Benefit of Intensive Glycemic Control Challenged

Internal med news Volume 41, Issue 12, Page 1 (15 June 2008)

Benefit of Intensive Glycemic Control Challenged: Macrovascular event rates not reduced.
SAN FRANCISCO — Lowering hemoglobin A1c levels below currently recommended levels did not reduce the risk of macrovascular events in high-risk patients with established type 2 diabetes in two large studies, and significantly increased the risk of death in one of the studies.
Clinicians should focus on managing blood pressure and lipid levels to reduce cardiovascular risk in patients with type 2 diabetes who are at high risk for macrovascular complications, and stick to the currently recommended goal of an HbA1c level between 7% and 7.9%, several investigators suggested during a press briefing held at the annual scientific sessions of the American Diabetes Association.
Approximately 25% of people with diabetes might fall into this high-risk category of patients, experts at the press briefing estimated. There were suggestions in some of the data that intensive glycemic control may reduce cardiovascular events in lower-risk patients.
The 11,140-patient ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial targeted an HbA1c level of 6.5% or lower. The 10,251-patient ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial aimed for an HbA1c level of 6% or lower. Approximately one-third of patients in each study (32% in ADVANCE and 35% in ACCORD) had a past cardiovascular event such as MI or stroke, and the rest of the cohorts had risk factors or subclinical disease that put them at high risk.
The studies used different pharmacologic strategies and showed that each could achieve and maintain tight glycemic control, but with different risks and benefits. Both studies were published online in the New England Journal of Medicine and will appear in the June 12 issue of the print journal.
In the ADVANCE study, reducing HbA1c levels from an average baseline of 7.5% to 6.5% after 5 years of intensive treatment reduced the risk of new or worsening nephropathy by 21%, compared with the standard group, which achieved an HbA1c level of 7.3% (N. Engl. J. Med. 2008 June 6 [doi:10.1056/NEJMoa0802987]). The incidence of nephropathy was 4.1% in the intensive group and 5.2% in the standard group.
These results confirm previous studies that showed that intensive control of blood glucose helps prevent microvascular complications, reported Dr. Anushka Patel of the University of Sydney, Australia.
The rate of severe hypoglycemic events was significantly higher in the intensive group than the standard group (2.7% vs. 1.5%). Intensive glycemic control did not significantly affect the rates of heart attack, stroke, or death from cardiovascular disease, although there was a trend toward improvement in these macrovascular outcomes.
The ADVANCE trial was funded by the Australian government and the pharmaceutical company Servier, which makes some of the diabetes medications used in the trial. Dr. Patel has received lecture fees or grants from Servier, Pfizer Inc., Abbott Laboratories, and Sanofi-Aventis.
In the ACCORD study, reducing HbA1c levels from an average baseline of 8.2% to 6.4% after 3.5 years of treatment in the intensive group (compared with 7.5% in the standard group) was associated with a 22% relative increase in all-cause mortality (N. Engl. J. Med. 2008 June 6 [doi:10.1056/NEJMoa0802743]). Death rates were 1.4% in the intensive therapy group and 1.1% in the standard treatment group, reported Dr. Hertzel Gerstein, lead investigator in the trial and professor of medicine at McMaster University, Hamilton, Ont.
That interim finding prompted the National Heart, Lung, and Blood Institute (NHLBI) to stop the intensive therapy group earlier this year, 18 months before the end of the 5-year trial. Patients on intensive therapy were switched to standard glycemic control for the remainder of the study.
The ACCORD study was funded primarily by the NHLBI; medications and equipment were supplied by 12 pharmaceutical and health care companies. Dr. Gerstein is an adviser to or has received funds from 15 pharmaceutical companies, including some that make diabetes treatments.
The incidence of combined fatal and nonfatal cardiovascular events did not differ significantly between groups—6.9% with intensive control and 7.2% with standard control. Secondary outcomes showed a 35% higher relative risk for cardiovascular-related deaths in the intensive therapy group and a 24% lower relative risk for nonfatal heart attacks in the standard therapy group. Both of the differences were significant.
The ADVANCE study, the largest trial to date of treatment to prevent complications in diabetes, randomized patients at 215 centers on four continents. All patients received the ACE inhibitor perindopril and the diuretic indapamide or placebo for blood pressure control. Diabetes treatment started with the sulfonylurea gliclazide (modified release, 30–120 mg daily), and physicians could add other drugs as needed.
By the end of the study, most patients were on multiple medications, and around 30% were using insulin.
“We tested a strategy for glucose control, not a particular drug,” emphasized Stephen McMahon, Ph.D., professor of cardiovascular medicine and epidemiology at the University of Sydney, Australia, and an investigator in the ADVANCE study. Dr. McMahon is an adviser to or has received fees or grants from Servier, Pfizer, and Novartis.
The ACCORD trial also did not focus on a particular drug, said Dr. Denise G. Simons-Morton of the NHLBI. The findings apply to a combination of three things—the particular treatment strategy, the glycemic goal, and the population of high-risk patients. Dr. Simons-Morton disclosed no potential conflicts of interest.
The ACCORD study, which was conducted at 77 sites in North America, incorporated three complementary strategies for intensive or standard control of blood sugar levels, blood pressure, or lipids. The blood pressure and lipid portions of the trial continue.
For diabetes treatment, physicians could choose from any of the approved drug classes. Analyses of the interim results could find no specific reason for the increased risk of death from intensive glycemic control.
“The only conclusion we can make is [that] it is the strategy causing increased risk,” Dr. Gerstein said.
A secondary analysis suggested that intensive control did decrease the incidence of fatal and nonfatal cardiovascular events in patients with no previous cardiovascular event, he added.
The studies differed in some key respects. The decrease in HbA1c levels with intensive therapy was quicker in ACCORD than in ADVANCE. ACCORD patients had higher HbA1c levels; glucose control at the start of ADVANCE was better than at the end of ACCORD. The intensive therapy group in ACCORD gained 8 pounds on average, compared with no significant weight gain in the ADVANCE intensive group. None of these factors were associated with increased risk for macrovascular events, the investigators said.
Based on results from both studies, said Dr. John Buse, professor of medicine at the University of North Carolina at Chapel Hill and vice chair of the ACCORD steering committee, “Focusing on blood pressure and lipids is really where the money is if you want to decrease cardiovascular events” in high-risk patients with diabetes.
Dr. Buse, who is president of the ADA, reported having an equity interest in Insulet, MicroIslet, and dLife and receiving grant support from Bristol-Myers Squibb, Novartis, Pfizer, Novo Nordisk, Amylin Pharmaceuticals, Eli Lilly & Co., and Medtronic. Dr. Buse is an adviser, consultant, and speaker for Merck & Co., which makes medications for diabetes, hypertension, hyperlipidemia, and other diseases.
Also in the June 6 online issue of the New England Journal of Medicine, the journal's editors, Dr. Robert G. Dluhy and Dr. Graham T. McMahon, wrote in an editorial that clinicians could better serve patients by helping more of them reach current goals for glycemic control rather than focusing on intensive control, and use other strategies to reduce cardiovascular risk (N. Engl. J. Med. 2008 June 6 [doi:10.1056/NEJMe0804182]). They reported no conflicts of interest related to these topics.