Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

Abstract

OBJECTIVE This study assessed the efficacy/safety of canagliflozin (CANA), a sodium–glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-naïve type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA1c at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA1c lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA1c <7.0% (<53 mmol/mol). RESULTS From mean baseline HbA1c of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA1c versus MET (median dose, 2,000 mg/day) by –1.77%, –1.78%, and –1.30% (–19.3, –19.5, and –14.2 mmol/mol; differences of −0.46% and –0.48% [–5.0 and –5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by –1.37% and –1.42% (–15.0 and –15.5 mmol/mol; differences of –0.40% and –0.36% [–4.4 and –3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA1c lowering and had significantly more weight loss versus MET (–2.8, –3.7, and –1.9 kg [–3.0%, –3.9%, and –2.1%]; P = 0.016 and P = 0.002). Greater attainment of HbA1c <7.0% (50%, 57%, and 43%) and significantly more weight loss (–3.2, –3.9, and –1.9 kg [–3.5%, –4.2%, and –2.1%]; P = 0.001) occurred with CANA100/MET and CANA300/MET versus MET. The incidence of adverse events (AEs) related to SGLT2 inhibition (genital mycotic infections, osmotic diuresis– and volume depletion–related AEs) was higher in the CANA arms (0.4–4.4%) versus MET (0–0.8%). AE-related discontinuation rates were 1.3–3.0% across groups. The incidence of hypoglycemia was 3.0–5.5% in the CANA arms and 4.6% with MET. CONCLUSIONS Initial therapy with CANA plus MET was more effective and generally well tolerated versus each monotherapy in drug-naïve type 2 diabetes. CANA monotherapy demonstrated noninferior HbA1c lowering versus MET.

Metformin: clinical use in type 2 diabetes

“…In general, the changes in HbA 1c changes recapitulated the approximate glucoselowering effect of these drugs as monotherapy. Such studies, therefore, provide little insight into metformin itself, other than the observation that these respective combinations are effective, well tolerated and without any substantial added risk of hypoglycaemia [19][20][21][22][23][24][25]. Other investigations have examined initial combination therapy, mainly in treatmentnaive individuals; these have further reinforced the concept that combining two drugs with distinct mechanisms of action leads to greater glucose-lowering potential than the constituents alone [23], allowing patients to better achieve HbA 1c targets.…”

Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes

“…When administered as an add-on treatment to metformin, canagliflozin was associated with reductions in glycated hemoglobin (HbA1c), weight loss, and BP lowering in a broad range of patients in Phase 2 [22, 23] and Phase 3 studies [24–26]. These effects were also observed in a Phase 3 study of the initial combination therapy with canagliflozin plus metformin [27]. The benefits noted in these studies were similar to those seen in other Phase 3 studies when canagliflozin was administered to patients on a background of metformin plus pioglitazone [28], metformin plus sulfonylurea [29, 30], or metformin plus insulin [31].…”

“…The second study (NCT00968812) evaluated canagliflozin 100 and 300 mg versus glimepiride in 1450 participants at 52 weeks [25] and 104 weeks [26]. A separate randomized, double-blind, Phase 3 study evaluated the efficacy and safety of the initial combination therapy with canagliflozin 100 or 300 mg plus metformin versus metformin alone in 1186 drug-naïve patients over 26 weeks (NCT01809327) [27]. This study also evaluated the efficacy and safety of canagliflozin 100 and 300 mg monotherapy versus metformin [27].…”

“…In the initial combination therapy study, canagliflozin 100 mg/metformin and canagliflozin 300 mg/metformin significantly lowered HbA1c versus metformin monotherapy at week 26 ( p  = 0.001) [27]. …”

“…At week 26 in the initial combination therapy study, significantly greater weight loss was seen with canagliflozin 100 mg/metformin and canagliflozin 300 mg/metformin than with metformin alone ( p  = 0.001) [27]. …”