Dapagliflozin is a novel, potential first-in-class, selective sodium glucose co-transporter 2 (SGLT2) inhibitor, currently in Phase III trials, under joint development by Bristol-Myers Squibb Company and AstraZeneca, as a once-daily oral therapy for the treatment of T2DM. SGLT2 inhibitors facilitate the elimination of glucose by the kidney, thereby returning serum glucose levels towards normal.
Role of Kidneys
The kidneys play a key but underappreciated role in the overall regulation of blood glucose levels in the body. In healthy individuals, the kidneys filter a large volume of glucose and actively reabsorb virtually all of it. Glucose reabsorption is necessary to retain calories, but becomes counterproductive in type 2 diabetes. A protein called SGLT2 is responsible for the majority of glucose reabsorption and helps the body retain glucose for its energy requirements.
In patients with type 2 diabetes who have hyperglycemia, a greater amount of glucose is filtered and reabsorbed by the kidneys despite the fact that this retention process contributes to sustaining the hyperglycemia of diabetes.
Over time, sustained hyperglycemia leads to glucotoxicity, which worsens insulin resistance and contributes to dysfunction in the beta cells of the pancreas. The degree of sustained hyperglycemia is directly related to diabetic microvascular complications and may also contribute to macrovascular complications. In this way, hyperglycemia appears to perpetuate a vicious cycle of deleterious effects that exacerbate type 2 diabetes control and complications.
Suppressing the activity of SGLT2 inhibits renal-glucose reabsorption in the body, thereby leading to the excretion of glucose in the urine.
A tale of two SGLTs
Although the inhibition of renal glucose reabsorption is a novel approach to the treatment of diabetes, data suggest that dapagliflozin has the potential to be an efficacious treatment for T2DM. However, inhibition of the SGLTs is complicated by differences in two important isoforms, SGLT1 and SGLT2. SGLT1 is highly expressed in the gastrointestinal tract and is the major transporter of dietary glucose and galactose.
Inactivating mutations in SGLT1 have been associated with glucose-galactose malabsorption syndrome in humans, which causes life-threatening dehydration on a glucose- or galactose-containing diet. SGLT1 is also expressed in the liver, lung, and kidney, while SGLT2, for which glucose is the primary substrate, appears to be selectively expressed in the kidney. SGLT2 expression in the kidney is localized to the S1 segment of the proximal tubule, where >90% of renal glucose reabsorption occurs, whereas SGLT1 is present in the more distal S3 segment of the proximal tubule.
Study shows great progress
Results from the 24-week study were presented at the 45th European Association for the Study of Diabetes Annual Meeting. This was the first public presentation of dapagliflozin Phase III data.
The data showed that after 24 weeks, individuals receiving dapagliflozin 2.5 mg, 5 mg and 10 mg plus metformin demonstrated a statistically significant adjusted mean change in HbA1c from baseline of -0.67 percent, -0.70 percent and -0.84 percent, respectively, compared to -0.30 percent for placebo (p-value less than 0.0005 for all treatment arms). Individuals treated with dapagliflozin demonstrated a statistically significant adjusted mean change in FPG, a secondary endpoint, from baseline at Week 24: -17.8 mg/dL for dapagliflozin 2.5 mg -21.5 mg/dL for dapagliflozin 5 mg and -23.5 mg/dL /dl for dapagliflozin 10 mg, compared to -6.0 mg/dL for placebo (p-value less than 0.005 for all treatment arms).
The adjusted percentage of individuals treated with dapagliflozin who achieved HbA1c of less than 7 percent at 24 weeks, a secondary endpoint, was 33.0 percent for dapagliflozin 2.5 mg, not significant (p-value 0.1775), 37.5 percent for dapagliflozin 5 mg, and 40.6 percent for dapagliflozin 10 mg statistically significant (both p-values less than 0.05) compared to 25.9 percent for placebo.
Study shows great progress
Results from the 24-week study were presented at the 45th European Association for the Study of Diabetes Annual Meeting. This was the first public presentation of dapagliflozin Phase III data.
The data showed that after 24 weeks, individuals receiving dapagliflozin 2.5 mg, 5 mg and 10 mg plus metformin demonstrated a statistically significant adjusted mean change in HbA1c from baseline of -0.67 percent, -0.70 percent and -0.84 percent, respectively, compared to -0.30 percent for placebo (p-value less than 0.0005 for all treatment arms). Individuals treated with dapagliflozin demonstrated a statistically significant adjusted mean change in FPG, a secondary endpoint, from baseline at Week 24: -17.8 mg/dL for dapagliflozin 2.5 mg -21.5 mg/dL for dapagliflozin 5 mg and -23.5 mg/dL /dl for dapagliflozin 10 mg, compared to -6.0 mg/dL for placebo (p-value less than 0.005 for all treatment arms).
The adjusted percentage of individuals treated with dapagliflozin who achieved HbA1c of less than 7 percent at 24 weeks, a secondary endpoint, was 33.0 percent for dapagliflozin 2.5 mg, not significant (p-value 0.1775), 37.5 percent for dapagliflozin 5 mg, and 40.6 percent for dapagliflozin 10 mg statistically significant (both p-values less than 0.05) compared to 25.9 percent for placebo.
Generally, adverse events were balanced across all groups. Overall, the number of individuals reporting at least one adverse event for dapagliflozin 2.5 mg, dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo were 89, 95, 98 and 88, respectively. Rates of urinary tract infections were similar for dapagliflozin 2.5 mg, 5 mg, 10 mg and placebo [4.4 percent, 7.3 percent, 8.1 percent and 8.0 percent, respectively]. Rates of genital infections were higher for the 2.5 mg, 5mg and 10 mg dapagliflozin treatment arms compared to placebo [8.0 percent, 13.1 percent, 8.9 percent, and 5.1 percent, respectively]. Genital tract infections were mild or moderate in nature and did not lead to discontinuation from the study. There were no clinically meaningful changes in markers for renal impairment, increases in mean serum creatinine, or increases in electrolyte abnormalities associated with dapagliflozin therapy.
The number of reported hypoglycemic events was similar across all treatment arms: 2.2 percent for dapagliflozin 2.5 mg, 3.6 percent for dapagliflozin 5 mg, 3.7 percent for dapagliflozin 10 mg and 2.9 percent for placebo. There was no occurrence of hypoglycemia that led to discontinuation of the study.
Reductions in blood pressure were observed without associated signs of hypotension. Changes in blood pressure at week 24 ranged from -3.1 to -5.9 systolic/-2.1 to -2.7 diastolic mmHg with dapagliflozin, compared to -0.3 systolic/-0.4 diastolic mmHg with placebo. A similar proportion of patients across all treatment arms, including placebo, had measured orthostatic hypotension.
“Given the continued rising prevalence of type 2 diabetes, development of novel treatments such as SGLT2 inhibitors are needed to help improve glycemic control. The preliminary data on weight loss and blood pressure may be important adjuvants to glycemic control,” noted Cliff Bailey, Professor of Clinical Science and Head of Diabetes Research at Aston University, Birmingham, UK. “We look forward to additional data from pivotal dapagliflozin studies which will explore the potential benefits of this new class of medicine for type 2 diabetes patients.”
The study was designed to assess the efficacy and safety of dapagliflozin as an add-on to metformin over 24 weeks in patients with inadequately controlled type 2 diabetes. The data represent findings from a randomized, double-blind, placebo-controlled study of 546 individuals with type 2 diabetes (ages 18 –77) whose HbA1c was greater than or equal to 7.0 percent and less than or equal to 10 percent at baseline. After a two-week lead-in phase, individuals were randomized to one of four separate treatment arms: dapagliflozin 2.5 mg (n= 137), dapagliflozin 5 mg (n= 137), dapagliflozin 10 mg (n= 135), or placebo (n= 137). Patients in all arms also received metformin (greater than or equal to 1500 mg/d).
The primary endpoint of the study compared mean HbA1c change from baseline for each dapagliflozin treatment arm compared to placebo after 24 weeks. Secondary endpoints included change from baseline in FPG and body weight at week 24 as compared to placebo, and adjusted percentage of individuals treated with dapagliflozin who achieved HbA1c of less than 7 percent at 24 weeks. Exploratory endpoints included body weight decrease of greater than or equal to 5 percent or greater than or equal to 10 percent as well as body weight percent change from baseline. The study includes an extension phase for a total duration of two years.
While lifestyle modification, including nutritional therapy and physical activity, should continue to be emphasized at the same time as pharmacotherapy is being used. Newer medications with unique mechanisms of action are still needed, as many patients fail to reach glycemic targets. Sodium-glucose co-transporter 2 inhibitor reduce hyperglycemia by inducing significant amounts of glucosuria. Clinical trials are defining the characteristics of this new class of medication and, as seen from these Phase III data, initial results are promising.
Researchers and market analysts assume that it will probably be another year before Bristol-Myers Squibb and AstraZeneca file for marketing approval of dapagliflozin in either the US or Europe. As a result, a potential approval is not expected before 2011.
For more information:
- Mark Kipnes. Dapagliflozin: an emerging treatment option in type 2 diabetes, Expert Opinion on Investigational Drug, Mar 2009, Vol. 18, No. 3, Pages 327-334
