Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 72nd Annual Scientific Sessions of the American Diabetes Association (ADA)

Philadelphia, Pennsylvania / June 8-12, 2012

Philadelphia - The prevalence of type 2 diabetes mellitus (T2DM) and its complications continues to grow. Outcomes in diabetes are still poor, primarily due to physical inactivity and failure to manage obesity. Failure to diagnose, treat early, achieve target HbA_1c, focus on other cardiovascular risk factors and hard outcomes (micro- and macrovascular) are also contributing factors. Diabetes management requires multiple strategies, but many commonly used antihyperglycemic agents are associated with hypoglycemia, weight gain, lack of durable glycemic control, intolerance and specific contraindications. Here at the ADA, data were presented on newer classes of agents that are aimed at reducing HbA_1c, fasting and postprandial glycemia, with minimal glycemic variability and a durable effect. This benefit was observed without increasing hypoglycemia or weight gain, along with additional beneficial effects on other cardiovascular risk factors such as high blood pressure.

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

Current American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) guidelines on the management of hyperglycemia in type 2 diabetes mellitus (T2DM) advocate metformin as first-line therapy; if metformin  is not effective, a second, then a third non-insulin antihyperglycemic drug should be added (Diabetes Care 2012;35:1364-79). However, the limitations of current agents have led to the search for newer alternative agents to use in combination therapy.

The sodium-glucose co-transporter (SGLT) 2 inhibitors currently in development offer a novel insulin-independent mechanism for diabetes management. SGLT2 is a low-affinity, high-capacity transporter that mediates glucose reabsorption in the proximal tubule of the kidney. Blocking SGLT2 decreases glucose reabsorption, leading to increased urinary glucose excretion (UGE).

According to Dr. Robert R. Henry, Center for Metabolic Research, University of California, San Diego, “Most patients will fail metformin over time and the addition of an SGLT2 inhibitor is an attractive concept because it would be working through a completely different mechanism from metformin, which primarily reduces excess hepatic glucose or endogenous glucose production.” Noted Dr. Lawrence Leiter, St. Michael’s Hospital, University of Toronto, Ontario, “SGLT2 inhibitors all lower glucose and they all have a favourable effect on weight and on blood pressure (BP).” A number of specific SGLT2 inhibitors are currently in development, including canagliflozin and dapagliflozin, phase III data on both of which were presented here at the ADA. Most data have accumulated for dapagliflozin, which was the first SGLT2 inhibitor to enter clinical trials.

Treating High-risk Patients

Lowering glucose and BP has been shown to produce greater reductions in cardiovascular (CV) events than lowering glucose alone, as demonstrated by the UKPDS and ADVANCE studies. In the Steno-2 study, multifactorial intervention was associated with a dramatic 20% reduction in risk of events (N Engl J Med 2003;348:383-93).

In 2 phase III studies presented here at the ADA, the addition of dapagliflozin to standard therapy was shown to improve glycemic control and BP and induce weight loss, notably in an older population (mean age 64 years) with advanced diabetes and comorbid CV disease. In both studies, T2DM patients with HbA_1c ≥7%-≤10.0%—despite antihyperglycemic therapy with 1 to 2 agents and/or insulin—were randomized to receive dapagliflozin 10 mg/day or placebo. The co-primary end point was combined reduction of ≥0.5% in HbA_1c, ≥3% in body weight and ≥3 mm Hg in seated systolic BP (SBP) at 24 weeks.

Dr. William T. Cefalu, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, reported that in 922 patients, all with a history of hypertension, 11% of patients on dapagliflozin met the 3-item end point vs. 0.9% of those on placebo (P<0.0001). Dr. Leiter reported that in 964 patients, 93% with a history of hypertension, 10% on dapagliflozin also achieved this end point vs. 1.9% on placebo (P<0.0001). In both studies, the agent produced significantly greater reductions in HbA_1c, body weight and SBP. Patients on placebo had their mean daily insulin dose increased by 10% vs. no change with active treatment. Incidences of adverse events (AEs) and serious AEs were balanced between groups.

“This is a group of patients who are not typically studied, because most clinical trials are done with younger patients; this is an older patient population, presumably at greater risk of side effects, yet what is reassuring is that no significant issues were observed and the efficacy is similar to what has been seen in other studies,” Dr. Leiter told delegates. In both studies, reductions in HbA_1c and proportions of patients achieving the primary end points were similar in both patients aged ≥65 and <65 years.

Typical T2DM Population

In a more typical population with T2DM, the same SGLT2 inhibitor was again shown to significantly reduce HbA_1c levels when added to existing sitagliptin therapy, with or without concomitant metformin.

A study discussed here at the ADA by Jabbour et al. (poster 1071P) involved a total of 447 patients whose glycemic control was still inadequate despite being on stable dipeptidyl peptidase 4 (DPP-4) inhibitor therapy with or without metformin. Patients were randomized to dapagliflozin 10 mg/day or placebo for a double-blind period of 24 weeks, followed by a 24-week blinded extension period.

After the initial 24 weeks of treatment, there was a significant 0.48% placebo-corrected reduction (P<0.0001) in HbA_1c from baseline in the cohort randomized to the SGLT2 inhibitor. When dapagliflozin was added to patients on sitagliptin monotherapy, there was a 0.56% placebo-corrected reduction in HbA_1c (P<0.0001) and a 0.40% reduction among patients receiving both sitagliptin plus metformin, which was still significant (P<0.0001). Reductions in HbA_1c were also noted at 4 weeks—the first recorded time point—and were maintained out to 48 weeks.

A significant reduction in body weight was also observed at 24 weeks among patients who received additional SGLT2 inhibition, at approximately 2 kg across the overall treatment cohort and in the 2 different treatment strata; weight loss was also sustained out to 48 weeks. At 48 weeks, AE rates were similar among patients receiving active additional therapy vs. placebo at approximately 66% and 61%, respectively, as were rates of hypoglycemia at approximately 5% for active treatment patients and approximately 6% for placebo patients. Serious AEs were also similar at 6.7% for dapagliflozin patients and 8% for placebo controls.

The efficacy of dapagliflozin also increases with increasing baseline HbA_1c, according to an analysis of pooled data from 5 24-week phase III studies presented here at the ADA by clinical researcher Dr. Elise Hardy, Wilmington, Delaware. Overall, HbA_1c levels were reduced with the SGLT2 inhibitor at 2.5 mg, 5 mg or 10 mg daily vs. placebo and across all baseline HbA_1c levels in T2DM patients. As expected, greater UGE and reductions in HbA_1c were seen at 24 weeks with higher baseline HbA_1c. However, body weight reduction (2 kg in all groups) was not associated with baseline HbA_1c, although there was a trend toward a greater reduction in BP. The investigators remarked that these inconsistent results might be due to differences in regulatory pathways.

New Developments

A phase III study explored the hypoglycemic benefits of a related molecule, canagliflozin, another SGLT2 inhibitor also in development for the management of T2DM. Results from this trial were revealed here at the ADA (oral 81-OR). Findings showed that in a group of 584 patients with inadequate glycemic control despite diet and exercise, canagliflozin monotherapy 100 mg reduced HbA_1c from a baseline of 8.1% to 7.3% at week 26; at 300 mg, the investigational agent decreased HbA_1c to 7.0% at the same end point (P<0.001 vs. placebo). Both doses significantly improved fasting plasma glucose as well, improvements being greater with the higher dose. Reductions in body weight at 2.2 kg with the 100-mg dose and 3.3 kg with the 300-mg dose at week 26 were again significantly greater than for placebo (P<0.001). Overall incidence of AEs was modestly higher with both active treatment doses at approximately 60% vs. placebo at 49%. Rates of serious AEs and AE-related discontinuations were low and similar among groups. 

Summary

Among the SGLT2 inhibitors currently in phase III trials, dapagliflozin is expected to be the first in class to become available following a recent review by European health authorities. “Clearly, it can also be used with metformin and it could be used in triple combination therapy across the board,” Dr. Henry told delegates. Promising data presented here at ADA indicate that the SGLT2 inhibitors may be important agents in combatting T2DM by significantly reducing HbA_1c, body weight and SBP.