ADA 2013
Novel SGLT-2 Inhibitors: The Impact on Outcomes in Diabetes and Cardiovascular Health
There are at least 8 important pathways that are related to the development of diabetes, including insulin resistance, reduced incretin action, the loss of pancreatic β-cell function, and increased hepatic glucose production (HGP). However, glucose excretion by the kidneys also affects hyperglycemia, and as such, by targeting renal glucose absorption and excretion, a novel mechanism for managing hyperglycemia has recently become a therapeutic option in the United States and in Europe.

The sodium glucose co-transporter (SGLT)-2 is a functionally important and the most prevalent transporter for glucose reabsorption in the kidneys, and a lack of SGLT-2 expression can result in familial renal glycosuria, which leads to a 170-gram loss of glucose through the urine every day. Interestingly, patients with this condition maintain normal bladder function and plasma glucose levels without hypoglycemia, hypervolemia, increased risks for diabetes or chronic kidney disease (CKD), nor increased incidence of urinary tract infections (UTIs). Despite the lack of SGLT-2 expression, complications remain minimal, which shines an optimistic light on the clinical utility of pharmacologic agents that inhibit SGLT-2 cotransporters. As such, there a number of SGLT-2 inhibitors on the market and in the drug pipeline, including dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin. Currently, dapagliflozin is approved in Europe, whereas canagliflozin is approved in the US.

While the differences in pharmacokinetic and pharmacodynamic profiles between SGLT-2 inhibitors are minimal, the specificity for SGLT-2 and reductions in HbA1c, which are typically under 1%, are quite variable. Furthermore, agents such as canagliflozin and dapagliflozin have also demonstrated the additional benefit of consistent reductions in body weight. A head-to-head trial of canagliflozin vs. sitagliptin, when added to metformin and a sulfonylurea, found that canagliflozin induced a greater reduction of HbA1c by week 12 of treatment. Similarly, a head-to-head comparison of dapagliflozin vs. a sulfonylurea found that the SGLT-2 inhibitor was able to induce a gradual and progressive reduction in HbA1c, whereas sulfonylureas induced an early reduction in HbA1c, only to be followed by an increase.

Canagliflozin is associated with a low risk of hypoglycemia, a weight loss of 2-3 kg, and a reduction in blood pressure. As these are all components that may reduce a patient's cardiovascular risk, current trials are looking to evaluate the implications of SGLT-2 inhibitors on cardiovascular outcomes by examining large sample populations. These ongoing studies with canagliflozin and dapagliflozin may also be drawing from a parallel between SGLT-2 inhibitors and acarbose, which inhibit the absorption of glucose in the gastrointestinal tract to produce modest reductions in HbA1c, and may also significantly reduce cardiovascular events. For instance, STOP-NIDDM is a small study that demonstrated a significant reduction in cardiovascular events (HR 0.51; 95% CI 0.29-0.95 over 1400 days) with acarbose. And in the Acarbose Cardiovascular Evaluation (ACE), a highly powered and larger study that features approximately 7,500 subjects, investigators are evaluating the impact of acarbose intervention on cardiovascular-related death, myocardial infarction (MI), and stroke frequency to assess for reductions in cardiovascular events.

Although type 2 diabetes (T2DM) often steals the spotlight of attention, the discussion for improving the therapeutic landscape for type 1 diabetes (T1DM) is never neglected. In a single-arm, open-label, early pilot study, Perkins and colleagues examined the effects of 8 weeks of treatment with the SGLT-2 inhibitor, empagliflozin, on glycemic control and hypoglycemia in patients with T1DM. The results of the study demonstrated a statistically significant average reduction of 0.4% in HbA1c (P<0.0001), an average daily reduction of insulin doses by 9 units, and a concurrent reduction in the risk of hypoglycemia among patients.

Overall, numerous studies have shown, continue to show, and aspire to show that the mechanism of targeting glucose absorption and excretion is an appropriate pharmacologic strategy for patients with T1DM or T2DM. Agents such as SGLT-2 inhibitors target novel pathways and may provide substantial clinical benefit to patients with diabetes by delivering complementary glycemic control, modest HbA1c reductions, some weight loss, and limited incidences of hypoglycemia. Although ongoing research continues to examine the role of SGLT-2 inhibitors, the results of current studies, such as ACE, may have significant implications for treatment guidelines and the future of pharmacologic management for diabetes and concurrent cardiovascular health.
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