Publications of the Week, March 22

Reducing cardiovascular and renal risks in type 2 diabetes: A therapeutic revolution in the making?

For a recent McMaster Perspective episode on the use of SGLT-2 inhibitors and GLP-1 analogues in diabetes, click here.

The basic premise of treating diabetes mellitus (DM) has been to attain good glycemic control that would reduce patients’ risk for microvascular and macrovascular complications and the associated mortality. In recent years, however, evidence has emerged that cardiovascular (CV) morbidity and mortality can be reduced by mechanisms that appear to be independent of the level of glycemic control. This network meta-analysis aimed to quantify the effects of newer classes of antidiabetic mediations on morbidity as well as on all-cause and CV mortality.

The eligible studies included those comparing treatments with sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists against each other, against another glucose-lowering treatment, or against a less precisely defined usual care. The duration of treatment was ≥24 weeks. To investigate the potential benefits, subsequent models examined the effects of SGLT-2 and GLP-1 use in patients at different risks of morbidity and mortality, comprising those at very low risk (<3 CV risk factors present), low risk (≥3 CV risk factors present), moderate risk (CV disease present), high risk (estimated glomerular filtration rate [eGFR] of 45-75 mL/min/1.73 m² with albuminuria >30 mg/mmol or eGFR of 15-45 mL/min/1.73 m²), or very high risk (both CV and renal disease present).

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to establish the quality of evidence (confidence in or certainty of data), with the network analysis providing both direct and indirect estimates.

SGLT-2 inhibitors lowered the risk of all-cause mortality compared with placebo by ~23% (odds ratio [OR], 0.77; 95% CI, 0.71-0.83). For every 1000 moderate-risk patients (those with CV disease present) treated for 5 years, this translates into 25 fewer deaths; for very high–risk patients the corresponding number is 48; and for those with very low risk, it translates into 5 fewer deaths.

GLP-1 receptor agonists lowered the risk of all-cause mortality compared with placebo by ~12% (OR, 0.88; 95% CI, 0.83-0.94). For every 1000 moderate-risk patients (those with CV) treated for 5 years, this translates into 13 fewer deaths; for very high–risk patients the corresponding number is 24; and for those with very low risk, it translates into 2 fewer deaths.

Both classes of medications reduced the risk of all-cause mortality, nonfatal myocardial infarction, kidney failure, and serious hyperglycemia. Based mostly on indirect comparisons, SGLT-2 inhibitors appeared to reduce all-cause mortality and hospital admissions for heart failure more than GLP-1 receptor agonists, whereas the GLP-1 receptor agonists appeared to lower the risk of nonfatal stroke more than SGLT-2 inhibitors.

At an individual level, the absolute benefits of these antidiabetic medications are proportional to the patient’s baseline risk of morbidity and mortality and may differ by a factor of 10 according to baseline risk.

This year marks the 100th anniversary of the discovery of insulin, which truly revolutionized the treatment of diabetes—specifically type 1 diabetes. The newer treatments for type 2 diabetes, including SLGT-2 inhibitors and GLP-1 receptor agonists, may not have the same impact as insulin, but they represent important advances and warrant our attention.