Meta-Analysis of Clinical Data Showed No Increased Cardiovascular Risk Associated With Investigational Compound Dapagliflozin in Adult Patients With Type 2 Diabetes

MISSISSAUGA, ON, Nov. 17, 2011 /CNW/ - Bristol-Myers Squibb Canada and AstraZeneca Canada today announced results from a pre-specified meta-analysis of cardiovascular safety data from 14 phase 2b/3 trials in adult patients with type 2 diabetes that showed no increased risk of cardiovascular (CV) events associated with the investigational compound dapagliflozin relative to all comparators pooled in the clinical program. Dapagliflozin is a novel drug in a new class under evaluation for the treatment of type 2 diabetes mellitus (T2DM).  The meta-analysis, presented yesterday at the American Heart Association (AHA) Scientific Sessions in Orlando, FL, was conducted in accordance with the U.S. Food and Drug Administration (FDA) guidelines for the assessment of CV safety in new anti-diabetic treatments.

Cardiovascular disease is the leading cause of death in type 2 diabetes patients.1 Diabetes patients are at acute (two- to four-fold) increase risk for cardiovascular events.2

"Diabetes is a major risk factor for cardiovascular disease and these preliminary results are reassuring because they show no increase in heart disease. This new class of medications for the treatment of type 2 diabetes is very promising as it significantly lowers glucose and is associated with weight loss," said Dr. Vincent Woo, Professor of Medicine, University of Manitoba, Endocrinologist.

The meta-analysis included 6,228 patients with type 2 diabetes, including 4,287 patients treated with dapagliflozin (2.5 mg, 5 mg, 10 mg doses) with or without add-on/combination anti-diabetes medication and 1,941 patients in the control group, treated with a placebo or an active comparator with or without add-on/combination anti-diabetes medication.3

The findings of the meta-analysis indicated that dapagliflozin is not associated with an increase in cardiovascular disease risk, and are consistent with a potential reduction in cardiovascular disease risk.3 The primary end point was a composite of time to first event of CV death, myocardial infarction (MI), stroke, and hospitalization for unstable angina.3

About the Study

A pre-specified meta-analysis was conducted using data from 14 phase 2/3 studies (n=6228) to assess the cardiovascular disease safety of all dapagliflozin doses (2.5 to >10mg/d) pooled (n=4287), relative to all comparators (active or placebo) pooled (n=1941). Cardiovascular disease events were systematically identified from investigator reports of adverse events and adjudicated by an independent committee. Adjudication was blinded to treatment allocation and conducted prospectively for the majority of trials3. The primary end point was a composite endpoint of time to first event of cardiovascular disease death, myocardial infarction (MI), stroke, or hospitalization for unstable angina. The secondary end point included measurements of the primary end point, in addition to unplanned coronary revascularization, and hospitalization for heart failure. Baseline characteristics were balanced between groups: mean age=56 years, body mass index=31.5 kg/m2, and T2DM duration=six years. Characteristics mirrored cardiovascular disease risk in the general T2DM population and included hypertension (62%), dyslipidemia (49%), smoking history (40%), and cardiovascular disease history (19%).3

Study Results

A total of 78 primary end point events were confirmed with a stratified event rate (subjects with events/1000 subject years) of 11.3 for dapagliflozin vs. 16.6 for comparators. The estimated hazard ratio (HR) using a Cox proportional hazards method was 0.674 (98% CI: 0.385, 1.178; 95% CI: 0.421, 1.078). Analyses of the secondary end point (HR: 0.632; 95% CI: 0.416, 0.959) and of a composite cardiovascular death, MI, and stroke end point (HR: 0.596; 95% CI: 0.357, 0.996) were consistent with primary results. Analyses by dose (dapagliflozin 2.5, 5 and 10 mg) were comparable to overall results. Review of data from the four month safety update confirmed the conclusions from the initial pre-specified analysis. The results suggest that dapagliflozin is not associated with an increase in cardiovascular disease risk, and are consistent with a potential reduction in cardiovascular disease risk.3

Diabetes Trends in Canada

Type 2 diabetes is a growing epidemic and today, more than nine million Canadians live with diabetes or prediabetes.4 Type 2 diabetes is a chronic, progressive disease characterized by insulin resistance and/or dysfunction of beta cells in the pancreas, which decreases insulin sensitivity and secretion, leading to elevated glucose levels.6 Over time, this sustained hyperglycemia contributes to worsening insulin resistance and further beta cell dysfunction.5

New class of treatment for type 2 diabetes

The kidney plays an important role in glucose balance, normally filtering ~180g of glucose each day, with virtually all glucose being reabsorbed back into circulation.8 SGLT2 is the major sodium-glucose cotransporter in the kidney and is an insulin-independent pathway for the reabsorption of glucose back into the blood. 5,8

Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor currently under evaluation for the treatment of type 2 diabetes mellitus.  Dapagliflozin is currently under review by Health Canada.  If approved, dapagliflozin will be the first SGLT2 inhibitor in its class.  Studies have shown that dapagliflozin promotes urinary glucose excretion, leading to osmotic diuresis, caloric loss and weight loss.7

To date, treatments for type 2 diabetes have focused primarily on insulin-dependent mechanisms.5 An approach that acts independently of insulin could provide an additional option for adults with type 2 diabetes.9,10

Bristol-Myers Squibb and AstraZeneca Collaboration

Bristol-Myers Squibb and AstraZeneca entered into a collaboration in January 2007 to enable the companies to research, develop and commercialize two investigational drugs for type 2 diabetes - saxagliptin and dapagliflozin. The Bristol-Myers Squibb/AstraZeneca diabetes collaboration is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of type 2 diabetes. The companies' collaboration in this therapeutic area is driven by their joint commitment to global patient care and improving patient outcomes, and is further strengthened by their deep collective experience in cardiovascular disease.

About Bristol-Myers Squibb

Bristol-Myers Squibb Canada is an indirect wholly-owned subsidiary of Bristol-Myers Squibb Company, a global pharmaceutical and related health care products company whose mission is to extend and enhance human life. Bristol-Myers Squibb Canada is a leading provider of medicines to fight cancer, cardiovascular and metabolic disorders, infectious diseases (including HIV/AIDS), nervous system diseases and serious mental illness. Bristol-Myers Squibb Company is listed on the New York Stock Exchange under the BMY symbol (NYSE: BMY). Bristol-Myers Squibb Canada's operations are headquartered in Montréal, Québec. For more information about Bristol-Myers Squibb Canada, visit www.bmscanada.ca.

About AstraZeneca

AstraZeneca is committed to the research, development and manufacturing of valuable prescription medicines. We have an extensive product portfolio spanning six therapeutic areas: gastrointestinal, cardiovascular, infection, neuroscience, oncology and respiratory. AstraZeneca's Canadian headquarters are located in Mississauga, Ontario, and a state-of-the art drug discovery centre is based in Montreal, Quebec. For more information, please visit the company's website at www.AstraZeneca.ca.

References:

  1. Frank Lavernia, Improving Glycemic Control and Cardiometabolic Risk Through Integrated Treatment Plans. The Journal of Osteopathic Association. July 1, 2010 vol. 110 no. 7 suppl 7 eS13-eS19.
  2. Frank B. Hu, Meir J. Stampfer, et al. Elevated Risk of Cardiovascular Disease Prior to Clinical Diagnosis of Type 2 Diabetes. Presented in Diabetes Care July 2002 vol. 25 no. 7 1129-1134.
  3. Langkilde AM, Sugg J, Johannson P, Ying L, List J, Parikh S. A Meta-Analysis of Cardiovascular Outcomes in Clinical Trials of Dapagliflozin, Presented at American Heart Association Scientific Sessions 2011.
  4. The Prevalence and Costs of Diabetes. Canadian Diabetes Association | Home. Web. 27 Oct. 2011. http://www.diabetes.ca/diabetes-and-you/what/prevalence/.
  5. Washburn WN. Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. J Med Chem. 2009; 52(7):1785-1794.
  6. Srinivasan BT, Jarvis J, Khunti K, Davies MJ. Recent advances in the management of type 2 diabetes mellitus: a review. Postgrad Med J. 2008;84(996):524-531.
  7. Woo V, Langkilde AM, Sugg, Parikh.  Dapagliflozin, a novel antihyperglycemic agent that promotes urinary glucose excretion, reduces systolic blood pressure in patients with type 2 diabetes mellitus. Presented at American Heart Association Scientific Sessions 2011.
  8. Rajesh R, Naren P, Vidyasagar S, Unnikrishnan, Pandey S, Varghese M, Gang S. Sodium glucose co transporter 2 (SGLT2) inhibitors: a new sword for the treatment of type 2 diabetes mellitus. Int J Pharm Sci Res. 2010;1(2):139-147.
  9. Bailey C, Gross J, Pieters A et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375(9733):2223-33.
  10. Wilson, Carol. Diabetes: Dapagliflozin: an insulin-independent, therapeutic option for type 2 diabetes mellitus. Nature Reviews Endocrinology 6, 531 (October 2010).

SOURCE AstraZeneca Canada Inc.

For further information:

Media:
Jane Lee Cheung, Fleishman-Hillard Canada, 416-645-8175, jane.lee-cheung@fleishman.ca
Daniela Cohen, AstraZeneca Canada, 905-615-6827, daniela.cohen@astrazeneca.com


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