Why Lowering A1c Below 6.0% Is Not Dangerous

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Over the past year I have heard from a horrifying number of people with diabetes whose doctors have reproached them for lowering their A1cs below 6% and warned them that lowering A1c to that level will give them heart attacks.

This is obscenely bad advice. But there is a reason why so many doctors are giving it. It goes back to a study called ACCORD, which was published in Februrary of 2008. You can read it here:

Effects of Intensive Glucose Lowering in Type 2 Diabetes The Action to Control Cardiovascular Risk in Diabetes Study Group.[ACCORD] NEJM Volume 358:2545-2559, June 12, 2008 Number 24.

What ACCORD Really Found

This study was designed to see if lowering A1c to 6.5%, instead of the ADA's recommended 7.0%, could prevent heart attacks. The study was stopped early when analysis of preliminary data showed a slight excess of heart attack deaths in the subjects in the group who were striving to lower their A1cs.

This is all most doctors ever heard about ACCORD--that lowering A1c led to an increased risk of heart attack. What they didn't hear about was the methodology used in the study. That methodology makes it very clear that it wasn't the lowering of blood sugars that caused the deaths, but the way the study attempted to lower A1c.

ACCORD studied only people with long-standing Type 2 diabetes who had been diagnosed with heart disease before the start of the study. These patients were put on a statin drug (which we now know can further raise blood sugar) and a fibrate drug.

Then the researchers set out to lower blood sugar by putting their subjects the discredited high carbohydrate, low fat diet--which a large body of research has shown not only raises blood sugar but worses triglycerides and LDL. To counteract the blood-sugar-raising effect of this diet, the ACCORD researchers put the study subjects trying to lower blood sugar on a cocktail of every diabetes drug available at the time, including Avandia and Actos.

90.2% of ACCORD Subjects Were Taking Heart-attack Raising Avandia

In fact, a subsequent analysis of ACCORD data found that 4,702 of the 5,128 people in the intensive treatment arm of ACCORD were taking a drug in the TZD class that includes Avandia and Actos--That's 91.7% of all of them. But here's the kicker: almost all of them--4,677 or 91.2%--were taking Avandia. And of course, we now know that taking Avandia raises the risk of cardiac death independent of how much it lowers blood sugar.

The researchers who came up with this finding concluded,
Although other differences in drug exposure warrant further analysis, we think that the authors[of the ACCORD publications] should consider (and address in a secondary analysis) the role of rosiglitazone in the excess deaths from cardiovascular causes, especially in the absence of biologic plausibility of a glucose-mediated effect. Given unbalanced exposure, we think that the ACCORD trial is inconclusive and that the recommendation to abandon lower glucose targets is not supported and has unknown consequences for the long-term management of diabetes. [Emphasis mine]
Intensive Glucose Lowering and Cardiovascular Outcomes N Engl J Med 2011; 364:2263-2264 June 9, 2011

Those Who Lowered A1c Were Not Those Who Had More Heart Attacks

However, another analysis of ACCORD data actually overturned the idea that it had been the people with lowered A1cs who experienced the excess heart attacks.

Diabetes in Control reported on a presentation given at the 2009 ADA Scientific Sessions which found that further analysis of ACCORD data "did not confirm the proposed theory that low A1c levels might be the cause" of the elevated risk of death in the ACCORD patients who attempted to achieve tighter control.

Matthew C. Riddle, MD, Professor of Medicine, Oregon Health Science University and a member of the Glycemia Management Group of ACCORD, who was a site principal investigator for the ACCORD study is quoted as saying,

An A1c below 7% alone does not appear to explain the excess deaths in the ACCORD trial and is not necessarily a predictor of mortality risk...Further, the rate of one-year change in A1c showed that a greater decline in A1c was associated with a lower risk of death.[emphasis mine]
Dr. Riddle and his peers subsequently published these results in this paper:
Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial. Matthew C. Riddle et al. Diabetes CareMay 2010 vol. 33 no. 5 983-990. doi: 10.2337/dc09-1278

This study concludes,

...a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. [emphasis mine]

These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.
So the bottom line is that ACCORD actually proved that not lowering A1c was more likely to cause a heart attack. But neither of these later findings made their way into the medical newsletters that are what most doctors rely on to keep up with medical research. So as a result, most doctors are still convinced that ACCORD "proved" that lowering blood sugar is dangerous for people with Type 2 diabetes.

The Veterans Study

A second study has been interpreted to mean that lowering blood sugar is useless for people with diabetes. It was conducted among a group of veterans with Type 2 diabetes, whose average average age was 60. This study concluded, "Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications, with the exception of progression of albuminuria [protein in the urine, a marker for kidney damage]"

It also found a higher rate of hypoglycemia in the intensive management group.

Dangerous Drugs Again

A look at the methodology of this study reveals why we can ignore its findings. The researchers explain, "In both study groups, patients with a BMI of 27 or more were started on two oral agents, metformin plus rosiglitazone [Avandia]; those with a BMI of less than 27 were started on glimepiride plus rosiglitazone [Avandia]. Patients in the intensive-therapy group were started on maximal doses, and those in the standard-therapy group were started on half the maximal doses."

Avandia and glimipiride are both known to raise the risk of heart attack, so it is actually interesting that this study found no excess deaths, just no improvement in the incidence of cardiovascular deaths.

The excessive hypos are almost certainly due to the way that insulin was prescribed to the veterans. The "methods" section does not specify how insulin was prescribed, or even what kind of insulin was prescribed Were subjects put only on basal insulin, which only lowers fasting blood sugar, or were they given fast-acting insulins to cover their meals? Given how insulin was dosed in hospitals at the time this study was conducted, it is very likely that "insulin" was prescribed in the from of 70/30 mixtures which contain NPH, an insulin notorious for causing hypos, and that if fast acting insulin was prescribed at all, it was prescribed using the simple, but ineffectual "sliding scale dosing" technique which does not match the dose of fast-acting insulin to the amount of carbohydrate consumed.

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. William Duckworth, et al.

What The Studies Didn't Study

No patients in ACCORD attempted to lower blood sugar solely by using a strategy of lowering the intake of the carbohydrates that raise blood sugar.

No patients in any of these studies attempted to lower blood sugar without the dangerous drugs Avandia, Actos, or one of the sulfonylurea drugs now known to raise the risk of heart attack.

And it is very unlikely that any of the patients using what researchers only call "insulin" were using modern, effective basal/bolus insulin dosing schemes that match insulin to carbohydrate intake and prevent hypos.

Therefore, if you are controlling your blood sugar with any combination of carbohydrate restriction, metformin, or a modern insulin regimen that matches the dose to the amount of carbohydrates you consume on a meal-to-meal basis, these studies are completely irrelevant, and you'd do well to pay attention to the many other studies that have shown that lowering blood sugar will prevent and, at times, reverse all the classic diabetic complications.

Bottom Line: There is not a scintilla of evidence that lowering blood sugar using techniques that do not involve dangerous drugs is harmful.

There is a great deal of evidence, even from ACCORD and the Veteran's study, that lowering blood sugar even to the still-too-high level of 6.5% improves kidney function and reduces the risk of heart attack. Other studies cited elsewhere on this site confirm that lowering blood sugar also lowers the incidence of nerve damage and of the retinal damage that leads to diabetic blindness.

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