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Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study

BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4772 (Published 29 August 2019) Cite this as: BMJ 2019;366:l4772

Re: Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study

Sodium glucose cotransporter 2 (SGLT2) inhibitors were developed to improve glycaemic control in type 2 diabetes. However, they are now widely promoted as cardiovascular protective agents. Pasternak and colleagues present a real-life study that highlights what the drugs actually do away from the clinical trial situation.

There is no doubt that they improve single and composite clinical outcomes that include heart failure. This is independent of the level of glycaemic control. Indeed, the DAPA-HF trial, 1 results of which were presented to the meeting of the European Society of Cardiology a few days ago showed that the benefits extended to non-diabetic patients with heart failure. The favourable impact of SGLT2 inhibitors on renal outcomes is now also beyond doubt. 2 The haemodynamic effects of the drugs include modest blood pressure lowering, and account for their benefit in heart failure and renal disease. These beneficial effects relate more to effects on sodium transport than to effects on glucose transport. The outcome benefits with SGLT2 inhibitors have little to do with improved glycaemic control, and possibly nothing to do with diabetes.

A key question is whether SGLT2 inhibitors influence cardiovascular outcomes other than heart failure in a clinically meaningful way. The observations of Pasternak et al. suggest that they do not. Other cohort studies have yielded mixed information, 3,4 although there are methodological issues with these studies, as pointed out by Pasternak et al. In contrast to SGLT2 inhibitors, GLP-1 agonists clearly protect against myocardial infarction and stroke, and also improve heart failure and renal outcomes. 5 They are the drugs of first choice for diabetic patients at risk from cardiovascular disease. 6 In practice, GLP-1 agonists are more potent than SGLT2 inhibitors in lowering blood glucose and have a more sustained effect on weight loss.

SGLT2 inhibitors are generally safe but may increase risk of lower limb amputation and euglycaemic ketoacidosis and have recently been associated with serious genital infections in both men and women. Recent data suggest that they do not increase risk of osteoporotic fracture. The blanket prescription of SGLT2 inhibitors for cardiovascular protection is not justified at this stage. The choice of drugs for diabetes control and cardiovascular protection needs to be made according to individual needs.

If the major effects of SGLT2 inhibitors on cardiovascular outcomes are haemodynamic, rather than glucose lowering, then we have to ask ourselves whether they are the most effective and cost-effective means of achieving this haemodynamic advantage. Also, we must never forget that a major goal in treating diabetes is to improve glycaemic control and thus minimise the risk of microvascular complications.

References
1. McMurray JJV, DeMets DL, Inzucchi SE, et al. The dapagliflozin and prevention of adverse outcomes in heart failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Failure 2019 doi: 10.1002/ejhf.1548
2. Neven BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2019 doi.org/10.1016/52213-8587(19)30256-6
3. Kosiborod M, Lam CSP, Koshaka S, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs. The CVD-REAL Study. J Am Coll Cardiol 2018:71;doi.org/10-1016/j.jacc.2018 03 009
4. Udell JA, Yuan Z, Sicignano NM, Galitz M, Rosenthal N. Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor. Circulation 2018:137;1450-1459
5. Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019 doi.org.10.1016/52213-8587(19)30249-9
6. Home P. Cardiovascular outcome trials of glucose-lowering medications: an update. Diabetologia 2019:62;357-69

Competing interests: No competing interests

11 September 2019
R Lee Kennedy
Physician and Endocrinologist
Gordian Health
Torquay VIC 3228, Australia