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Effectiveness of Invokamet in Drug-Naïve Type 2 Diabetes

Study answers question of just how effective is a SGLT-2 inhibitor with metformin.

Metformin (MET) is the first choice to improve glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose by decreasing hepatic glucose production and intestinal absorption. Also, it increases peripheral glucose uptake and utilization, thus improving insulin sensitivity. On the other hand, Canagliflozin (CANA) is a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor that lowers the renal threshold for glucose and increases urinary glucose excretion by interfering with the reabsorption of renally filtered glucose across the tubular lumen of the proximal renal tubules.

The objective of this study is to compare the effectiveness of the combination therapy of CANA and MET extended release (XR) versus CANA alone or MET XR alone in patients with drug naïve type 2 diabetes with inadequate control despite lifestyle management with diet and exercise. The study also assessed the safety and tolerability of CANA. The study was a double-blinded, parallel group, phase 3 study over 26 weeks. A total of 1,186 participants were randomized into five-arms of 216 participants in each to receive CANA100/MET XR, CANA300/MET XR, CANA100, CANA300, or MET XR. In the first 2 arms, participants received either CANA100 or CANA300 capsule before the morning meal, a placebo with the evening meal, and a placebo with the evening meal to match the MET XR. In the 3rd arm, participants received MET XR once daily in titrated doses over nine weeks, a placebo before the morning meal and a placebo with the evening meal to match the CANA. In the 4th and 5th study arms, participants received either CANA100 or CANA300 with the evening meal, a placebo before the morning meal, and MET XR once daily in doses titrated over nine weeks with the evening meal for 26 weeks.

Patient demographics included all sexes from 18-75 years of age with inadequate glycemic control on diet and exercise. Participants were not on antihyperglycemic agent therapy for at least 12 weeks before screening and had a screening visit HbA1c of ≥7.0% and ≤12.5%. Prior to randomization, participants must have fasting plasma glucose (FPG) ≤300 mg/dL and fasting fingerstick glucose >120 mg/dL performed at home or at the study center. The primary endpoint was to compare the change in HbA1c from baseline at week 26 between the five study arms. The secondary endpoints assessed changes from baseline in FPG, body weight, systolic blood pressure (SBP), and achieving HbA1c <7.0% at week 26. Modified intent-to-treat (miTT) population received ≥1 dose of the study drug to conduct efficacy analyses and safety analyses in the miTT population according to the predominant treatment received. A mixed model for repeated measures (MMRM) was analyzed through observed data for changes in the primary efficacy endpoint from baseline HbA1c <9.0% or ≥9.0% at screening, visits, and treatment-by-visit as categorical effects and at baseline and baseline-by-visit interaction as continuous fixed covariates. 95% confidence interval (CIs) was estimated at week 26 for the combination therapies versus monotherapies.

Combination therapy, CANA100/MET and CANA300/MET significantly lowered HbA1c from the mean baseline HbA1c of 8.8% versus MET with median dose of 2 g/day by –1.77%, –1.78%, and –1.30%, respectively versus CANA100 and CANA300 by –1.37% and –1.42%, respectively. In comparison to MET, CANA100 and CANA300 monotherapies demonstrated noninferiority in lowering HbA1c and had significantly more weight loss by –2.1%, –3.0%, and –3.9%, respectively. Also, the combination therapies drastically attained HbA1c <7.0% and significant weight loss (P = 0.001) versus MET. However, adverse effects (AEs) related to SGLT2 inhibition mechanism were higher in CANA/MET and CANA arms versus MET arms. Thus, the discontinuation rates due to AE-related throughout the groups were 1.3–3.0% with incidence of hypoglycemia in the CANA arms (3.0–5.5%) and MET arms (4.6%).

In conclusion, combination therapy consisting of CANA100 or CANA300 with MET yielded better glycemic improvements than CANA or MET monotherapy in drug-naive type 2 diabetes patients. The combination therapy achieved HbA1c <7.0% than MET alone and CANA monotherapy demonstrated noninferiority in HbA1c lowering and greater reductions in body weight versus MET. Thus, CANA may provide an alternative to standard 1st line treatment in type 2 diabetes patients with poor gastrointestinal or poor MET tolerability.

Practice Pearls:

  • CANA may be used as an alternative to MET in patients with baseline HbA1c >8.5% and/or with poor tolerability to MET.
  • CANA monotherapy or combination with MET treatments cannot be used if experienced AEs related to SGLT2 inhibition mechanism.
  • The study results support the efficacy and safety of initial combination therapy with CANA100 or CANA300 plus MET in drug naïve patients with type 2 diabetes.


Dumitrescu R, Mehedintu C, Briceag I, Purcarea VL, and Hudita D. Metformin-Clinical Pharmacology in PCOs. J Med Life. 2015 Apr-Jun; 8(2): 187-192.

Poudel RR. Renal glucose handling in diabetes and sodium glucose cotransporter 2 inhibition. Indian J Endocrinol Metab. 2013 Jul-Aug; 17(4): 588-593.

Rosenstock J, Chuck L, Gonzalez-Ortiz M, Merton K, Craig J, Capuano G, and Qiu R. Initial combination therapy with canagliflozin plus metformin versus each component as monotherapy for drug-naïve type 2 diabetes. Diabetes Care. 2016 Mar; 39(3): 353-362.