How Do These 3 Diabetes Agents Compare in Reducing Mortality?

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A meta-analysis reveals that there may be advantages associated with SGLT-2 inhibitors and GLP-1 agonists that are not associated with DPP-4 inhibitors.



Practice Changer

A 64-year-old man with type 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care A1C is 9.5%, and he is currently taking only metformin (1000 mg bid). You are considering the addition of an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and CV mortality risk?

Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people (1 of every 11) now struggle to reduce their blood sugar.2 As prevalence of the disease has increased, so has the number of available medications that aim to lower blood glucose and improve diabetes control.2 In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.

The American Diabetes Association’s Standards of Medical Care in Diabetes points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin and the GLP-1 agonist liraglutide as agents that should be added to metformin and lifestyle modification for patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.3 Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”3

The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.4 The American Association of Clinical Endocrinologists/American College of Endocrinology guidelines include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in the strength of recommendation for each class is noted to be small.5


SGLT-2s, GLP-1s equal better mortality outcomes

Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.

A majority of the patients in both the intervention and control groups were taking additional diabetes medications (eg, metformin) prior to enrollment and during the trials. About half the patients analyzed were enrolled in trials that specifically evaluated those at elevated CV risk—notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.

The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).

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