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PRIORITY PRESS - 48th Annual Meeting of the European Association for the Study of Diabetes

Berlin, Germany / October 1-5, 2012

Berlin - Barriers to effective type 2 diabetes mellitus treatment include risk of hypoglycemia and weight gain, which may be associated with an increased risk of mortality and cardiovascular (CV) events. The new class of selective sodium glucose co-transporter 2 (SGLT2) inhibitors reduces plasma glucose independently of insulin secretion or action, is associated with weight loss and a lower risk of hypoglycemia than comparator oral anti-diabetic medications. In Berlin, data were presented on the long-term antihyperglycemic and weight loss effects of these drugs as well as ongoing investigations into their effects on CV risk factors, renal function and overall safety.

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

Type 2 diabetes mellitus (T2DM) is associated with a progressive loss of glycemic control irrespective of treatment. Two of the main obstacles to effective glycemic control are rates of hypoglycemia and weight gain, noted Prof. Kamlesh Khunti, University of Leicester, UK. Clinical trials such as ACCORD (N Engl J Med 2008;358:2545-59) showed that hypoglycemia may be associated with an increased risk of mortality and cardiovascular (CV) events. Most current anti-diabetic therapies, particularly sulfonylureas and insulin, result in weight gain, up to 8 kg over 12 years according to the UKPDS (Lancet 1998;352:854-65). 

SGLT2 Inhibition

Approximately 180 g of glucose is filtered daily in a healthy adult, most of which is reabsorbed by SGLTs, principally SGLT2, with <1% being excreted in the urine, explained Dr. Paolo Fioretto, University of Padova, Italy. SGLT2 inhibitors are aimed at blocking the reabsorption of filtered glucose, leading to glycosuria and thereby reducing plasma glucose, improving glucose tolerance and reducing plasma insulin levels. Weight loss associated with SGLT2 inhibitors is believed to be initially due to osmotic diuresis followed by caloric loss in the urine. Two SGLT2 inhibitors, dapagliflozin and canagliflozin have already been submitted for regulatory approval in the US and the European Union. Empagliflozin, ipragliflozin and tofogliflozin are also in phase III worldwide, and others, including a dual SGLT1 and 2 inhibitor, are in earlier clinical development.

HbA_1c and Weight Reduction

Obesity is a known risk factor for the development of diabetes and CV disease. Use of an SGLT2 inhibitor in overweight/obese diabetic patients increases glycosuria, which is maintained independently of insulin over 2 years with consistent reductions in weight and HbA_1c, according to a study presented by Prof. Clifford J. Bailey, Aston University, Birmingham, UK. In pooled results from 4 phase III randomized, double-blind clinical trials of dapagliflozin 10 mg/day vs. placebo as monotherapy or as add-on to metformin or insulin, or vs. glipizide as add-on to metformin, “SGLT2 inhibition produced consistent clinically meaningful reductions in HbA_1c from baseline (-0.52 to -0.91%) sustained for up to 102/104 weeks,” Prof. Bailey reported. Significant reductions in total body weight (adjusted mean change -1.72 to -3.38 kg) with dapagliflozin at 24-weeks were sustained over 102/104 weeks (-1.97 to -3.70 kg). Adverse events (AEs) were generally balanced across the groups.

An analysis of pooled data from 9 double-blind, randomized clinical trials showed that consistent reductions in body weight are observed with SGLT2 inhibition across a range of patient subgroups. The trials compared dapagliflozin vs. placebo as monotherapy, add-on to metformin, glimepiride, pioglitazone or insulin, or as initial combination with metformin. Researchers reported that weight loss maintained over 102 weeks (-0.46 to -2.16 kg vs. placebo) appeared to be independent of age, gender, baseline HbA_1c, BMI, eGFR or duration of diabetes. As expected, based on the mechanism of action of SGLT2 inhibition, the magnitude of reduction in HbA_1c was related to baseline levels (P<0.0001) and eGFR (P=0.015), with higher measures being associated with greater efficacy.

Dr. Vincent Woo, Assistant Professor of Medicine, University of Manitoba, Winnipeg, also showed that adding the oral SGLT2 inhibitor canagliflozin 100 mg to metformin led to a mean change in HbA_1c of -0.76 % at 12 weeks, of -0.92% with the 300 mg dose compared to -0.22% for placebo. In triple therapy, canagliflozin added to metformin plus a sulfonylurea significantly reduced HbA_1c by a mean of 0.85% and 1.06% for the 100 mg and 300 mg doses, respectively, vs. 0.13% for placebo (P<0.001).

Regardless of whether the SGLT2 inhibitors are used alone or in combination with other antihyperglycemics, they consistently reduce weight by 2.5 to 3.5 kg, usually occurring within the 3 months of treatment initiation after which it tends to plateau, Dr. Woo noted.

According to data presented by Prof. Jan Bolinder, Karolinska Institute, Stockholm, Sweden, long-term weight changes with SGLT2 inhibition in overweight/obese patients are principally (68%) due to loss of fat mass, as shown by dual-energy X-ray absorptiometry measurements. In a placebo-controlled trial of 182 patients taking metformin, add-on dapagliflozin 10 mg/day was associated with rapid decreases in body weight and waist circumference over the first 24 weeks, followed by a more gradual decrease up to 102 weeks (-2.4 kg and -2.1 cm, respectively).

CV Safety

Since some therapeutic interventions for blood glucose control can induce an increase in CV mortality, the CV safety of SGLT2 inhibition is being studied in 2 ongoing phase III studies. Nine hundred older patients (mean age 63 years) with advanced diabetes and comorbid CV disease were randomized to dapagliflozin 10 mg/day added to standard therapy or placebo. The 52-week data presented at the meeting showed that improvements of factors contributing to CV morbidity such as glycemic control, blood pressure (BP) and weight loss with add-on therapy have been maintained in this population.

In one of the studies, reported by Dr. William T. Cefalu, Louisiana State University Health Sciences Center School of Medicine, New Orleans, placebo-corrected HbA_1c was -0.66%, total body weight -2.5 kg and systolic BP (SBP)  -3.58 mm Hg. In addition, 6.65% of patients had met a composite end point (reductions of ≥0.5% HbA_1c, ≥3% body weight and ≥3 mm Hg SBP) compared with only 0.7% in the placebo group. In the second study, placebo-corrected HbA_1c was -0.51%, total body weight -1.92 kg and SBP -2.85 mm Hg, reported lead investigator Prof. Lawrence A. Leiter, University of Toronto, Ontario. “Three times as many in the dapagliflozin group as the placebo group (10.6 vs. 3.1%) reached the composite end point.” In both studies, age-stratified (<65 or ≥65 years) were consistent with overall results. Safety results were consistent with other phase III studies.

Overall Safety and Renal Function

Pooled data from 12 phase IIb/III short-term, double-blind placebo-controlled trials (4684 patients) demonstrated a favourable overall safety profile for dapagliflozin, according to Prof. Andreas Pfeiffer, Charité University Hospital, Berlin, Germany. AEs were slightly more frequent vs. placebo (61.5% vs. 56.9%) with serious AEs at about 3% in each group. Discontinuations due to AEs were infrequent in all groups and balanced vs. placebo. Genital and urinary tract infections occurred at slightly higher frequencies with dapagliflozin vs. placebo but were mild to moderate, responded to standard antimicrobial therapy and seldom led to discontinuation of study treatment, Prof. Pfeiffer reported. Renal impairment and failure were few and equally distributed among all groups including placebo (0.9-1.4% vs. 0.9%). Volume depletion AEs (hypotension/dehydration/hypovolemia) were slightly more frequent and non-serious (0.6-1.2% vs. 0.4% for placebo). No unacceptable increased risk in CV events was identified. Malignant and unspecified tumours incidence rates were similar for dapagliflozin vs. comparators (1.47 vs. 1.35 per 100 patient-years), Prof. Pfeiffer noted.

Data also showed no long-term effect on eGFR over 2 years. They concluded that dapagliflozin is not associated with acute renal toxicity or long-term deterioration of renal function and suggested that the improved glycemic control, weight reduction and BP reduction associated with the agent may help preserve kidney function in T2DM patients.

A study presented in Berlin, showed that SGLT2 inhibition will have reduced effect in patients with moderate to severe renal impairment (CrCL 30-50 mL/min and <30 mL/min, respectively). In these patients, a 20 mg/day dose resulted in incrementally high exposures to dapagliflozin and its metabolite, D3OG with renal glucose clearance values 77% and 85% lower, respectively, compared to subjects with normal renal function, with corresponding reductions in steady-state glucose clearance, mean 24-h urinary glucose excretion and changes in fasting serum glucose. As efficacy is decreased in patients with renal impairment because GFR is reduced, patients with moderate impairment still benefit and no detrimental effect on renal function was observed.

Summary

Side effects such as hypoglycemia and weight gain, associated with many current therapies, present obstacles to the achievement of optimal and durable glycemic control in individuals with diabetes. SGLT2 inhibitors reduce the plasma glucose concentration by producing glycosuria by an insulin-independent mechanism improving glycemic control while reducing the risk of hypoglycemia and promoting weight loss. Studies to date have generally found SGLT2 inhibitors to be safe and well tolerated.