Results from a Phase III clinical study, announced on December 8th by Bristol-Myers Squibb Company and AstraZeneca, demonstrated that observed reductions in blood glucose levels (glycosylated hemoglobin levels, or HbA1c) at 24 weeks in adults with type 2 diabetes, who were treated with the investigational compound dapagliflozin added to current glimepiride (sulphonylurea) treatment, were maintained at 48 weeks in comparison to participants receiving placebo combined with glimepiride.

These results are from a 24-week extension period of a 24-week trial and were presented during the International Diabetes Federation (IDF) 2011 World Diabetes Congress in Dubai, UAE. In September 2010, the initial 24-week results were presented at the 46th European Association for the Study of Diabetes (EASD) Annual Meeting in Stockholm, Sweden.

The 48-week trial also reported that participants who received dapagliflozin combined with glimepiride maintained post-prandial glucose (PPG), reductions in fasting plasma glucose levels (FPG), and total body weight.

In participants who received dapagliflozin in addition to glimepiride, events suggestive of genital infections were more prevalent than participants who received placebo added to glimepiride. For both groups events suggestive of urinary tract infections were similar in the study. In intensity, these events were typically mild to moderate and were proactively monitored, with the majority of participants responding to standard treatment.

Krzysztof Strojek, M.D., Department of Internal Diseases, Diabetology and Nephrology, Silesian Medical University (Poland) explained:

“Given that patients with type 2 diabetes often need multiple therapies to help manage blood sugar levels over the course of this progressive disease, it is important to assess the ability of new compounds to work in combination with commonly prescribed anti-diabetic treatments. This study demonstrated that the addition of dapagliflozin to existing glimepiride therapy maintained reductions in blood sugar levels over 48 weeks.”

Dapagliflozin is being developed by Bristol-Myers Squibb in collaboration with AstraZeneca as an addition to diet and exercise. Dapagliflozin is an inhibitor of SGLT2, a target in the kidney. Investigators are assessing Dapagliflozin’s safety and effectiveness of enhancing glycemic control in adult individuals who suffer with type 2 diabetes, for use as a monotherapy and in combination with other anti-diabetic agents. In January 2011, The European Medicines Agency (EMA) validated a Marketing Authorization Application (MAA). In March 2011, the U.S. Food and Drug Administration (FDA) accepted for review a New Drug Application (NDA) for dapagliflozin to treat individuals with type 2 diabetes mellitus. January 28, 2012 is the FHA Prescription Drug User Free Act (PDUFA) date.

The 24-week Phase III, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial with a 24-week extension included 592 adults aged 18+ with type 2 diabetes with inadequate glycemic control (HbA1c ≥ 7% and ≤ 10%). Participants were randomly assigned to four groups:

  • 154 participants received 2.5 mg dapagliflozin added to 4 mg glimepiride per day
  • 142 participants received 5 mg dapagliflozin added to 4 mg glimepiride per day
  • 151 participants received 10 mg dapagliflozin added to 4 mg glimepiride per day
  • and 145 participants received placebo added to 4 mg glimepiride per day

The primary endpoint at 24 weeks was mean change in blood sugar levels from baseline of dapagliflozin (2.5 mg, 5 mg or 10 mg per day) added to glimepiride (4 mg/day) compared to placebo added to glimepiride.

The 24-week extension was designed in order to evaluate the maintenance of efficacy of dapagliflozin combined with glimepiride, and tolerability and safety, over 48 weeks of treatment compared to placebo combined with glimepiride in adults with type 2 diabetes.

At the start of the 24-week extension there were 546 participants of which 519 completed the extension. At the end of 48 weeks, patients taking dapagliflozin 2.5 mg, 5 mg and 10 mg combined with glimepiride showed the following mean improvements in comparison to participants who received placebo combined with glimepiride:

  • FPG: -1.07 mmol/L (95% CI: -1.59, -0.55), -1.06 mmol/L (95% CI: -1.57, -0.54) and -1.74 mmol/L (95% CI: -2.24, -1.24), respectively
  • Body weight: -0.59 kg (95% CI: -1.46, 0.28), -0.76 kg (95% CI: -1.63, 0.11) and -1.64 kg (95% CI: -2.48, -0.79), respectively
  • HbA1c: -0.37% (95% CI: -0.60, -0.14), -0.53% (95% CI: -0.75, -0.30) and -0.70% (95% CI: -0.92, -0.47), respectively
  • 2-hour PPG: -0.88 mmol/L (95% CI: -2.00, 0.24), -1.38 mmol/L (95% CI: -2.49, -0.27) and -1.20 mmol/L (95% CI: -2.26, -0.14), respectively

Over the 48-week trial, the percentage of participants who experienced at least one side effect was 58.4%, 60.7% and 58.9% for dapagliflozin 2.5 mg, 5 mg and 10 mg combined with glimepiride, respectively, versus 55.5% for placebo combined with glimepiride. The most prevalent side effects (≥ 3% in any group) were as follows for dapagliflozin 2.5 mg, 5 mg and 10 mg added to glimepiride compared to placebo added to glimepiride:

  • Upper respiratory tract infection (3.2%, 4.8%, 4.6% vs. 2.7%)
  • Nasopharyngitis (3.9%, 7.6%, 6.6% vs. 6.8%)
  • Urinary tract infection (3.2%, 2.8%, 4.0% vs. 4.8%)
  • Back pain (1.9%, 2.1%, 4.6% vs. 2.7%)
  • Cough (0.6%, 1.4%, 3.3% vs. 1.4%)
  • Dyslipidemia (3.2%, 1.4%, 2.6% vs. 0%)
  • Bronchitis (1.3%, 2.8%, 3.3% vs. 0.7%)
  • Arthralgia (5.2%, 0%, 2.0% vs. 3.4%)
  • Hypertension (5.8%, 3.4%, 2.0% vs. 6.8%)
  • Dyspepsia (1.3%, 2.8%, 0.7% vs. 3.4%)
  • Diarrhea (2.6%, 2.8%, 0.7% vs. 4.8%)

The percentage of participants who experienced at least one serious side effect was 10.4%, 11.0% and 8.6% for dapagliflozin 2.5 mg, 5 mg and 10 mg in addition to glimepiride, respectively, versus 8.9% for placebo in addition to glimepiride. The percentage of participants who discontinued as a result of side effects was 3.2%, 3.4% and 2.6% for dapagliflozin 2.5 mg, 5 mg and 10 mg groups, respectively, versus 3.4% for the placebo group. In the dapagliflozin 2.5 mg group two deaths occurred as well as one death in the dapagliflozin 10 mg group, all of which were believed to be unrelated to therapy.

In the dapagliflozin group hypoglycemic events were more prevalent (9.7% in 2.5 mg group, 10.3% in 5 mg group, 11.3% in 10 mg group) versus the placebo group (6.8%), with no participants ending treatment as a result of hypoglycemia. Although, in the dapagliflozin 2.5 mg group there was one major episode of hypoglycemia.

The proportion of participants with events suggestive of genital infections was higher for dapagliflozin combined with glimepiride (5.2% 2.5 mg, 6.2% 5 mg and 8.6% 10 mg) than placebo combined with glimepiride (1.4%). Overall, in women events suggestive of genital infections were higher than in men.

Across the treatment groups, the proportion of participants with events suggestive of urinary tract infection was similar: 4.5% 2.5 mg, 7.6% 5 mg and 7.9% 10 mg dapagliflozin versus 7.5% with placebo combined with glimepiride. Overall, in women events suggestive of urinary tract infections were higher than in men.

In the investigation no kidney infections were reported.

About Type 2 Diabetes

Type 2 diabetes os the most common form of diabetes accounting for around 90 to 95% of all cases of diagnosed diabetes in adults . In 2011, it was estimated that diabetes affects over 365 million individuals aged between 20-79 years old globally. As a result of the aging population and higher obesity rates, by 2030 the prevalence of diabetes is projected to affect over 550 million people.

Type 2 diabetes is a lifelong, progressive disease in which the pancreas does not produce enough insulin or the cells ignore the insulin, resulting in increased blood sugar levels. Over time, this sustained hyperglycemia contributes to worsening insulin resistance and further cell dysfunction.

So far, treatments for this condition have mainly focused on insulin-dependent mechanisms. A method that acts independently of insulin may offer individual with type 2 diabetes an additional option.

Given that almost half of the treated patients current glucose-lowering regimen remains uncontrolled, suggests that significant needs remain unmet. Many type 2 diabetes patients have additional co-morbidities , like obesity for example, which potentially complicates the management of glycemic control

Written by: Grace Rattue