Intensive Glucose Lowering: Too Much of a Good Thing?

Abstract & Commentary

By Allan J. Wilke, MD, Residency Program Director, Associate Professor of Family Medicine, University of Alabama at Birmingham School of Medicine—Huntsville Regional Medical Campus, Huntsville. Dr. Wilke reports no financial relationship to this field of study.

Synopsis: Intensive hemoglobin A1c lowering does not reduce the rate of cardiovascular death, and results in an increase in hypoglycemic events.

Source: Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

Source: ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572.

June witnessed the publication in the New England Journal of Medicine of two articles that challenge our understanding of the treatment of diabetes mellitus. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials were designed to test the hypothesis that tight control of type 2 diabetes mellitus (T2DM) would result in a decrease in cardiovascular disease. (Preterax® is a perindopril-indapamide combo and Diamicron® is the sulfonylurea, gliclazide. Neither product is available in the United States, but the ACE-inhibitor perindopril, Aceon®, is. Indapamide, previously marketed as Lozol®, is available generically.) Ten years ago the results of the U.K. Prospective Diabetes Study (UKPDS) were published.1 Its conclusion was that intensive treatment of T2DM with insulin or a sulfonylurea (chlorpropamide, glibenclamide [aka, glyburide], or glipizide) with the goal of achieving a fasting plasma glucose < 6 mmol/L (108 mg/dL) resulted in a decreased risk of microvascular complications (nephropathy, retinopathy, etc.), but not macrovascular disease (myocardial infarction, heart failure, stroke, peripheral vascular disease, etc.). The average hemoglobin A1c (HbA1c) achieved in the intensive treatment group was 7.0 and in the usual care group 7.9. The authors of the current studies presumed that the UKPDS investigators didn't try hard enough and set the HbA1c bar lower. We'll review each study separately and then compare the two.

ADVANCE is a randomized controlled study conducted in Asia, Australasia, Europe, and North America. It enrolled 12,877 patients, and after reasonable exclusion, randomized 11,140 to either intensive glucose control (target HbA1c £ 6.5%) with gliclazide or standard care and followed them for 5 years. All patients received perindopril-indapamide. Patients in the intensive care group (ICG) who did not achieve the target HbA1c with increasing doses of gliclazide, saw the addition of metformin, thiazolidinediones, acarbose, or insulin (basal initially, then short-acting insulin at meals). The intervention and control groups were remarkably similar: average age 66 years, 42% female, duration of diabetes 8 years. Mean body mass index (BMI) was 28 kg/m2 and waist circumference (WC) was 99 cm. In both groups, 32% had a history of major macrovascular disease. The mean HbA1c was 7.5% and mean fasting blood glucose (FBG) was 8.5 mmol/L (153 mg/dL).

BMI and WC did not change over the course of the study. However, the difference in body weight at the end of the study favored the standard care group (SCG) by 0.7 kg. The ICG pushed their mean HbA1c to 6.5% and their FBG to 6.6 mmol/L (119 mg/dL), while the SCG values fell to 7.2% and 7.8 mmol/L (140 mg/dL), respectively, significant differences. The mean systolic blood pressure (SBP) fell from about 145 mm Hg to 135.5 mm Hg in the ICG and 137.9 mm Hg in the SCG; this was statistically significant. The rate of smoking fell from 14% to 8% with no significant difference between the groups. At study's end, a larger percentage of patients in the ICG were using insulin and a thiazolidinedione than the SCG (40.5% vs 24.1% and 16.8% vs 10.9%). The combination of major macrovascular or microvascular events occurred in 18.1% of patients in the ICG vs 20.0% of patients in the SCG (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.82-0.98), which is significant. However, the reduction in microvascular events (HR, 0.86; 95% CI, 0.77-0.97) accounted for all of this. There was a reduction in new or worsening nephropathy in the ICG (HR, 0.79; 95% CI, 0.66-0.93), but no difference in new or worsening retinopathy. There was no significant reduction in macrovascular events (HR, 0.94; 95% CI, 0.84-1.06). There was a nonsignificant drop in mortality favoring the ICG (HR, 0.93; 95% CI, 0.83-1.06). Patients in the ICG were hospitalized more frequently than patients in the SCG (44.9% vs 42.8%; HR, 1.07; 95% CI, 1.01- 1.13) and had more severe hypoglycemia (2.7% vs 1.5%; HR, 1.86; 95% CI, 1.42-2.40).

ACCORD is similar to ADVANCE, but different in several important respects. It is a 2 ´ 2 factorial trial that randomized 10,251 patients to intensive glycemic control (HbA1c < 6.0%) or standard care (HbA1c 7.0-7.9%) and intensive blood pressure control (SBP < 120 mm Hg) or standard care (SBP < 140 mm Hg) in middle-aged or older patients with established or at risk for cardiovascular disease. A subset was also randomized to fenofibrate or placebo in addition to simvastatin to control low-density lipoprotein (LDL) cholesterol. The BP and LDL studies are ongoing. The patients averaged 62.2 years, were 38.5% female, and had an average duration of T2DM of 10 years. Average weight was 93.5 kg with a mean BMI of 32.2 kg/m2 and a mean WC of 106.8 cm. Mean SBP was 136 mm Hg. The initial median HbA1c was 8.1% and mean fasting serum glucose was 175 mg/dL. Thirty-five percent had a history of a previous cardiovascular event. Fourteen percent smoked cigarettes at the start of the study, 10% at the end.

By the fourth month of the trial, median HbA1c levels in the ICG had fallen to 6.7%, and by 1 year had stabilized at 6.4%. At 1 year, the median HbA1c level was 7.5% in the SCG. The ICG was highly medicated compared to the SCG. The most commonly used medications and medication classes were metformin (95% vs 87%), secretagogues (87% vs 74%), thiazolidinediones (92% vs 58%), and insulin (77% vs 55%). Somewhat counterintuitively, the ICG received ACE-inhibitors less frequently than SCG (70% vs 72%); however, mean SBP was lower in ICG (126.4 mm Hg vs 127.4 mm Hg). Both groups gained weight, but the ICG gained 3.1 kg more than the SCG. Hypoglycemia requiring medical assistance occurred in 10.5% of the ICG compared to 3.5% of the SCG. The ICG saw a reduction in major microvascular events (HR, 0.86; 95% CI, 0.77-0.97), but not major macrovascular events (HR, 0.94; 95% CI, 0.84-1.06). Although nonfatal myocardial infarction occurred less frequently in the ICG (3.6% vs 4.6%), all-cause and cardiovascular death were more frequent (5.0% vs 4.0% and 2.6% vs 1.9%). The Data and Safety Monitoring Committee of ACCORD halted the glycemic control portion of the study earlier this year when the preplanned safety analysis indicated an increased all-cause mortality rate in the ICG. Follow-up at the time the study closed was 3.5 years.

Commentary

Mae West famously quipped, "Too much of a good thing is wonderful." We can only imagine what she had on her mind, but it certainly wasn't glycemic control.

It's not clear what was at the root of the increase in mortality in ACCORD or the lack of improvement in ADVANCE despite near-normal HgbA1c levels. Is it the journey or the destination? In other words, did the medications used in these studies have adverse side effects or is euglycemia a deleterious condition in a diabetic? Was it the speed or the HbA1c depth to which ACCORD dived? Before you start snickering about those hypotheses, think about what happens when a hypernatremic patient is brought to normal electrolyte balance too quickly or when a starvation survivor is given something to eat. It could be the medications. There is good evidence that rosiglitazone increases the risk for heart attacks,2 and both thiazolidinediones are associated with an increase in heart failure.3

Or could it be the passengers? It can be argued that comparing ACCORD and ADVANCE is comparing apples and oranges. The patients in ACCORD were younger, sicker, heavier, and wider at the waist; smoked more frequently, had more CVD at onset, and had worse glycemic control and longer duration of DM than the ADVANCE patients. Their SBP was lower at baseline and at the close of the study. Any or all of these in combination could reasonably predict more frequent deaths in ACCORD than ADVANCE, but this doesn't explain the increased deaths within ACCORD.

ADVANCE confirmed the reduction in new or worsening nephropathy seen in UKPDS, and we should be encouraged by this result. However, there does not at present appear to be a mortality or CVD advantage to aggressive lowering of HbA1c below 7.0%, which is just as well since we haven't done a good job of getting our patients to that level, let alone the lower4 levels that ACCORD and ADVANCED achieved.

References

1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.

2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-2471.

3. Lincoff AM, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: A meta-analysis of randomized trials. JAMA 2007;298:1180-1188.

4. Schmittdiel JA, et al. Why don't diabetes patients achieve recommended risk factor targets? Poor adherence versus lack of treatment intensification. J Gen Intern Med 2008;23:588-594.