One meta-analysis, which was published in JAMA on April 17 and covered in the May ACP Diabetes Monthly, focused on type 2 diabetes and reviewed 236 trials that compared dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and sodium–glucose cotransporter 2 (SGLT-2) inhibitors to controls or to each other. The outcomes of interest included all-cause mortality, cardiovascular (CV) mortality, heart failure (HF), myocardial infarction, stroke, and hypoglycemia.
The second analysis, which was published by Diabetes, Obesity and Metabolism on Feb. 16, looked at the efficacy and safety of adding SGLT-2 inhibitors to insulin in type 1 diabetes. The 11 included randomized trials compared weekly SGLT-2 inhibitors with placebo in adult patients with type 1 diabetes. Outcomes included HbA1c level, weight, systolic blood pressure, total insulin dose, and safety outcomes.
Abstracts of the studies in type 2 diabetes and type 1 diabetes were published with the following commentary by Aoife M. Egan, MB BCh, PhD, and Victor M. Montori, MD, MSc, FACP, in the ACP Journal Club section of the July 17 Annals of Internal Medicine.
The paucity of trials directly comparing the efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors led Zheng and colleagues to explore the network of pertinent evidence. They found that SGLT-2 inhibitors and GLP-1 agonists prevented more deaths and episodes of HF than DPP-4 inhibitors. These differences relied mainly on results of indirect comparisons calculated using network meta-analysis, although results for direct and indirect comparisons were largely consistent. The review could not explore differences between drugs of the same class. For example, although SGLT-2 inhibitors as a class did not increase risk for lower limb amputations, trials of specific agents yielded inconsistent results. This includes 2 large trials that found an increased risk for amputations with canagliflozin.
Similar to results in patients with type 2 diabetes, the systematic review and meta-analysis by Yamada and colleagues found that adding SGLT-2 inhibitors to insulin in patients with type 1 diabetes reduced HbA1c (by 0.4%), blood pressure, and body weight. Use of these agents also increased risks for diabetic ketoacidosis (DKA) and genital tract infection. DKA may occur in patients using SGLT-2 inhibitors because lowering glycemia through an insulin-independent mechanism increases the glucagon-to-insulin ratio, resulting in elevated rates of lipolysis, hepatic ketogenesis, and an increased tendency toward DKA, especially in the setting of a precipitant.
Taken together, the body of evidence continues to favor GLP-1 agonists and, particularly, SGLT-2 inhibitors for their ability to reduce CV and renal events in patients with type 2 diabetes; the potential benefits in patients with type 1 diabetes remain speculative. The favorable effects of SGLT-2 inhibitors on weight, glycemia, and CV risk without severe hypoglycemia in patients with type 2 diabetes must be contrasted with the unfavorable ones—genitourinary infections; DKA; and, in the case of canagliflozin, amputations. Clinicians and their patients can use the results of the review by Zheng and colleagues to develop a preference for which drug to consider—including SGLT-2 inhibitors or GLP-1 agonists—when further glycemic control is needed for type 2 diabetes. In patients with type 1 diabetes, the role of SGLT-2 inhibitors in improving care and outcomes are uncertain.