dose Combination (Synjardy) [Internet].

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Executive Summary

Introduction

Diabetes mellitus is a metabolic disorder characterized by persistent elevations in blood glucose (hyperglycemia) and impaired glycemic control, which, if prolonged, may result in damage to blood vessels, and consequently causes dysfunction and failure of various organs including heart, brain, kidneys, retina, and lower limbs. Type 2 diabetes mellitus (T2DM) accounts for approximately 90% of cases of diabetes. Diabetes is one of the most common chronic diseases in Canada. The Canadian Diabetes Association estimated that there were 3.4 million people (9.3% of the population) with diabetes in 2015, and by 2025 this number will increase to five million people (12.1%). The economic burden of diabetes in Canada is heavy.

Empagliflozin (EMPA) is an inhibitor of sodium-glucose cotransporter-2 (SGLT2), which has an antihyperglycemic effect by reducing renal reabsorption of filtered glucose and which lowers the renal threshold for glucose, leading to increased urinary glucose excretion. SGLT2 inhibitors are also generally associated with weight loss and lower blood pressure.

The objective of this review was to perform a systematic review of the beneficial and harmful effects of EMPA/metformin (MET) fixed-dose combination (Synjardy) for the treatment of adults with T2DM who have experienced inadequate glycemic control on MET alone or on combination therapy of MET and other glucose-lowering products, or who are already being treated with EMPA and MET co-administered as separate tablets.

(Note: EMPA/MET [Synjardy] was submitted to the CADTH Common Drug Review before issuance of a Health Canada Notice of Compliance, and the indication that the protocol and subsequent inclusion of studies was based on was the following:

Empagliflozin and metformin hydrochloride [Synjardy] is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus when:

  • treatment with both empagliflozin and metformin is appropriate
  • inadequately controlled with metformin alone
  • inadequately controlled with metformin in combination with other glucose-lowering products, including insulin
  • already treated with empagliflozin and metformin co-administered as separate tablets.

Late in the review process, the wording of the official indication changed to the following:

Empagliflozin and metformin hydrochloride [Synjardy] is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus inadequately controlled on:

  • metformin;
  • sulfonylurea in combination with metformin;
  • pioglitazone in combination with metformin;
  • insulin in combination with metformin;

Or in patients already being treated and achieving glycemic control with:

  • metformin and empagliflozin as separate tablets;
  • sulfonylurea in combination with metformin and empagliflozin as separate tablets;
  • pioglitazone in combination with metformin and empagliflozin as separate tablets;
  • insulin in combination with metformin and empagliflozin as separate tablets.

At the time of completion of this review, the Health Canada Reviewer’s report was not available, and clarification as to the reason for the change in wording was therefore not available.)

Results and interpretation

Included studies

No randomized controlled trials (RCT) of Synjardy were identified from the literature search. Three international, multi-centre, placebo-controlled, double-blind (DB) RCTs were submitted by the manufacturer and included in this review. All three studies had a 24-week treatment period that evaluated the efficacy and safety of EMPA 10 mg or 25 mg once daily in patients with T2DM who had inadequate glycemic control (glycated hemoglobin [A1C] ≥ 7.0% and ≤ 10%) on a background therapy of MET alone (Study 1245.23MET, N = 638), MET and a sulfonylurea (SU; Study 1245.23MET+SU, N = 669), or MET and pioglitazone (PIO; Study 1245.19, N = 499). The doses of the background medications were ≥ 30 mg per day for PIO, ≥ 1,500 mg per day for MET, ≥ 50% the maximum dose of an SU, or the maximum tolerated dose, or maximum dose according to local label for each of these medications. Patients were randomized in a 1:1:1 ratio to EMPA 10 mg per day, EMPA 25 mg per day, or placebo add-on to the background therapy after a two-week open-label (OL), placebo lead-in period. The primary outcome was the change from baseline in level of A1C at week 24. Key secondary outcomes included the change in fasting plasma glucose (FPG) and body weight from baseline at week 24. Other efficacy outcomes included the change in blood pressure from baseline at week 24, health-related quality of life (HRQoL) measured with the EuroQol 5-Dimensions Questionnaire (EQ-5D), and safety outcomes outside of a testing hierarchy.

The clinical efficacy and safety of EMPA 10 mg or 25 mg once daily in patients with T2DM who had inadequate glycemic control on a background therapy of MET alone or on combination therapy of MET + SU or MET + PIO are summarized below.

Efficacy

Outcomes are presented in the order pre-specified in the review protocol (Table 3).

Mortality: In total, three patients in the EMPA 10 mg or 25 mg groups and one patient in the placebo group died during the 24-week DB treatment period. The deaths were not considered to be related to the study drugs. Diabetes-related morbidity was not assessed in the included studies.

Glycemic control: EMPA 10 mg or 25 mg once daily is associated with a statistically and clinically significant greater reduction in A1C compared with placebo after 24 weeks (Table 1). The between group differences in change in A1C from baseline ranged from –0.48% to –0.61%, –0.57% to –0.64%, and –0.59% to –0.64% for EMPA versus placebo when added on to MET + PIO, MET alone, or MET + SU, respectively. EMPA as an add-on to the background therapy was also associated with a statistically and clinically significant greater reduction in FPG.

Table 1. Summary of Results.

Table 1

Summary of Results.

HRQoL: Change in EQ-5D was descriptively analyzed, and statistical comparisons between treatment groups were not performed. Change in EQ-5D from baseline was small and similar across all the studies and treatment groups. These results suggest that 24-week treatment with EMPA can provide additional glycemic control and weight benefit when added to a background of MET monotherapy or combination therapy of MET + PIO or MET + SU, in a population with inadequate glycemic control.

Change in body weight: EMPA was associated with a statistically significant greater weight loss in the study population after 24 weeks of treatment in all three studies. The magnitude of the reduction in body weight ranged from 1.63 kg to 2.16 kg versus placebo, depending on the dose of EMPA and the background therapy (Table 1); however, these differences versus placebo were not considered clinical significant.

Change in blood pressure: EMPA was superior to placebo in reducing systolic blood pressure (SBP) at 24 weeks in all three studies. The magnitude of the reduction in SBP versus placebo ranged from 2.1 mm Hg to 4.8 mm Hg; these values were not considered clinically significant. EMPA was also superior to placebo in reducing diastolic blood pressure (DBP) at 24 weeks when added on to MET + PIO and to MET alone, but not when added on to MET + SU. None of the improvements in DBP were considered clinically significant.

Findings from an extension study (Study 1245.31) indicated that the improvement in A1C, body weight, SBP, and DBP observed in the 24-week core studies were maintained through the 76-week extension phase (0).

The bioequivalence of Synjardy to EMPA + MET co-administered as individual tablets was demonstrated in healthy individuals (0).

The main limitations of these studies included the lack of data regarding diabetes-related comorbidity (microvascular or macrovascular) and imbalanced baseline patient characteristics between the EMPA groups and the placebo group (such as gender, the proportion of patients with a history of hypertension, and the distribution of time since initial diagnosis of T2DM). According to the protocols, patients and investigators could review and discuss changes in glycemic parameters, body weight, blood pressure, and adverse events (AEs) during the studies. Some specific drug effects, such as weight loss and urogenital AEs, are known to be associated with the administration of SGLT2 inhibitor class drugs. This may have allowed certain patients (and/or investigators) to surmise that the patients were randomized to receive the active treatment. However, the primary outcome variable in all of the studies, change in A1C, is an objective (hard) outcome measure, which was determined by central laboratories; therefore, if unblinding occurred, it is unlikely that it had an important impact on the study results for the primary analysis. Results of the outcome measures outside of the testing hierarchy, such as change in blood pressure and patient-reported outcome, should be interpreted with caution. There was a lack of adjustment in multiple comparisons in the subgroup analyses; in addition, due to the smaller number of patients in the subgroups, the results of subgroup analyses should also be interpreted with caution.

Generalizability to the Canadian population is limited due to the restricted inclusion criteria of the studies. Based on the eligibility criteria of the included studies, patients with uncontrolled hyperglycemia, recent occurrence of cardiovascular (CV) events, severe renal impairment, or a number of other conditions were excluded. The recruited patient population had milder severity of the disease (close to normal level of A1C, normal renal function or mild renal impairment, and well-controlled blood pressure); therefore, the generalizability of the study results to a broader population with diabetes is uncertain. A lack of longer-term efficacy and safety data (beyond six months) was another limitation.

Harms

Overall, the proportion of patients reporting an AE was balanced between the EMPA and the placebo groups. Isolated cases of serious AEs (SAEs) and withdrawal due to AEs were reported across the studies and treatment groups. In the included studies, a higher proportion of patients in the EMPA group had a confirmed AE of hypoglycemia than the placebo group at 24 weeks. Renal impairment was rarely reported across the treatment groups. There were more patients in the EMPA groups who reported developing a genital infection during the 24-week period than in the placebo group. Ketoacidosis was not reported in any study; this may be because the patient population was at low risk of developing this AE, with the relatively mild conditions.

Longer-term safety was explored in an extension study (Study 1245.31). Findings from this study suggested that the overall frequency of AEs was generally similar across the treatment groups at week 76. The frequency and severity of the AEs during the extension phase were similar to those reported during the core studies.

Potential place in therapy

This information is based on that provided in draft form by the clinical expert consulted by CDR reviewers for the purpose of this review.

Patients with T2DM have an increasing choice of drugs with low risk of hypoglycemia and low or reduced risk of weight gain. SGLT2 inhibitors add to this choice, with additional benefits for blood pressure reduction. Like other members of this drug class, EMPA is a good choice for people who have hypertension and wish to avoid weight gain and hypoglycemia. EMPA is indicated for use as an adjunct to diet and exercise to improve glycemic control in adult patients with T2DM for whom MET is inappropriate owing to contraindications or intolerance, and as add-on therapy when MET used alone does not provide adequate glycemic control, in combination with MET, MET and an SU, PIO (alone or with MET), basal or prandial insulin (alone or with MET). The revised Canadian Diabetes Association guidelines also suggest EMPA as the first choice for the prevention of CV events as an adjunct to standard care therapy in patients with T2DM at high CV risk; however, MET remains the cornerstone of treatment, and it is to be expected that 60% of people prescribed EMPA will also be on MET. Combining the two in one pill is likely to reduce pill burden for patients and facilitate adherence to prescribed therapy. As other SGLT2 inhibitors are available in combination with MET, there will also be patient expectation that EMPA will be available in this way.

Conclusions

No phase III RCTs evaluating the efficacy and safety of EMPA/MET fixed-dose combination (Synjardy) were available. Instead, three international, multi-centre, placebo-controlled, DB RCTs with a 24-week treatment period met inclusion criteria for this review. The efficacy and safety of EMPA 10 mg or 25 mg once daily was evaluated in patients with T2DM who had inadequate glycemic control on MET monotherapy, or on a combination therapy of MET and an SU, or MET and PIO.

Results from the three studies suggest that EMPA 10 mg or 25 mg once daily is associated with a statistically and clinically significant reduction in A1C and FPG compared with placebo after 24 weeks. Diabetes-related morbidity was not assessed in any of the studies. The use of EMPA was also related to non–clinically significant reductions in body weight and blood pressure, but its effect on patient-reported quality of life (measured with EQ-5D) was minimal. Longer-term efficacy and safety data suggested that, by week 76, the treatment effect of EMPA on A1C, FPG, body weight, and blood pressure was maintained. The safety profile at week 76 was similar to that reported in the core studies. Imbalances in the baseline characteristics of the EMPA and placebo groups were noted, which may represent a failure of the randomization methods; however, there was no apparent evidence or strong clinical reason for these imbalances to have a clinically relevant impact on the primary study results. Additional limitations of the studies included a lack of long-term comparative efficacy and safety data, and limited generalizability of the study results to a typical Canadian T2DM patient population. Statistical methodology for some secondary outcomes is of questionable validity.

Findings from bioequivalence studies demonstrated that Synjardy is bioequivalent to the individual components administered separately. Data from other non-pivotal phase III DB RCTs suggested that EMPA was superior to glimepiride for improving glycemic control outcomes, decreasing blood pressure, and reducing weight. EMPA was also superior to placebo in glycemic control, body weight reduction, and insulin usage reduction in patients on a background therapy of MET combined with insulin.

AE data were generally similar between groups. Isolated cases of SAEs and withdrawal due to AEs were reported in the included studies. There was a greater proportion of patients in the EMPA group who reported hypoglycemic episodes and genital infections. Ketoacidosis was not reported in any studies.

Copyright © 2017 Canadian Agency for Drugs and Technologies in Health.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

Bookshelf ID: NBK532804

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