Abstract
Background
The impact of sodium–glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular
outcomes in patients with type II diabetes mellitus (DM) is not well established.
Methods
We searched electronic databases from inception through July 2016 for randomized,
placebo-controlled trials, involving SGLT-2 inhibitors. Fixed-effects summary odds
ratios (OR) were constructed using Peto model.
Results
Eighty-one trials with a total of 37,195 patients were included. The mean follow-up
was 89 weeks. Compared with placebo, SGLT-2 inhibitors were associated with a lower risk
of all-cause mortality (OR 0.72; 95% CI 0.59–0.86; P < 0.001), cardiovascular mortality (OR 0.67; 95% CI 0.53–0.84; P = 0.001), and heart failure (OR 0.67; 95% CI 0.51–0.87; P = 0.003), but a similar risk of myocardial infarction (OR 0.89; 95% CI 0.74–1.09; P = 0.29) and stroke/transient ischemic attack (OR 1.09; 95% CI 0.87–1.37; P = 0.47). The reduction in all-cause mortality was noticed with empagliflozin (OR 0.66;
95% CI 0.54–0.81; P < 0.001), but not with other SGLT-2 inhibitors (ORdapagliflozin 1.37; 95% CI 0.71–2.62; P = 0.35; ORcanagliflozin 0.82; 95% CI 0.41–1.68; P = 0.59; ORluseogliflozin 4.6; 95% CI 0.07–284.25; P = 0.47; and ORipragliflozin 4.73; 95% CI 0.08–283.14; P = 0.46) (Pinteraction = 0.19). Potential harm was observed with dapagliflozin on cardiovascular mortality
(OR 2.15, 95% CI 0.92–5.04, P = 0.08).
Conclusions
In patients with type II DM, SGLT-2 inhibitors appeared to reduce both all-cause and
cardiovascular mortality, primarily due to reduction in the risk of heart failure.
The benefit was only seen with empagliflozin. There was suggestion of potential harm
with dapagliflozin, thus future trials are needed to ascertain the cardiovascular
safety of other agents in this class.
Keywords
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References
- A review of sodium glucose co-transporter 2 inhibitors canagliflozin, dapagliflozin and empagliflozin.Cardiovasc. Hematol. Agents Med. Chem. 2015; 13: 105-112
- Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications.Kidney Int. 2009; 75: 1272-1277
- SGLT2 inhibition—a novel strategy for diabetes treatment.Nat. Rev. Drug Discov. 2010; 9: 551-559
- Renal glucose reabsorption inhibitors to treat diabetes.Trends Pharmacol. Sci. 2011; 32: 63-71
- Update on SGLT2 inhibitor warning.JAMA. 2016; 315: 243
- Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo-controlled trial.Diabetes Obes. Metab. 2015; 17: 936-948
- Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial.BMC Med. 2013; 11: 43
- 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: 1267-1282
- Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N. Engl. J. Med. 2015; 373: 2117-2128
- Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.BMJ. 2009; 339: b2535
- Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2 years.J. Diabetes Complicat. 2015; 29: 1295-1303
- Efficacy and tolerability of canagliflozin as add-on to metformin in the treatment of type 2 diabetes mellitus: a meta-analysis.Eur. J. Clin. Pharmacol. 2015; 71: 1325-1332
- The efficacy of dapagliflozin combined with hypoglycaemic drugs in treating type 2 diabetes mellitus: meta-analysis of randomised controlled trials.BMJ Open. 2014; 4e004619
- Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials.BMC Endocr. Disord. 2013; 13: 58
- Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials.Diabetes Obes. Metab. 2014; 16: 457-466
- Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis.Lancet Diabetes Endocrinol. 2016; 4: 411-419
- Systematic reviews in health care: assessing the quality of controlled clinical trials.BMJ. 2001; 323: 42-46
- 9.4.4.2. Peto odds ratio method.in: Higgins J.P. Green S. Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2011
- Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [Updated March 2011].The Cochrane Collaboration, 2011 (Available from www.cochrane-handbook.org)
- Meta-analysis in clinical trials.Control. Clin. Trials. 1986; 7: 177-188
- Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560
- Bias in meta-analysis detected by a simple, graphical test.BMJ. 1997; 315: 629-634
Effect of dapagliflozin on microvascular and macrovascular circulation and total body sodium content. Available at https://clinicaltrials.gov/ct2/show/NCT02383238. Last accessed 2016.
- Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial.Eur. Heart J. 2016; 37: 1526-1534
- Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension.Diabetes Care. 2015; 38: 420-428
- EMPA-REG - the “diuretic hypothesis”.J. Diabetes Complicat. 2015; 30: 3-4
- Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus.Clin. Ther. 2015; 37: 1773-1788.e1
- Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes.Diabetes Care. 2014; 37: 1815-1823
- Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.Diabetes Obes. Metab. 2015; 17: 1180-1193
- The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus.Cardiovasc. Diabetol. 2014; 13: 28
- Prognostic impact of aortic stiffness in high-risk type 2 diabetic patients: the Rio deJaneiro Type 2 Diabetes Cohort Study.Diabetes Care. 2013; 36: 3772-3778
- Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative.Eur. Heart J. 2010; 31: 703-711
- EMPA-REG OUTCOME investigators. empagliflozin and progression of kidney disease in type 2 diabetes.N. Engl. J. Med. 2016; 375: 323-334
- Perioperative statin therapy for patients undergoing coronary artery bypass grafting.Ann. Thorac. Surg. 2016; 101: 818-825
- A. Meta-analysis of 12 trials evaluating the effects of statins on decreasing atrial fibrillation after coronary artery bypass grafting.Am. J. Cardiol. 2015; 115: 1523-1528
- Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.Diabetes Care. 2015; 38: 403-411
- FDA Drug Safety Communication: interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate.(Available at) (Accessed July 16, 2016)
Safety alerts for human medical products - canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR): drug safety communication - strengthened kidney warnings. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm506554.htm. Accessed July 16, 2016.
Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events. Available at https://clinicaltrials.gov/ct2/show/NCT01730534. Accessed July 20, 2016.
Safety and effectiveness of SGLT-2 inhibitors in patients with heart failure and diabetes. Available at https://clinicaltrials.gov/ct2/show/NCT02397421. Accessed July 20, 2016.
Article info
Publication history
Published online: November 08, 2016
Accepted:
November 6,
2016
Received:
September 1,
2016
Identification
Copyright
© 2016 Elsevier Ireland Ltd. All rights reserved.
