The online version of this article (doi:10.1186/s12933-017-0517-7) contains supplementary material, which is available to authorized users.
Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of canagliflozin in patients with T2DM based on CV disease history or CV risk factors.
Analyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports.
At week 26, both canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (−0.95 and −1.07%) versus no history of CV disease (−0.71 and −0.90%), history of hypertension (−0.72 and −0.89%) versus no history of hypertension (−0.73 and −0.95%), baseline statin use (−0.77 and −0.99%) versus no statin use (−0.69 and −0.85%), and 0–1 CV risk factor (−0.72 and −0.87%) versus ≥2 CV risk factors (−0.74 and −1.02%). Similar body weight and systolic BP reductions were seen with canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups.
The efficacy and safety of canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors.
Trial registration numbers and dates ClinicalTrials.gov: NCT01081834, 4 March 2010; NCT01106625, 1 April 2010; NCT01106677, 1 April 2010; NCT01106690, 1 April 2010
Additional file 1. Terms used to define history of CV disease, history of hypertension, and statin use at baseline.
International Diabetes Federation. IDF diabetes atlas. 7th ed. Brussels: International Diabetes Federation; 2015.
Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–22. CrossRef
Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero RM, Woerle HJ, Broedl UC, Johansen OE. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diabetes Vasc Dis Res. 2015;12(2):90–100. CrossRef
Johansen OE. Cardiovascular disease and type 2 diabetes mellitus: a multifaceted symbiosis. Scand J Clin Lab Investig. 2007;67(8):786–800. CrossRef
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. 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(1):140–9. CrossRefPubMed
GLUCOTROL ® (glipizide) TABLETS [package insert]. New York: Roerig; 2008.
Glynase ® PresTab ® (micronized glyburide tablets) [package insert]. New York: Pharmacia & Upjohn Company; 2010.
ACTOS (pioglitazone) tablets for oral use [package insert]. Deerfield: Takeda Pharmaceuticals America, Inc; 2013.
Sha S, Devineni D, Ghosh A, Polidori D, Chien S, Wexler D, Shalayda K, Demarest K, Rothenberg P. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13(7):669–72. CrossRefPubMed
Polidori D, Sha S, Ghosh A, Plum-Mörschel L, Heise T, Rothenberg P. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2013;98(5):E867–71. CrossRefPubMedPubMedCentral
Lavalle-González FJ, Januszewicz A, Davidson J, Tong C, Qiu R, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56(12):2582–92. CrossRefPubMedPubMedCentral
Wilding JP, Charpentier G, Hollander P, Gonzalez-Galvez G, Mathieu C, Vercruysse F, Usiskin K, Law G, Black S, Canovatchel W, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013;67(12):1267–82. CrossRefPubMedPubMedCentral
Burrows N, Parekh S, Li Y, Geiss L. Prevalence of self-reported cardiovascular disease among persons aged ≥35 years with diabetes—United States, 1997–2005. MMWR Wkly. 2007;56(43):1129–32.
Meininger G, Canovatchel W, Polidori D, Rosenthal N. Canagliflozin for the treatment of adults with type 2 diabetes. Diabetes Manag. 2015;5(3):183–201. CrossRef
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Gogo-Jack S, Defronzo RA, Einhorn D, Fonseca VA, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22(1):84–113. CrossRefPubMed
Sinclair A, Bode B, Harris S, Vijapurkar U, Mayer C, Fung A, Shaw W, Usiskin K, Desai M, Meininger G. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14(1):37. CrossRefPubMedPubMedCentral
Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts): developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur J Prev Cardiol. 2016;23(11):NP1–96. CrossRefPubMed
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685–96. CrossRefPubMed
JARDIANCE ® (empagliflozin) tablets, for oral use [package insert]. Ridgefield: Boehringer Ingelheim Pharmaceuticals, Inc; 2016.
Neal B, Perkovic V, Mahaffey KW, Fulcher G, Erondu N, Desai M, Shaw W, Law G, Walton MK, Rosenthal N, de Zeeuw D, Matthews DR; CANVAS Program collaborative group. Optimising the analysis strategy for the CANVAS Program - a pre-specified plan for the integrated analyses of the CANVAS and CANVAS-R trials. Diabetes Obes Metab. 2017. doi: 10.1111/dom.12924.
Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, Desai M, Shaw W, Jiang J, Vercruysse F, et al. Rationale, design, and baseline characteristics of the canagliflozin cardiovascular assessment study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217–23. CrossRefPubMed
Neal B, Perkovic V, Matthews DR, Mahaffey KW, Fulcher G, Meininger G, Erondu N, Desai M, Shaw W, Vercruysse F, et al. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab. 2017;19(3):387–93. CrossRefPubMed
Tanaka A, Inoue T, Kitakaze M, Oyama J, Sata M, Taguchi I, Shimizu W, Watada H, Tomiyama H, Ako J, et al. Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial. Cardiovasc Diabetol. 2016;15:57. CrossRefPubMedPubMedCentral
- Efficacy and safety of canagliflozin in patients with type 2 diabetes based on history of cardiovascular disease or cardiovascular risk factors: a post hoc analysis of pooled data
Michael J. Davies
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II