Pharmacy & Therapeutics - September 2008 - (Page 549)

Meeting Highlights: American Diabetes Association 7.5-year study was to examine a typical older population of veterans, mostly men, who were approximately 60 years of age at the outset. All patients had failed to respond to what Dr. Duckworth called “simple therapy” and had unacceptable HbA1c levels; while taking maximal doses of at least one oral antidiabetes drug, insulin, or both. Their average level was 9.5%, whereas normal is 6%. This population, he added, was at higher risk than those in other outcome studies, with 40.4% having had prior CVD events, 80% having hypertension, more than 50% having lipid abnormalities, and the majority being obese. Presenting preliminary findings, Dr. Abraira pointed out that although a direct relationship between glucose levels and CVD has been shown, prior studies have failed to demonstrate a significant CVD event risk reduction from good glycemic control. The VADT trial enrolled 1,791 U.S. veterans from 20 centers. All participants were treated intensively with drugs and lifestyle therapies to control blood pressure and blood lipid levels. Half the participants were randomly assigned to the intensive blood glucose control group, and the other half were assigned to the standard control group. Patients were followed for an average of 6.25 years. All patients received oral drugs and insulin as needed; 90% of the intensive-therapy group and 74% of the standard group eventually used insulin, and slightly more individuals in the intensive group took oral drugs. Within six months, the intensive group achieved a median HbA1c of 6.9%, the standard group, 8.4%. The average difference for the duration of the trial was 1.5% between the groups. The primary endpoint of composite CVD events was reported in 29.3% of patients in the standard-treatment glucose control group and in 25.9% of the intensive-treatment control group (P = 0.11). “There was no significant effect of glucose control on cardiovascular events,” Dr. Duckworth said. Differences in time to primar y outcome were also not significant (P = 0.12). Among predictors of first primary outcome were prior events, age, duration of diabetes, lower highdensity lipoprotein-cholesterol (HDL-C) levels, higher HbA1c values, and hypoglycemia. Among predictors of cardiovascular death (hypoglycemia, HbA1c, HDL-C, age, prior events), the strongest was recent severe hypoglycemia, with a hazard ratio of 4.042. Although hypoglycemia was a stronger predictor of death in the standard-treatment glucose-lowering group than in the intensive-treatment group, severe hypoglycemia (defined as causing either impaired or total loss of consciousness) was more frequent with intensive treatment (21.1% vs. 9.7%). Severe hypoglycemia was also a significant predictor of CVD events (P = 0.002). An analysis of the interaction between intensive therapy and diabetes duration showed that intensive therapy was initially protective, especially if it was initiated soon after diagnosis of diabetes. However, as the duration of diabetes increased (15 years), the benefit disappeared. “Intensive glucose control may be detrimental in longestablished type-2 diabetes,” Dr. Duckworth said. In an ADA press conference, Dr. Abraira commented, “I’m not ready to make any recommendations. Diabetes is extremely complicated, and I’m not sure I know anything for certain. This is a work in progress.” Dr. Duckworth said, “I think stating target goals of HbA1c for everybody is wrong. I treat patients, not numbers.” Sitagliptin (Januvia) plus Metformin (Glucophage) • Deborah Williams-Herman, MD, Merck Research Laboratories, Rahway, N.J. • Priscilla Hollander, MD, Baylor University Medical Center, Dallas, Tex. In a study of initial therapy for type-2 diabetes mellitus with sitagliptin (Januvia, Merck) and metformin (Glucophage), the combination led to sustained improvements in both beta-cell function and in HbA1c values. Dr. Williams-Herman presented the results of the study, which included a 104-week extension among 587 patients. In the study’s first 24 weeks, 1,091 patients received the sitagliptin/metformin combination or placebo. An active-treatment phase followed in which the 762 placebo subjects were switched to metformin. Evaluable patients in the extension phase (n = 402) received one of five treatment regimens: • sitagliptin 50 mg twice daily plus metformin 500 mg twice daily (n = 96) • sitagliptin 50 mg twice daily plus metformin 1,000 mg twice daily (n = 105) • metformin 1,000 mg twice daily (n = 87) • metformin 500 mg twice daily (n = 67) • sitagliptin 100 mg daily (n = 50) Beta-cell function was analyzed in 125 self-selected subjects who underwent a frequently sampled standard meal-tolerance test at baseline and again at week 104. Dr. Williams-Herman reported substantial improvements in the steady-state rate of insulin secretion as a function of glucose concentration (median increases from baseline: group 1, 20.2; group 2, 22.5; group 3, 10.4; group 4, 9.8; and group 5, 13.6). Mean HbA1c levels also decreased from baseline: group 1, 1.4%; group 2, 1.7%; group 3, 1.3%; group 4, 1.1%; and group 5, 1.2%. The data for the sitagliptin/metformin combination, Dr. Williams-Herman said, “translate to an increased responsivity of the beta cell to glucose and to HbA1c lowering.” Dr. Hollander reinforced that viewpoint in an interview: Type-2 diabetes is defined now as a disease of beta-cell deterioration over time requiring increasing levels of treatment to maintain the type of glucose control we would like. Although we have not previously thought of metformin as a drug that increases beta-cell function, these data show that sitagliptin and metformin make an attractive combination that may offer some longer durability of treatment without having to increase therapy. I Vol. 33 No. 9 • September 2008 • P&T® 549

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - September 2008

Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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