Studies challenge benefit of intensive glycemic control

Lowering haemoglobin Alc levels below currently recommended levels did not reduce the risk of macrovascular events in high-risk of patients with established type 2 diabetes in two large studies, and significantly increased the risk of death in one of the studies.

Clinician 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 the annual scientific sessions of the American Diabetes Association.

Approximately 25% of people with diabetes might fall into this high-risk category of patient, 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: Proterax and Diamicron Modified Release Controlled Evaluation) trial targeted an HbA1 level of 6.5% or lower. The 10,251-patient ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial aimed for an HbAlc 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 sub-clinical 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 HbAIc 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 HbAIc LEVEL OF 7.3% (N. Engl. J. Med. 2008 June 6 [doi:10,1056/NFJMoao802987]. The incidence of nephpropathy 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.

The rate of severe hypoglycacmic 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.

In the ACCORD study, reducing HbAlc 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.

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.

The incidence of combined fatal and nonfatal cardiovascular events did not differ significantly between group –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 data 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 standard with ulfunylurea 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.

The ACCORD trial also did not focus on a particular drug. The findings apply to a combination of three things — the particular treatment strategy, the glycemic goal, and the population of high-risk patients 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 portion 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.

A secondary analysis suggested that intensive control did decreased the incidence of fatal and nonfatal cardiovascular event.

The studies differed in some key respects. The decrease in HbAlc levels with intensive therapy was quicker in ACCORD than in ADVANCE. ACCORD patients had higher HbAlc 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.

Based on results from both studies, focusing on blood pressure and lipid is really where the money is if you want to decrease cardiovascular events in high-risk patients with diabetes.

They have an empty interest in Isulet, MicroIslet, and dLife and receiving grant support from Bristol-Myers, Squibb, Novartis, Pfizer, Novo Nordisk, Amylin Pharmaceuticals, Eli Lilly & Co., and Medtronic as advise and consulted b, which makes medications for diabetes, hypertension, hyperlipidemia, and other diseases.

Also they 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 and reported no conflicts of interest related to these topics.