SGLT2 Inhibitors in Early Type 2 Diabetes Management

By addressing many of the overall risk factors associated with type 2 diabetes mellitus (T2DM), sodium glucose co-transporter 2 (SGLT2) inhibitors could have a significant impact on the early management of patients with recent-onset T2DM either as monotherapy or in combination with other classes of glucose-lowering agents, according to a new review of the literature.

SGLT2 inhibitors are a new class of pharmacologic agents for T2DM that reduce hyperglycemia by targeting the kidney to promote urinary glucose excretion.

“SGLT2 inhibitors have a unique mechanism of action that is independent of pancreatic beta-cell function or the degree of insulin resistance, conferring these agents the potential to be used at any stage of the disease, and in combination with any of the existing classes of glucose-lowering agents, including insulin,” stated the reviewer, Stephen A. Brunton, MD, of the Primary Care Metabolic Group in Charlotte, NC.

These new drugs can be used at any stage of the disease, and may be particularly appropriate for patients with long-standing T2DM, he stated. They also have a promising role as an early intervention in patients recently diagnosed with T2DM, which was the aim of this review.

The author found clinical trials of the SGLT2 inhibitors dapagliflozin, canagliflozin, and empagliflozin that investigated their efficacy, safety, and tolerability as monotherapy and as add-on combination therapy with other anti-diabetes agents, including metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase -4 inhibitors, and insulin.

These SGLT2 inhibitors produce clinically significant reductions in hemoglobin A1c (HbA1c), fasting plasma glucose, body weight, and systolic blood pressure. They have been well tolerated and generally have favorable safety profiles, and few serious adverse events have been reported from clinical trials. The frequency of hypoglycemic events was low, he noted.

Genital infections and urinary tract infections have been consistently reported with SGLT2 inhibitors; these episodes were mostly mild and non-recurrent.

Clinical trial data demonstrate that SGLT2 inhibitors, in addition to decreasing HbA1c, induce beneficial changes in a number of cardiovascular risk factors, such as lowering blood pressure and body weight. Data is limited on clinical outcomes such as stroke, myocardial infarction, and cardiovascular death. “We must await the completion of the various ongoing cardiovascular trials,” Brunton stated.

He also noted that preliminary clinical data identified the potential renal effect of SGLT2 inhibitors beyond lowering blood glucose, and this may influence the natural course of renal function decline in individuals with T2DM.

Preliminary evidence suggests that SGLT2 inhibitors may have a protective effect on the kidney beyond blood glucose lowering. Similar to agents that block the renin–angiotensin system, SGLT2 inhibitors reduce single-nephron glomerular filtration rate in the chronically altered kidney function states. SGLT2 inhibitors also cause modest reductions in plasma uric acid.

In conclusion, Brunton stated: “Obviously, the ideal combination therapy using SGLT2 inhibitors would need to be tailored to an individual's risk factors. The fixed-dose combination products emerging onto the market, or soon to do so, may provide further options in this area.”

Reference: Brunton SA. The potential role of sodium glucose co-transporter 2 inhibitors in the early treatment of type 2 diabetes mellitus. Int J Clin Pract. 2015 Oct;69(10):1071-1087.