Canagliflozin Plus Metformin in Type 2 Diabetes

June 13, 2016

Investigators compared initial therapy with canagliflozin plus metformin to metformin monotherapy in drug naïve type 2 diabetes patients.

Initial therapy with canagliflozin plus metformin is more effective at lowering HbA1c and body weight than metformin monotherapy in drug naïve patients with T2DM, according to results from a phase 3 randomized control trial published in Diabetes Care.1

“CANA100 [canagliflozin 100 mg] and CANA300 [canagluflozin 300 mg] in combination with MET [metformin] provided significantly greater reductions in HbA1c and body weight compared with monotherapy with MET, CANA100, or CANA300, with a tolerability profile consistent with the respective monotherapies. In addition, CANA100 and CANA300 monotherapy provided comparable HbA1c reductions and greater weight loss compared with MET monotherapy,” wrote first author Julia Rosenstock, MD, of Dallas Diabetes and Endocrine Center at Medical City (Dallas, TX), and colleagues.

The results largely paved the way for the US Food and Drug Administration (FDA) to expand the indication for Janssen’s canagliflozin/metformin HCL (INVOKAMET®) as first-line therapy in adults with T2DM.2

That decision occurred on May 24, 2016 and is in keeping with recent recommendations about dual therapy from several professional organizations. The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) both support initiating dual therapy in recently diagnosed patients whose HbA1c is >9.0%.3,4 The American Association of Clinical Endocrinologists (AACE) supports starting dual therapy in patients with a HbA1c of ≥7.5%,5 while Canadian guidelines recommend combination therapy for HbA1c ≥8.5%.6

The 26-week double-blind phase 3 study took place at 158 centers in 12 countries between May 2013 and December 2014. It included 1186 adult participants with T2DM who were drug naïve and inadequately controlled with diet alone. Researchers randomized participants to canagliflozin 100 mg/metformin extended release (CANA100/METXR, n=237), canagliflozin 300 mg/metformin XR (CANA300/METXR, n=237), canagliflozin 100 mg (CANA100, n=237), canagliflozin 300 mg (CANA300, n=238), or metformin XR (MET XR, n=237). The primary endpoint was change in HbA1c at 26 weeks for combined therapy vs monotherapy.

Participants had a mean HbA1c of 8.8% at baseline and 48% were male. They had a mean age 54.9 years and mean diabetes duration of 3.3 years. The median dose of metformin monotherapy was 2000 mg/day

Key results:

• Decrease in HbA1c from baseline:

♦ Significantly greater for CANA100/METXR (-1.77%) and CANA300/METXR (-1.78%) vs METXR (–1.30%) (least square mean differences [LSMD]: -0.46% and -0.48%, respectively; P=0.001 for both)

♦ Significantly greater for CANA100/METXR (-1.37%) and CANA300/METXR (-1.42%) versus CANA100 (-1.42%) and CANA300 (-1.30%) (LSMD: -0.40% and -0.36%; P=0.001 for both)

♦ CANA100 and CANA300 both met noninferiority criteria vs METXR (LSMD: -0.06% and -0.11%, respectively; noninferiority P=0.001 for both).

• Weight loss:

♦ Significantly higher for CANA100 (-2.8 kg) and CANA300 (-3.7 kg) vs metformin (-1.9 kg), (LSMD -0.9 and -1.8 kg, respectively; P=0.016 and P=0.002, respectively)

♦ Significantly higher for CANA100/METXR (-3.2 kg) and CANA300/METXR (3.9 kg) vs METXR (-1.9 kg) (LSMD -1.2 and -2.0 kg, P=0.001 for both)

• HbA1c <7.0%: Achieved by significantly more patients on CANA100/METXR (49.6%) and CANA300/METXR (56.8%) compared to METXR (43%), (P=0.0237 and P=0.016, respectively)

• Adverse events:

♦ Diarrhea most common, with highest incidence in CANA/METXR groups (4.2% for each dose)

♦ Genital mycotic infections, osmotic diuresis, and volume-depletion related adverse events were higher with canagliflozin (0.4–4.4%) compared to metformin (0–0.8%).

• Hypoglycemia: 3.0–5.5% with canagliflozin vs 4.6% with metformin

The authors noted that the overall incidence of adverse events was smaller in this study than in previous ones. The discrepancy may be explained by differences in study populations, though the reason remains unknown, they explained. They also noted that a longer study may be needed to evaluate the long-term impact of combination therapy with canagliflozin and metformin on outcomes.

“Overall, these findings support the efficacy and safety of initial combination therapy with CANA100 or CANA300 and MET in drug-naïve patients with type 2 diabetes, particularly for patients with baseline HbA1c >8.5%... and suggest that CANA [monotherapy] may also be used as an alternative to MET in this population,” they concluded.

Take-home Points

• A 26-week double-blind phase 3 study found dual therapy with canagliflozin and metformin results in significantly better reduction in HbA1c and weight compared to metformin monotherapy in drug naïve patients with T2DM.

 Canagliflozin monotherapy also performed better in reducing HbA1c and weight than metformin monotherapy.

• The incidence of hypoglycemia was similar across therapy groups.

• This study paved the way for the FDA to expand the indication for Janssen’s canagliflozin/metformin HCL (INVOKAMET®) as first-line therapy in adults with T2DM on May 24, 2016. 

The study was supported by Janssen Research & Development, LLC.

One or more authors report scientific advisory board or speaker’s bureau service, honoraria, consulting fees, grants from one or more of the following: Bristol-Myers Squibb, AstraZeneca, Janssen, Merck, Boehringer Ingelheim, Eli Lilly, Lexicon, Pfizer, Merck, Lexicon. L.C., Johnson & Johnson, Sanofi, Silanes, Takeda, and/or Merck Sharp & Dohme.

Authors Kate Merton, Jagriti Craig, George Capuana and Rong Qui are employees of Janssen Research & Development, LLC.


1. Rosenstock J, et al. 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.

2. Janssen Press Release. U.S. FDA Expands Indication of INVOKAMET® (canagliflozin/metformin HCl) to Include First-Line Treatment of Adults with Type 2 Diabetes. Accessed June 7 2016 at:

3. American Diabetes Association. Standards of Medical Care in Diabetes–2015. Diabetes Care. 2015;38(Suppl. 1):S1–S93.

4. Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015; 38:140-149.

5. Garber AJ, et al. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr Pract 2015;21: 438-447.

6. Cheng AY; Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Introduction. Can J Diabetes 2013;37(Suppl. 1):S1-S3.