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Chicago - The order in which oral agents are employed to control type 2 diabetes mellitus (T2DM) is under consideration as a result of the introduction of sodium glucose co-transporter 2 (SGLT2) inhibitors, based on clinical trial results and expert opinion presented here. There are now extensive efficacy and safety data with empagliflozin, which is the most recent SGLT2 inhibitor to complete phase 3 trials, dapagliflozin, which is approved in Europe, and canagliflozin, which is approved in the United States. The data suggest these drugs could be used earlier and widely because they show efficacy at least equivalent to other oral drugs, they pose little or no risk of hypoglycemia and they are associated with blood pressure and weight reduction. Their potential to lower the risk of cardiovascular events is also being investigated. In evaluating current data, more than one expert predicted that SGLT2 inhibitors will diminish a role for sulfonylureas. 

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Despite a lengthening list of oral antidiabetic therapies, control has remained suboptimal on current options. In a 2010 study of treatment gaps in the management of cardiovascular (CV) risk factors in patients with type 2 diabetes mellitus (T2DM) in Canada, only 53% of the more than 3000 screened were at optimal HbA_1c levels (Braga et al. Can J Cardiol 2010;26:297-302). The improvements in glucose control and acceptable adverse event profile so far associated with once-daily sodium glucose co-transporter 2 (SGLT2) inhibitors supports the expectation that they may have a significant role in combating this disease.

The vast amount of new data generated by SGLT2 inhibitors is clarifying where these agents will be employed in routine care of T2DM. The most significant limitation of agents within this class, which inhibit glucose uptake in the kidney, is advanced renal impairment. In patients with adequate kidney function, these agents demonstrate versatility and benefits beyond blood glucose control, also demonstrating a reduction in weight and blood pressure (BP). While the data suggests their introduction early in the treatment of T2DM, the spectrum of clinical investigations also includes preliminary work as adjunctive therapy in patients with type 1 diabetes mellitus (T1DM).

 “The most likely initial use as clinicians and patients develop comfort with their safety and efficacy is as an add-on in patients already on metformin, but we are seeing data here suggesting they may be used alone or combined, I think, with any other antidiabetic drug including insulin,” reported Hans-Ulrich Häring, MD, University of Tübingen, Tübingen, Germany. First author of two multicenter, placebo-controlled phase 3 trial that evaluated empagliflozin as an add-on, Dr. Häring presented results that have been reflective of the class.

Continuing to Demonstrate Efficacy and Safety

In one of the phase 3 studies, 637 patients with uncontrolled T2DM on at least 1500 mg metformin per day were randomized to receive once-daily doses of 10 mg or 25 mg empagliflozin, or placebo (abstract 1092-P). The primary end point was change from baseline in HbA_1c at week 24, which was reduced by 0.13% in the placebo group, 0.7% on the 10 mg dose of the SGLT2 inhibitor, and 0.77% on the 25 mg dose (P<0.001 vs. placebo). The relative advantage of the agent over placebo for fasting plasma glucose and postprandial glucose were on the same magnitude and highly statistically significant (P<0.001 respectively for both doses).

In addition, treatment was accompanied by body weight reductions of 2.08 and 2.46 kg for the 10 mg and 25 mg doses, respectively, and systolic BP (SBP) reductions ranging from 4.5 to 5.2 mmHg, respectively (all P<0.001 vs. placebo). More placebo patients discontinued therapy for an adverse event than patients on treatment and hypoglycemia was characterized as ‘rare’ in both groups. The only remarkable treatment-related adverse event were genital infections, observed in 3.7% of those on the 10 mg dose and 4.7% of those on the 25 mg dose (0% on placebo).

“The fungal infections are class effect,” Dr. Häring reported. “SGLT2 inhibitors increase sugar in the urine. The infections are easily treated and prevented with better hygiene, but these are characteristic.”

The other phase 3 study, with 666 patients, produced almost identical results (abstract 1082-P). In this study, patients inadequately controlled on metformin and a sulfonylurea were randomized to the same 2 doses of empagliflozin or placebo. At week 24, reductions in HbA_1c, fasting blood glucose, postprandial glucose, body weight, and SBP on each dose of treatment relative to placebo were almost identical to the metformin-alone study and highly statistically significant  (P<0.001 except for SPB which were P=0.005 and P=0.032 for the 10 mg and 25 mg doses, respectively). Again, more patients on placebo discontinued therapy for an adverse event, but genital infection rates were higher on treatment.

The SGLT2 inhibitors may also have a role as a first-line monotherapy, judging from a study conducted with dapagliflozin that was presented by Dr. Ji Linong, Director, Department of Endocrinology and Metabolism, People's Hospital, Beijing University, Beijing, China (abstract 1105-P). In the 24-week, double-blind study, 393 previously untreated patients with T2DM were randomized to 5 mg dapagliflozin, 10 mg dapagliflozin, or placebo. The primary end point was a reduction in HbA_1c, which fell from baseline by 0.29% in the placebo group and by 1.04% and 1.11% in the 5 mg and 10 mg dapagliflozin groups, respectively (P<0.0001 for both doses vs. placebo). Reductions in several secondary end points were also statistically significant, including fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and body weight. Similar to other SGLT2 inhibitor studies, genital infections were more common on active therapy but the rates of other adverse events were similar.

Mechanism of Action

The low risk of hypoglycemia and the increased risk of genital infections on SGLT2 inhibitors are both explained by a renal-dependent mechanism of action that lowers blood glucose by a manner that is completely independent of the beta cell or insulin activity (Ferrannini et al. Nat Rev Endocrinol 2012;8:495-502). In the kidney, glucose is reabsorbed from the proximal tubule by active transporters of which SGLT2 is by far the most active (Nair et al. Pract Diabetes Int 2010;26:179-83). By blocking this sodium glucose co-transporter, glucose is prevented from uptake and excreted in the urine. A combination of increased sodium excretion and weight loss produced by SGLT2 inhibition is thought to explain the favorable effects on SBP. Weight loss is at least partially due to calorie loss, but experimental studies with the dual SGLT1/SGLT2 inhibitor LX4211 suggests inhibition of SGLT subtypes may favorably influence other metabolic functions (Zambrowicz et al. ADA 2013; Abs 243-OR).

The increased risk of genital infections, a consequence of glycosuria (Ly et al. J Am Soc Nephrol 2011;22:113-23), is typically fungal rather than bacterial for most if not all SGLT2 inhibitors. In a pooled analysis of four 26-week phase 3 studies with canagliflozin, only a slight increase in UTI was detected (5.1% vs. 4.0%) despite a clear increase of genital infections (abstract 1139-P). Pooled data with empagliflozin demonstrated no increased risk for UTI versus placebo despite the increase in genital infections overall, 4% vs. 1% (abstract 74-LB).

Renal function also appears to be unaffected by SGLT2 inhibition in follow-up safety analyses so far conducted, including a latebreaking pooled analysis with canagliflozin that included patients who had chronic kidney disease when therapy was initiated (abstract 73-LB). The U.S. Food and Drug Administration (FDA) explicitly cautions against using canagliflozin in patients with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m², but this caution stems from an increased risk of hyperkalemia, volume loss, as well as, reduced efficacy. There is no evidence, supported by the pooled analysis, that SGLT2 inhibitors adversely affect renal function or contribute to declining function in those who already have renal impairment.

Potential for CV Benefit

Overall, the efficacy and safety profile of SGLT2 inhibitors support the prediction that they will be introduced in the early control of T2DM, particularly before sulfonylureas. In addition to experimental evidence that SGLT2 inhibitors may protect beta cell function (Jurczak et al. Diabetes 2011;60:890-8), these agents are associated with favorable effects on multiple cardiovascular risk factors. In another pooled analysis of phase 3 trial, this time with empagliflozin, clinically meaningful improvements were observed across multiple predictors of cardiovascular disease in addition to improvement in glycemic control (Hach et al. ADA 2013; Abs 69-LB). Expressed as a change from baseline, these included significant improvements in blood pressure, uric acid and weight reduction. Total cholesterol and LDL cholesterol rose modestly but significantly on treatment, but HDL was also significantly increased and triglycerides were significantly reduced. A trial with CV events as the primary end point has already been launched.

“The empagliflozin CV outcome trial is an ongoing multicenter, randomized, double blind, placebo-controlled trial designed to assess the impact of 10 or 25 mg of the SGLT2 inhibitor on CV events,” reported Dr. Bernard Zinman, Mount Sinai Hospital, Toronto, Canada, who presented the trial design in a published abstract (Zinman et al. ADA 2013; Abs 2349-PO). “The primary outcome is time-to-first occurrence of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke.”

Conclusion

The efficacy and safety data generated in large multicenter trials with SGLT2 inhibitors continues to support the potential for a versatile role in improving blood glucose control. Improvements in glucose control, associated with blood pressure and weight reduction, is appealing. The benefit of SGLT2 inhibition on multiple risk factors has generated the hypothesis that they may also reduce cardiovascular events. This hypothesis is now being tested.