Tight Control and Cardiovascular Disease (Part 2): ACCORD

This is my second report on the large studies of tight blood glucose control and cardiovascular disease risk in Type 2 diabetes that were presented at the ADA Scientific Sessions earlier this month. You can read about the results of the ADVANCE trial in "Tight Control and Cardiovascular Disease (Part 1): ADVANCE." This week, I’ll discuss the Action to Control Cardiovascular Risk in Diabetes, or ACCORD, trial.


The ACCORD trial made headlines earlier this year (see “The ACCORD Trial Findings: What You Should Know”) when its intensive blood-glucose-lowering arm was stopped early because a higher rate of death was found in that group. Now, the full results of the blood-glucose-lowering arm of the ACCORD trial have been published online in The New England Journal of Medicine (NEJM).

The ACCORD Trial
Sponsored by the National Heart, Lung, and Blood Institute (NHLBI), the ACCORD trial enrolled 10,251 people in the United States and Canada. It consisted of three branches: a blood-glucose-lowering arm, a blood-pressure-lowering arm, and a blood-lipid-lowering arm (cholesterol and triglycerides), each of which were divided into “intensive control” and “standard control” groups. The blood-pressure and blood-lipid arms of the study will end in 2009, and their results will probably be published in 2010.

The main aim of the blood-glucose arm of the trial was to see whether a strategy of intensive blood glucose control—aiming for an HbA1c level of less than 6%—would reduce the risk of cardiovascular disease (defined as heart attack, stroke, or death from a cardiovascular cause) in people with Type 2 diabetes. Death from any cause was one of the other outcomes that was measured.

ACCORD participants had an average age of 62, body-mass index (BMI) of 32 (meaning that they were, on average, obese), and HbA1c of 8.3%, and had had diabetes for an average of 10 years at the beginning of the trial. Women accounted for 38% of participants. Participants were considered to be at high cardiovascular risk; 35% had had a prior “cardiovascular event” (heart attack or stroke), and the rest had either a major risk factor in addition to diabetes, such as left ventricular hypertrophy (enlargement of part of the heart) or microalbuminuria (a sign of kidney problems), or at least two of the following risk factors: high LDL (“bad”) cholesterol, low HDL (“good”) cholesterol, high blood pressure, obesity, or smoking.

The ACCORD participants were all randomly assigned to be in the intensive glucose control group or the standard group. Members of the intensive group saw a health-care professional every two months and monitored their blood glucose levels two to four times per day if their HbA1c levels were above target; the standard group was seen every four months and was only required to monitor once a day. Both groups were treated with a variety of drugs and insulin, but the intensive group tended to be prescribed more drugs. (For example, 52% of people in the intensive group took three oral diabetes drugs plus insulin, but only 16% of the standard group was prescribed this regimen.) By the time the study was stopped, the intensive group had a median HbA1c of 6.4% and the standard group had an Hba1c of 7.5%.

The blood-glucose-control branch of the ACCORD study was terminated 17 months early when a safety review showed an increased death rate in the intensive treatment group. The participants had been involved in the study for an average of 3.5 years.

At this point, the researchers found the following:

  • No significant difference between the standard-control group and the intensive-control group in total major fatal or nonfatal cardiovascular events
  • A 22% higher rate of death from all causes in the intensive group (257 deaths in the intensive group compared to 203 deaths in the standard group)
  • A 35% higher rate of cardiovascular death in the intensive group
  • A 24% lower risk of nonfatal heart attacks in the intensive group
  • No significant difference in nonfatal strokes or heart failure between the groups
  • An average weight gain of 7.7 pounds in the intensive group and about 1 pound in the standard group

So, unlike the ADVANCE trial, which simply found no cardiovascular benefit to intensively lowering blood glucose levels in people with diabetes and high cardiovascular risk, the ACCORD trial found evidence of harm. Why is this?

To see if they could explain the higher rates of death and cardiovascular death in the intensive-control group of ACCORD, the researchers performed further analyses considering people’s age, sex, ethnicity, other diseases, blood glucose control, current or severe hypoglycemia, diabetes drugs used, or combinations of these factors, but were not able to identify any group of people that was more likely to die in response to intensive treatment. Based on these analyses, Robert Byington, Ph.D., one of the lead ACCORD researchers, said that it was probably the “strategy of intensive glycemic lowering itself, compared to a standard approach, in a population of people with Type 2 diabetes at high risk for cardiovascular disease, [that] increases mortality over the course of three and a half years of treatment.”

In editorials published in NEJM analyzing the ACCORD and ADVANCE results, doctors not affiliated with the studies discussed a few other factors that may help explain the increased risk of death that was found in the ACCORD study. (You can read the full editorials here and here.)

  • Speed of blood glucose lowering. Blood glucose levels in the intensive group of the ACCORD trial were lowered rapidly: HbA1c levels in the group fell from 8.1% to 6.7% in the first four months of the study, a decline of 1.4 percentage points. In contrast, they only fell to 7.5% in the same period in the ACCORD standard group (a decline of 0.6 percentage points); and in the intensive-control arm of the ADVANCE study, which did not see an increased risk of death in a similar group of participants, blood glucose levels also dropped more gradually: 0.5 percentage points in the first six months. Whether the rate of reducing blood glucose levels has an impact on cardiovascular risks will need to be tested in future studies.
  • Starting weight and weight gain. The participants in the ACCORD trial’s intensive group were heavier at the outset of the study and gained more weight during the study than those in the ADVANCE trial’s intensive group. Overweight is an established risk factor for cardiovascular disease.
  • Differing drug treatments. While both studies used multiple drugs to enable participants to reach the study’s blood glucose goals, drug treatments prescribed differed substantially between the studies. For instance, thiazolidinediones and insulin were used much more often in both groups of the ACCORD study than in either group in the ADVANCE study, while the ADVANCE study’s intensive-control group used the sulfonylurea gliclazide (not available in the United States) at high rates. (However, ACCORD’s analyses did not find any increased risk associated with the use of different drugs.)
  • Hypoglycemia. In their editorial, Robert G. Dluhy, M.D., and Graham T. McMahon, M.D., M.M.Sc., point out that 19 of the 41 excess deaths from cardiovascular causes in the intensive-control group in the ACCORD accord were classified as “unexpected or presumed cardiovascular disease.” These events, the doctors write, may have been triggered by episodes of hypoglycemia and could possibly have been miscategorized as cardiovascular death. (In fact, hypoglycemia played a role in predicting cardiovascular events in the VADT trial, which will be discussed next week.)

You can view a chart comparing and contrasting the ACCORD and ADVANCE trials in more detail here.

The Take-Home Message
Neither the ADVANCE nor the ACCORD trial found any cardiovascular benefit to intensively lowering blood glucose levels in people with Type 2 diabetes and high risk of cardiovascular disease. However, the ACCORD researchers estimated at the June 2008 ADA Scientific Sessions that only about 25% of people with Type 2 diabetes today have the same age and risk factors as the people who participated in the trial, so it is hard to apply the trial’s findings to people with Type 2 diabetes in general.

Also, as William T. Cefalu, M.D., pointed out in his NEJM editorial, participants in ACCORD who had not had a previous cardiovascular event or whose HbA1c at the start of the trial was under 8% “had significantly fewer fatal and nonfatal cardiovascular events than did patients at higher risk,” implying that intensive blood glucose control may be better at protecting people who have lower cardiovascular risk and/or start off with better diabetes control. Further clinical trials that are under way now will hopefully help shed more light on these questions in the next few years.

You can read more of our previous coverage of the ACCORD trial in “ACCORD Travesty” and “What We’re Reading: Reactions to ACCORD.”

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  • Calgarydiabetic

    Dear Tara.

    The 7.7 lb extra on average (and you wonder what was the range) could explain partially the extra deaths. This is the biggest downside of intensive treatment. The study group was poorly chosen for a comparaison of intensive versus ordinary since they are at mosts risk from hypoglyceamia. Could be wrong but I still believe one should aim for HA1c in the normal range. The more so since at least in my case high BG correlates with high cholesterol very well.

  • Helen

    It is a question to me if these that had at least chf or other cardiovascular deaths were also on statins while in the study as statins weaken the heart muscle by lowering the Co-Q10 I think that most doc put diabettics on statin way too easily and did they look at this as a variable?

  • sunderbunny

    I’ve been diabetic since 1984. In March I had a heart attack, and during a follow up appt. I was told to include co-Q10 suppliment because of blood tests. The doctor told me not to increase it on my own, but wait until my next A1c – AS ALWAYS – never take anything unless you ask your doctor because you never know how it may affect your meds.

  • Calgarydiabetic

    Dear Tara. Is it true that statins lower the CO-Q10? What are the other bad side effects? Very popular here in Canada all the Doctor’s urging me to indulge. So far have resisted. I can try to avoid most saturated fat and this will help but this means no cheese hence no calcium. And the most important to have low cholesterol and low triglicerides is the keep the blood sugar normal at all times as much as humanly possible.

    For those diabetics that dont drink vitamin D fortified milk which all is in Canada presumably the same in the States but have not been since the crackdown on Canadian tourists in the last few years. 911 was a total disaster they really did it to us. What I find funny it with the real estate meltdown potential foreign, renters or buyers are extremely unvelcome and treated like criminals when we cross the border. Canadians are welcome in the EU, the Frech border guard did not even bother looking at my passport.and did not proceed to a general mugging.

    Well anyways there may be a new hope in the US by this fall and we might be able to spend some of our tourist dollars in the good old USA And dont worry we wont take a dump truck and steal your palm trees or the unisulated property that would not survive the first winter back to Canada. WE could be temporay custodians and sell the properties back to Americans when the prices recover. Our gain would be to be able to enjoy a better Climat that canada fo a few years

    So much for politics, the punch line is that from September to May the sun in Canada is not sufficiently strong to generate enough D. So D fortified or 1000 IU of D3 is a must. My test showed that in May my level of D was quite low in spite of have taken some d3 supplement and drank so milk. This will apply to inhabitants on the northern states if you dont spend a lot of time down south or drink milk fortified with D.