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 - 47th Annual Meeting of the European Association for the Study of Diabetes (EASD)

Lisbon, Portugal / September 12-16, 2011

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

According to Dr. Peter Rossing, Chief Physician and Head of Research, Steno Diabetes Center, Gentofte, Denmark, in type 2 diabetes, progressive ß-cell dysfunction and insulin resistance cause treatment failure, and treatment side effects such as gastrointestinal disturbances, weight gain and hypoglycemia are common problems with many currently available agents like metformin and the sulfonylureas. “We need better tools to reach optimal glycemic control,” he stated.

The sodium-glucose co-transporter (SGLT) 2 pathway in the kidney may provide a new target. Inhibiting SGLT2 reduces hyperglycemia by increasing urinary glucose excretion independently of insulin secretion or action. Among SGLT2 inhibitors in clinical development are canagliflozin, empagliflozin and ipragliflozin and in the most advanced stage is dapagliflozin.

Overall SGLT2 Treatment Effects

SGLT2 inhibitors have beneficial effects on glucose, blood pressure (BP) and on body weight. As demonstrated by a 16-week phase III trial, ipragliflozin 50 mg once daily significantly reduced HbA_1c by 1.23%, mean body weight by 1.47 kg (both P<0.001) vs. placebo. The SGLT2 inhibitor also reduced mean BP (systolic -3.2 mm Hg, diastolic -2.5 mm Hg) from baseline (Poster 149). While treatment was generally safe and well tolerated, 1 case of hypoglycemia and 2 genital infections were reported. This study echoes data reported by the SGLT2 family class. However, more long-term data have been generated by dapagliflozin.

Reducing Hemoglobin A_1c

“Impressive mean reductions in hemoglobin A1c (HbA_1c), fasting blood glucose (FBG) and postprandial glucose (PPG) levels have been seen with SGLT2 inhibitors across a range of clinical settings,” Dr. Lawrence A. Leiter, Professor of Medicine and Nutritional Sciences, University of Toronto, Ontario, told delegates here at the EASD. As add-on to placebo, metformin, insulin, glipizide or pioglitazone, dapagliflozin has been studied over 24 weeks. “What is remarkable about this series of studies is the consistency of the results,” Dr. Leiter noted. “We see a nice dose response with similar HbA_1c [response], whether it is early in the disease as monotherapy, in more advanced therapy as add-on, being used as a second agent or, much later in the course of the disease, as an add-on to insulin.”

In a study of metformin with either dapagliflozin or glipizide, while mean HbA_1c reduction was greater with glipizide initially, they were identical at 52 weeks. Notably, the SGLT2 inhibitor significantly decreased the proportion of patients experiencing hypoglycemia vs. glipizide (3.5% vs. 40.8%, P<0.0001). Prof. Stefano Del Prato, University of Pisa, Italy, and colleagues reported on the extension study to 2 years. HbA_1c continued to rise in the glipizide group, whereas in patients treated with dapagliflozin, it remained relatively stable up to 104 weeks (Figure 1).

Effects on Body Weight and Blood Pressure

“Importantly, SGLT2 inhibitors are associated with weight loss and a reduction in blood pressure (BP) that can be extremely helpful in patients with type 2 diabetes, who are almost always hypertensive,” Dr. Leiter explained. The beneficial effects on body weight are due to caloric loss in the urine. Weight reduction was seen in 24-week studies with dapagliflozin as monotherapy or as add-on to metformin, glipizide or insulin. When added to pioglitazone, it prevented further weight gain.

In a 52-week study (Nauck et al. Diabetes Care 2011;34:2015-22), the SGLT2 inhibitor plus metformin was associated with a mean 3.2 kg weight loss compared with a 1.4 kg body weight increase with glipizide plus metformin. At 104 weeks, there was an overall difference of 5 kg in body weight in favour of dapagliflozin and the proportion of patients with =5% weight reduction was 23.8% vs. 2.8% with glipizide. “This compares very well with other drugs that have been released on the market as weight loss agents,” Dr. Leiter pointed out. Most of the weight loss seen with the SGLT2 inhibitor has been shown to be due to reduction in total body fat mass rather than to fluid loss.

In trials, BP reduction, a secondary end point, is “impressive and there is a nice dose response,” Dr. Leiter stated. A pooled analysis of 12 short-term studies resulted in a 4-5 mm Hg reduction in systolic BP and 2-3 mm Hg in diastolic BP. After 104 weeks of treatment, BP was lower in patients on dapagliflozin than in those on glipizide by almost 5 mm Hg systolic BP and 4 mmHg diastolic BP. This BP reduction is believed to be in part due to the diuretic effect and in part to inhibition of the renin-angiotensin system.

Dr. Leiter speculated that given the SGLT2 inhibitor beneficial effects not only on glucose but also on BP and on body weight, the drug might be particularly efficacious in reducing cardiovascular (CV) events. He noted that preliminary data from a meta-analysis of data from 14 trials showed an overall 33% reduction in CV events in patients treated with dapagliflozin relative to those on placebo or control drugs. “This is very promising,” he noted, “but these were small numbers and this will have to be confirmed in larger studies.”

Figure 1.

Safety Analysis

Most safety data on SGLT2 inhibitors have come from studies using dapagliflozin, noted Dr. Paola Fioretto, Associate Professor in Endocrinology, University of Padova, Italy. In presenting findings from a pooled analysis of data from 12 clinical trials, she reported, “Importantly, the use of dapagliflozin is not associated with an increased risk for hypoglycemia, unless it is used with a sulfonylurea or insulin.”

SGLT2 inhibitors are associated with an increase in risk for genital infections such as vulvovaginitis, balanitis and related infections (5% vs. 0.9% with placebo). Most studies with dapagliflozin showed no increase in urinary tract infections, although there was a “very slight” increase with high-dose dapagliflozin in women. This side effect is common to other SGLT2 agents, Dr. Fioretto noted.

Despite its diuretic effect, the risk for hypovolemia, hypotension and dehydration is extremely low. “These events are very rare (=1% vs. 0.4% with placebo),” Dr. Fioretto remarked. However, the significant reduction in serum uric acid levels “may potentially be important, since uric acid is well recognized as a CV risk factor,” she told delegates.

In the overall population and in patients with chronic kidney disease (GFR 45-60 mL/min/1.73 m²), a small decrease in eGFR was seen at 1 week, but subsequently returned to baseline levels and remained stable over 2 years of follow-up. Rates of renal adverse events were similar to controls. “These are very reassuring data,” Dr. Fioretto remarked.

Pooled analysis of clinical trial data showed no difference in the risk for malignant or unspecified tumours vs. controls. She stressed, “Dapagliflozin is known to be highly selective, not genotoxic, and it is important that there is no known linkage between its mechanism of action and tumour risk.” Numbers for individual malignancies were very small, but some imbalances were noted in the number of patients diagnosed with bladder cancer or breast cancer. “Overall we can conclude that there is no increase in the risk for malignancies in general, and that for individual cancers we need additional data from larger studies,” Dr. Fioretto told delegates.

Beyond safety and efficacy, researchers reported a high level of patient-reported treatment satisfaction as expressed in 2 randomized clinical trials involving =48 weeks of treatment with dapagliflozin added to metformin (Poster 848). Scores on the Diabetes Treatment Satisfaction Questionnaires for both status (DTSQs) and change (DTSQc) were numerically higher with the SGLT2 inhibitor than control in both studies and patients had a better perceived frequency of hyperglycemia.