Glycemic control and coronary heart disease

Are we in ACCORD, and is there an ADVANCE?

A scene from a clinic, Anywhere, USA.

Patient: Doctor, I’m concerned. I read about this study that was stopped because tight blood sugar control was killing people. Do you think mine is too good? [Today’s HbA1c is 6.6%]

Doctor: You must be referring to the ACCORD study. You’re right. The study set out to compare average blood sugar control to ultra-tight blood sugar control. The patients who were assigned to ultra-tight control had a goal of getting their HbA1c below 6%. And, the sponsor of the study stopped the study 18 months early because the death rate was higher in that group than in the group with average blood sugar control. As for you…

Stephen A. Brietzke

The conventional wisdom in type 2 diabetes is rooted in observations of the natural history of the disease. Patients afflicted with the disease have an approximately four-fold increased risk of cardiovascular disease and are more likely to suffer fatal cardiovascular events when compared to non-diabetics.

Inferential reasoning then goes something like this: the most obvious difference between patients with diabetes and those without diabetes is that patients have high blood sugar; therefore, if the blood sugar in the patient with diabetes can be lowered to normal, the risks associated with diabetes will revert to those of the individual without diabetes.

Thus was born the “glucose hypothesis” of diabetes and its complications.

Two landmark randomized, clinical trials, the DCCT for type 1 diabetes, and the UKPDS for type 2 diabetes, seemed to clearly support the glucose hypothesis: participants randomized to intensive glycemic control strategies (HbA1c on treatment averaged about 7% to 7.1% in both studies) had fewer microvascular complications of retinopathy, neuropathy and nephropathy as compared to those randomized to “usual” care (HbA1c on usual care treatment averaged about 8.6% in DCCT and 7.9% in UKPDS). For patients with type 1 diabetes who participated in DCCT, the long-term follow-up EDIC study demonstrated a durable benefit of reduced risk of not only microvascular complications, but also cardiovascular events despite gradual loss of glycemic control so as to be indistinguishable from the former control group. With this foundation of evidence, it was appropriate and inevitable that the glucose hypothesis should be put to the test in the far more common disease of type 2 diabetes. Thus enters a tale of two clinical trials.

ACCORD trial

Researchers with the ACCORD trial randomized 10,251 adults aged between 40 and 82 years (mean age, 62 years) to receive either ultra-intensive glycemic control therapy with a goal HbA1c <6%, or usual care with a goal HbA1c of 7% to 7.9%. Duration of diabetes was about 10 years, on average, and to be eligible for the study participants had to either have an actual diagnosis of coronary heart disease based on a documented event or symptom of angina, or be over age 55 with additional risk factors of smoking, hypertension or elevated LDL.

In February 2008, the study’s Data and Safety Monitoring Board identified an excess death rate of approximately 20% in the intensive glycemic control group as compared with the control group (excess deaths of approximately 3 per 1,000 patient years). Based on this finding, the intensive glycemic control arm of the trial was terminated.

In both the intensive control and “usual care” groups, antihyperglycemic therapy could include any stand-alone or combination therapy of metformin, sulfonylurea, thiazoladinedione, and/or insulin, and no single agent or specific combination therapy was associated with a disproportionate rate of death. Of note, hypoglycemic events were not identified as disproportionately frequent or severe in the intensive therapy group.

Two other treatment arms comparing fibrate plus statin therapy with statin therapy alone, and ultra-intensive blood pressure lowering versus usual care, are continuing with a planned completion date in 2009.

ADVANCE trial

In contrast with ACCORD, the comparably designed ADVANCE trial was designed to assess the effect of aggressive glycemic control (with a goal HbA1c < 6.5%) to “usual care” (HbA1c target not specified), with both cardiovascular events and microvascular disease onset or progression as outcome measures.

This trial, which included centers in 20 countries in Europe and Asia, as well as Australia and Canada, has enrolled 11,140 patients. Interim safety data analysis of the trial was performed in late February because of concerns raised by the ACCORD study report; however, in the ADVANCE study, there was no appreciable increased rate of cardiovascular events in the intensive glycemic control study group as compared with the control group. Nor was there evidence of cardiovascular benefit conferred by intensive glycemic control.

Stance after results

So, from two huge well-designed and well-conducted clinical trials powered to address the “glucose hypothesis” in type 2 diabetes, we have one study showing increased risk and the other showing no increased risk, but not reduced risk.

How are we to reconcile the current science with our long-held beliefs?

First, and I believe most importantly to note, is that in both studies the actual observed incidence of cardiovascular events was significantly less than expected, in both the intensive antihyperglycemic and control groups. Most likely, this fact is due to concurrent glycemia-independent excellent care addressing blood pressure and lipid-lowering therapies. The Steno-2 study has previously validated the multiple cardiovascular risk factor intervention strategy, including routine use of statins and ACE inhibitors, as well as moderate-intensity anti-hyperglyemic therapy in patients with type 2 diabetes. The Steno-2 strategy is essentially the same strategy currently advocated by the American Diabetes Association in the published Clinical Practice Recommendations.

With regard to the “glucose hypothesis” and CVD risk and mortality in type 2 diabetes, the professional community stance has always been scattered along a spectrum bounded at its extremes by “zealots” and “unbelievers”.

Based on the ACCORD and ADVANCE trials, neither the “zealot” nor the “unbeliever” has clearly come out on top. It would appear that a moderate approach to glycemic control, coupled with conscientious use of statin and antihypertensive therapy including ACE inhibitors or ARB’s, may actually be the best course of action (and likely to replicate results observed in the Steno-2 study). Perhaps, this is good news.

I have personally found it difficult to attain HbA1c’s consistently <7% in many patients, and perhaps with the cautionary results of ACCORD and ADVANCE in hand, I can still feel that I have helped those patients unable to achieve a more “normal” level of glycemic control.

Feeling like a failure less often can’t be all bad, can it?

Epilogue — Meanwhile, back at the clinic in Anywhere, USA.

Patient: Okay doc, so we’ve got my blood pressure and cholesterol under good control. Is my blood sugar too good? Should I do something different? What do you think?

Doctor: Perhaps you should move to Australia!

For more information:

• Anonymous. 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.
• Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580-591.
• National Heart Lung and Blood Institute. Questions and answers: Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial. http://www.nhlbinihgov/health/prof/heart/other/accord/q_ahtm.2008.
• The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J Med. 1993;329:977-986.
• The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643-2653.

Stephen A. Brietzke, MD, FACP, FACE, is an Associate Professor of Clinical Medicine at the University of Missouri-Columbia, School of Medicine, and is an Endocrine Today Editorial Board member.