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

 The irritating imprecision of medicine - will network analysis help?

A friend of mine thought about buying a car the other day and went to the dealer to inspect new models. He’s interested in reliability of the car as he travels a long distance usually on back roads visiting customers and trying to make sales.

“The best model” the dealer said, “is this one. It rarely breaks down, in fact over 10 years only 16% have to be replaced or have major repairs.”

“That’s one in six” my friend said. The dealer replied that he could buy (expensive) insurance to cover the period not under warranty. “Best we can do” he said.

Each time I use the Framingham calculator I’m reminded of the similar imprecision of modern medicine.

As I fiddle with it today, entering a total cholesterol near the top of the range, a ‘good’ cholesterol in the middle of the range and a normal blood pressure yields a hypothetical me with a 16% chance of a heart attack over the next 10 years. While this is prognostically 4 times higher than if my total cholesterol were the lowest on the scale and my good cholesterol highest, it still means that even with these excessive cholesterol levels my chances of having a heart attack is still far below even 50/50. Most men my age with bad cholesterol values don’t have a heart attack or die. Indeed if there were 6 men similar to me only one of us would have a heart attack in the following 10 years.

Why do some get heart attacks and others don’t? This is the irritating imprecision of medicine. While all cholesterols (good and bad) are the same, each of the 6 men have different ‘other factors’ that play into a complex yet unknown equation that somehow leads one of us to suffer the bad outcome.

When I see a patient with a bad condition I always remember my first patient with cancer of the lung. Mr. Walker was 59, and other than pain in his shins (an infrequent but known secondary effect in a small number of patients with lung cancer) he was well. Yet there was no hope. Removal of the lung would not save Mr. Walker - we had good epidemiological studies showing dismal prognosis and as most older patients could not survive with a single lung, high operative mortality rates. I presented his case to our professor, a man older than the patient. To my recommendation that Mr. Walker be sent home without having his lung removed, my professor replied that a few of his lung cancer patients who had surgery survived for very long periods, so why deny this one the chance. The professor recommended that I see if my patient could walk up a flight of stairs without stopping. If he passed this ‘stress test’ he could survive with one lung, said the professor. He was old enough to have seen enough lung cancer to know that not all were alike.

Wouldn’t it be fine if our physician knew which of the 6 of us was going to suffer the bad outcome? Not everyone who smokes a pack a day for 40 years will get lung cancer. In fact, most won’t. We all know committed smokers who believe that inhaled smoke gives the lung tissues a protective coating. Perhaps they are right.

Of 100 men with prostate cancer limited to the prostate 75 will not have any evidence of metastases 10 years later. (For those having a prostatectomy only slightly more, 85, do not develop metastases over 10 years. Although the disease phenotypes are the same - cell type adenocarcinoma, anatomic location within the prostate at the time of diagnosis - only about 25% of men go on to develop metastases.   While this might look like the play of chance, science insists there must be a reason. Greater diagnostic precision will reduce prognostic imprecision and lead some men to avoid debilitating and unnecessary prostatectomy.

Physicians make diagnoses on the basis of anatomical location of symptoms, physical signs (anatomical and physiological - e.g. blood pressure) and laboratory tests that measure specific body systems for homeostasis such as oxygen transport, blood sugars, blood, immune response, the presence of pathogenic organisms and toxins, and so on.

A series of papers over the past decade have demonstrated that we need to rethink our reductionist conceptions of diseases as being a set of distinct entities, like congestive heart failure, or sickle cell disease or AIDS and begin to understand that these illnesses are each complex involving multiple genetic, environmental and social factors. As we begin to understand these factors and their relationships, our conceptions of disease will change, diagnostic and prognostic labels and estimates will be altered, and new systems of understanding human physiology and pathobiology will enter the language of diagnosis and the practice of medicine. These discoveries have arisen in the emerging field of network analysis.

The genetic component can be thought of as a limited but as yet incompletely identified set of genes that control human development and cellular function throughout life. Some genes are known to be involved in specific areas of human development and pathophysiological response because mutations in these genes result in specific diseases, such as sickle cell anemia, familial cardiomyopathy, pulmonary arterial hypertension, diabetes, various cancers and so on. Some of these are monogenetic in that a single mutation is common to all who have the defect. In others seemingly identical diseases can result from mutations in more than one gene or can arrive from different mutations in the same gene - for example the clinical disease -  familial pulmonary arterial hypertension -  can arise from over 50 different mutations.

It seems helpful to conceptualize two categories of genes, those that have a specific role with a particular type of cell and those that are more generic. The specific-role or primary genes become apparent when mutations arise. Sickle cell anemia derives from a mutation in a single gene that results in the substitution of valine for glutamic acid at a specific position in the molecule that makes up the beta-chain of hemoglobin. Under hypoxic (or other) conditions this results in the formation of hemoglobin polymers which cause the erythrocyte to assume a sickle shape. Genes involved in various malignancies probably function in a similar but more complex way.

The other category of disease modifying genes have broader effects that serve to modify threats to cells from the specific disease-related genes and from environmental threats such as temperature, radiation, hydration and tonicity, oxygen, micro and macro nutrients, infective agents and toxins. The ability of an individual to accommodate these genetic and environmental threats is also part of the genomic makeup of that individual. The resultant pathology depends on the interaction of the gene with the environment.

Conceptually, it might look like this:


From the same paper here is the disease network for sickle cell anemia, a disease that can present with many pathophenotypes:

The figure is copied from the article by Loscalzo, Kohane and Barabasi <1>
The primary genetic abnormality, hemoglobin S (red) can be affected by other genetic abnormalities, if they are present (grey). The various clinical presentations of sickle cell anemia (in blue) are thus the result of a network of cellular and sub-cellular events, aided and modified by environmental agents (green) and the genomic elements that control the bodies generic reactions (yellow).

On a general level none of this is new or surprising. We know that our genetic complement and our lifetime interaction with environmental factors are somehow responsible for our particular pathophenotype experience - the disease we have. What is perhaps new is the notion that although the phenotypes may look identical, they are not: What is different about them is how they are produced - their underlying networks of causation and damage control. Understanding these networks will add precision to diagnosis and will be helpful in developing pharmacologic interventions that disrupt or disconnect the disease causing elements of the network.

While the primary nodes of causality - primary and secondary genomes and environmental factors (physical and social) are limited, the secondary networks of each primary node are more complex and the number of possible interactions between them large. Thus a single anatomic or cellular or molecular pathophenotype might have been the product of a very large number of possible interactions involving the primary nodes of causation.

Even in this simple schematic model, there are an exponential set of of possible interactions each of which might produce a different presentation of the ‘same’ anatomic or functional disease or pathophenotype. Thus some adenocarcinomas of the breast are affected by primary genomes such as the BRACA genes, secondary genomes such as estrogen receptors, and are likely further modulated by environmental causes, and perhaps environmental factors that play a role in prognosis and the role of the secondary genome in control of proliferation, immune response, apoptosis/necrosis and so on.

Although logically unassailable the new model of disease would be mathematically unusable due to the exponential number of possible combinations of nodes and sub-nodes (if all possible connections are considered to be random events).

Fortunately they are not. The pathways are part of non-random networks between primary and secondary nodes of influence, themselves interconnected. Network analysis is changing the way we look at biological, social, economic, electronic and other networks.

Practical applications are in the future, perhaps decades from now. But we should pause when considering a diagnosis to hand on to a patient, for each diagnosis comes with a prognosis and a set of care burdens and, unfortunately, with considerable imprecision about likely outcomes. Recent publications on aggressive control of blood sugars are only the latest to confirm how little we know about the natural history of the diseases we diagnose. (see next post

References

1. Loscalzo J, Kohane I, Barabasi A. Human disease classification in the post-genomic era: A complex systems approach to human pathobiology.