Type 2 Diabetes - Time to relax: Two clinical trials show no benefit and some risk of tight control of blood sugar

What your doctor is reading or should be

Two clinical trials published earlier this month show that aggressive control of blood sugar not only failed to yield benefits, it made things worse - higher death rates and more myocardial infarctions and strokes in the group with tight control of their blood sugars, compared with the control group managed conventionally.

The ‘ADVANCE’ trial, sponsored by a pharmaceutical company using their drug gliclazide (a sulfonylurea) as the main agent to reduce blood sugar and the ‘ACCORD’, trial, funded almost entirely by the US NIH (National Institutes of Health) using several drugs evaluated the effects of tight control of blood sugar of the risks of developing complications of diabetes. The ACCORD study was terminated before the planned end date because a scheduled interim analysis showed a statistically significant higher death rate among patients in the tight control group. Tight control was a target of maintaining glycalated hemoglobin, Hbg A1C, - a measure of control of blood sugar levels now used by most physicians and patients to evaluate diabetes management - below 6 %.

The objective of both studies was to see if tight control, defined as getting the patient’s glycalated hemoglobin from an average of about 8% before the study to below 6% in patients randomized to tight control and to between 7 and 8% in the usual care group. These targets were fairly well achieved in both studies. Patients in the tight control groups were more likely to be prescribed oral agents and were more likely to be taking insulin (77% in the tight control group vs. 55% - ACCORD study).

The results were spectacular and unexpected - in both studies. The ACCORD study was stopped prematurely because of an excess of deaths in the tight control group (5%) compared to the standard therapy group (4%). This 22% increase in death rates per year (1.41 vs. 1.14 deaths per year) was statistically significant (95% CI 1.01 to 1.46) and forced the premature stop.

The ADVANCE study chose to define its primary outcome for the randomized trial as a combination of microvascular and macro-vascular complications. The rationale for choosing this mixed outcome is not explained. Using the combined outcome, the ADVANCE study showed that patients who were on tight control were more likely to avoid development of macroalbuminuria (an indicator or microvascular disease of the kidneys) 2.9% in the tight control group vs 4.1% in the usual care group, hazard ratio 0.70, 95% CI 0.57 to 0.85). There was no effect on development of clinically important microvascualar renal disease such as a need for dialysis/transplant or death from renal causes. Serum creatinine - a measure of renal deterioration that indicates patients might one day need dialysis or transplant doubled in 1.2% of tightly controlled patients vs 1.1% of usual care patients, a statistically insignificant difference.

In short, after an average of 5 years of tight control in the ADVANCE study, the only difference between the two study groups was in the proportion of patients who developed very early indications (macroalbuminuria) or microvascular disease. The study did not show an excess of deaths from macro-vascular causes (stroke and heart attacks).

While the authors of the industry funded ADVANCE study tout the result as showing “a one-fifth reduction in microvascular complications” the authors of the ACCORD study concluded that there is a previously “unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes mellitus.”

Here is a summary of the key outcomes in both trials:


Both studies, as expected showed that patients on tight control had more insulin reactions although the differences in frequency of severe events (in the ACCORD therapy defined as those that required medical attention) is remarkable. In the ADVANCE study severe hypoglycemia was defined as “transient dysfunction of the central nervous system” to the extent that they “required help from another person”.

Differences in softer (and perhaps harder) clinical outcomes may be due in part to the geographic locations of study participants and differences in the usual patterns of practice of clinical medicine. In the ADVANCE study it appears that patients were drawn from Australia, New Zealand, the UK, several European countries and China (perhaps including members eligible for care in a military hospital) as well as from Montreal and New York. The ACCORD study drew patients from across the US and Canada.

Interpretation

The results of both studies give pause and the results from the ACCORD study demand action on the part of clinicians treating patients with type 2 diabetes mellitus. In the face of an substantial increase in the risk of death from all causes, clinicians must be much less aggressive in encouraging patients to get better control of their blood sugars. This appears to be dangerous in patients with type 2 diabetes mellitus. In the ACCORD study only 50% of patients achieved glycalated hemoglobin Hbg A1C levels of 6.5% or less. Even this modest achievement in blood sugar control resulted in harm.

There is no good explanation for the results (why would more aggressive control of blood sugar in patients with type 2 diabetes lead to heart attacks, stroke and death). But there need not be an explanation in order for clinicians and their patients to change direction on the management of type 2 diabetes mellitus. More is not only not better, it is worse - in terms of life expectancy and the frequency of severe hypoglycemic episodes.

The negligible benefit on microvascular disease noted in the ADVANCE study is perhaps not a surprise as there is some evidence that tight control does result in slower progression of damage to very small blood vessels. Nonetheless it is worth noting that this did not manifest itself in a lesser frequency of development of retinopathy, nor of severe renal failure requiring treatment, nor in the worsening of renal function as measured by serum creatinine. These benefits can be considered minimal and come at a cost of higher death rates overall.

Implications

For patients and families

Patients with type 2 diabetes can’t escape being told daily on television and in magazine and Web advertisements that controlling blood sugar is essential to their health and longevity. Devices to measure blood glucose (after every meal and before and after every physical activity) abound, along with advertisements from multiple drug companies anxious about their market and share values.

Blood sugar, however, does not appear to be a central or perhaps even a peripheral cause of the complications of diabetes. Blood sugar more and more looks like an innocent bystander or itself the product (not the cause) of some other disorder of blood vessels. This is a bit like the old saw that a carpenter with only one tool - a hammer - sees the solution to every building problem as requiring a nail. We can measure blood sugar. So we develop ways to smash it down to the ‘normal’ range, with glucose meters, oral hypoglycemic agents and insulin.

Certainly blood sugar can be problematic, especially when it is very high and other metabolic changes occur - but these are rare in type 2 diabetes. When first diagnosed with diabetes, most patients have no symptoms. The diagnosis is an unwelcome surprise. Patients then learn they are at risk of developing ‘complications’ of diabetes such as renal failure, leg ulcers, blindness, heart attacks, congestive heart failure and stroke.

Commentators on these 2 studies agree that patients (and their physicians) should back away from the target of achieving ‘normal’ levels of glycalated hemoglobin (6%). They agree that it is more important to emphasize efforts to achieve normal body weight, to follow a Mediterranean diet, to take medication for hypercholesterolemia, and treated for hypertension if present. All interventions reduce the chances of heart attack, stroke and death.

But these 2 studies force a larger consideration - the wisdom of screening asymptomatic individuals for abnormal blood sugars. By doing so we label individuals as being at risk of later serious and life threatening complications for which there is no effective therapy. The ‘do no harm’ principle of medicine is violated. Sure, we can make weak arguments that perhaps their long term risks of microvascualar complications could be reduced by close attention to blood sugar, but even this is modest at best and comes with additional risks that are much more serious.

A diagnosis of type 2 diabetes mellitus is not a gift, it is a burden that patients will have to carry for the rest of their lives. A burden of increased frequency of visits to physicians, of glucose measuring devices, or pharmaceuticals with side effects of hypoglycemia and perhaps other risks and an instantaneous trip from the land of the healthy to the land of the sick, with no return ticket.

For society

The FDA and similar agencies in other countries must revise approvals for the advertisement to physicians and directly to patients of information about diabetes and its treatment. In future advertisements need to include a warning that tight control of blood sugar increases the likelihood of death.

Current guidelines (US American Diabetes Association) suggest “the A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia.” This recommendation requires revision as do the screening and case-finding recommendations for the detection of asymptomatic type 2 diabetes mellitus.


References
Advance Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72

Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2009;358:2545-59