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Use of SGLT-2 Inhibitors Combo with Metformin for Greater Glycemic Control

Feb 27, 2016

Is there actual benefit in dual therapy treatment? Study looks at canagliflozin plus metformin.

For patients with elevated HbA1c, the use of combination antihyperglycemic medications after inadequate control with metformin alone is commonly prescribed to help patients achieve individualized glycemic levels. The use of dual therapies has the support of the American Diabetes Association, as well as the European Association for the Study of Diabetes and the American Association of Endocrinologists, and has proven to be beneficial in lowering HbA1c levels. However, the HbA1c level at which dual therapies should be initiated is still up for debate. Some organizations choose a more aggressive approach and initiate therapy at HbA1c levels ≥ 7.5%, while others choose not to initiate until levels are ≥ 9.0%. Due to the lack of controlled studies to support such aggressive treatment for mild elevations in glycemic control, an evaluation of safety and efficacy in the use of two or more antihyperglycemic agents is an area of necessary exploration.


In this multi-centered, double-blind study, 1,186 patients were randomized into five treatment groups to receive either canagliflozin 100 mg with metformin extended release, canagliflozin 300 mg with metformin extended release, canagliflozin 100 mg monotherapy, canagliflozin 300 mg monotherapy, or metformin extended release monotherapy. Included patients were patients with type 2 between the ages of 18 and 75 who were treatment naïve and had HbA1c levels greater than 7.5%. The primary end point was to determine if a change in HbA1c occurred at week 26 for combination therapies versus monotherapies. Secondary endpoints included noninferiority in HbA1c lowering with canagliflozin monotherapy versus metformin; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA1c <7.0%.

Safety and efficacy analyses were conducted using a modified intent-to-treat population. That is to say all patients who were randomized and received at least one dose after randomization were included in the final analyses. Least squares mean differences and 95% confidence intervals were estimated at week 26 for each combination of therapy. Continuous secondary endpoints were analyzed with a mixed model for repeated measure similar to that of the primary efficacy end point. Percent changes from baseline in lipids were analyzed using an ANCOVA. The Wilcoxon rank sum test was used to evaluate treatment comparisons.

From mean baseline HbA1c of 8.8% , the canagliflozin 100 mg and 300 mg dual therapy arms significantly lowered HbA1c versus metformin monotherapy by –1.77%, –1.78%, and –1.30% (P = 0.001) respectively. Canagliflozin 100 mg and 300 mg monotherapy met noninferiority for HbA1c lowering, but had significantly more weight loss versus metformin (–3.0%, –3.9%, and –2.1% [–2.8, –3.7, and –1.9 kg]; P=0.002 and P = 0.016). Greater attainment of HbA1c <7.0% (50%, 57%, and 43%) and significantly more weight loss (–3.2, –3.9, and –1.9 kg; P = 0.001) occurred with the canagliflozin dual therapy arms versus metformin alone. Adverse effect-related discontinuation rates were 3.0% across groups. The incidence of hypoglycemia was 5.5% in the canagliflozin arms and 4.6% with metformin.

The authors concluded that initial therapy with canagliflozin plus metformin was more effective and generally well tolerated versus each monotherapy in drug-naive people with type 2 diabetes. The addition of dual medications to assist in lowering HbA1c levels is a concept that has been implemented clinically without much evidence to warrant a sound medical decision for several years. This is likely the case because knowing the mechanism by which these drug classes exert their effects, healthcare providers have been able to make this deduction prior to experimental proof. This study simply provides sound evidence that what has been practiced for years is also applicable to the usage of newer agents available to the market. A study with a longer duration may help to assess the potential long term benefits of combination therapies.

Practice Pearls:

  • Concurrent usage of antihyperglycemic agents, in patients with inadequate glycemic control on monotherapy, is paramount in lowering HbA1c levels.
  • Weight reduction is associated with both classes of medications; however a greater response can be noted in patients on dual therapy with a higher dose of SGLT-2 inhibitor.
  • In patients with elevated glucose, a dual therapy regimen should be considered in all patients, including those that are naïve to therapy.

Researched and prepared by Adaisha C. Rutledge, Doctor of Pharmacy Candidate FAMU College of  Pharmacy, reviewed by Dave Joffe, BSPharm, CDE

Rosenstock J, Chuck L, Gonzalez-Ortiz M, Merton K, Craig J, Capuano G, and Qi R. “Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naive Type 2 Diabetes.” Diabetes Care. 19 January 2016.