Dr. J Robin Conway MD

  J. Robin Conway M.D.

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	www.diabetesclinic.ca
	CANADIAN CENTRE for RESEARCH on DIABETES
	CENTRE CANADIEN de RECHERCHE sur le DIABETE
	218 Percy St.
	Smiths Falls, ON, K7A-4W8
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Dr. J Robin Conway  MD is a member of our advisory board  and a contributing author to this site.

Dr. J. Robin Conway M.D. Practices Diabetes Care in a small Ontario Town.

He is Medical Director of the Canadian Centre for Research on Diabetes carrying on clinical research on diabetes.

Dr. Conway says, "I feel my mission is in helping to educate the family physicians who treat diabetes about the disease and current treatment standards.

he is author of the booklet on Type 2 Diabetes, a Manual for Health Professionals of which 15,000 copies have been distributed to physicians in Canada along with a number of other educational supplements and research papers. Dr. Conway has served the Canadian Diabetes Association as an adviser for Canadian Diabetes Association Clinical Practice Guidelines and has served in that capacity for over 12 years.

Dr. Conway is Associate editor of Canadian Diabetes, a journal for health professionals of the Canadian Diabetes Association.

CANADIAN CENTRE for RESEARCH on DIABETES

 

DISCORD ON ACCORD

J. Robin Conway M.D.

Canadian Centre for Research on Diabetes,  www.diabetesclinic.ca                                               March 2008

For many years we felt that the complications of diabetes were an inevitable part of the disease process and were not related to glucose levels. Some people had suggested that lowering glucose levels close to the normal non diabetic range may result in decreased complication levels. In 1993 the Diabetes Control and Complications Trial (DCCT) in type 1 diabetes (T1DM) demonstrated that lower levels of glucose resulted in dramatically decreased microvascular complications of diabetes such as retinopathy, nephropathy and neuropathy. Subsequent follow up of the people involved in this trial (DCCT-EDIC) demonstrated that the people treated intensively with the aim of getting A1c down to below 7% also had significantly reduced risk of heart attack and stroke (macrovascular disease). We learned that persons with diabetes did not develop microvascular complications if the A1c level was less than 7% so this became the glycemic target in Type 1 diabetes and our definition of diabetes was based on the fact that people with fasting glucose levels less than 7 mmol/L did not develop diabetic retinopathy.

We suspected similar benefits would be apparent in type 2 diabetes (T2DM) and the United Kingdom Prospective Diabetes Study (UKPDS) confirmed that intensive control with an A1c target <7% decreased the risk of any microvascular endpoint by 25%, diabetes related death was reduced by 10% but it took almost 10 years for the beneficial effect on death to be seen and a 16% risk reduction for myocardial infarction took more than 3 years for evidence of benefit.

In the STENO-II trial reported in 2008 in the New England Journal of Medicine, the effect of multiple interventions on glucose levels, blood pressure and cholesterol levels was studied. The results confirmed the dramatic benefits of multifactorial intervention. The subjects in the intensive control arm had a higher mortality for the first 4 years but after 13 years, the mortality was only about half that in the conventional treatment arm.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial investigated people with diabetes and vascular disease or multiple cardiovascular risk factors and randomized them to an intensive treatment program targeting normal glucose values and an A1c less than 6% or a standard treatment program with an A1c 7.0-7.9%. The intensive glucose control arm of the trial was terminated early because there were excess deaths in this group. It should be pointed out that the increase in death did not appear to be associated with any particular drug or treatment regime. In particular there was no excess death rate linked to treatment with Avandia.

Generally we have seen that the rate of diabetes complications is proportional to glucose levels, irrespective of how we achieve those glucose levels. While life style changes including 30 minutes of exercise a day and a weight loss of 7% of total body weight have demonstrated efficacy in preventing new onset of diabetes in susceptible individuals, they have not shown as much promise in treatment of people with established diabetes. We need to recognize that there are multiple fundamental defects in diabetes, among which are insulin resistance, decreased insulin production, deficient incretin hormone production and excessive glucagon production. We need to rationally treat these defects, for some such as insulin resistance, life style measures hold promise but for others medications are needed. We should not fear rational medication treatments because the decreased glucose levels afforded will decrease risk of death and complications. What is needed is a balanced treatment program with both lifestyle and medications to achieve glucose levels that minimize risk and maximize quality of life.

We do need to note that the risk of death in either arm of the ACCORD study was extremely small, 1.4 deaths per 100 patients per year in the intensive arm and 1.1 deaths per 100 patients per year in the conventional treatment arm. The difference of 0.3 deaths per 100 patients per year is miniscule. Another point that is seldom mentioned is that in this high risk diabetic cohort, the expected death rate is 6 per 100 patients per year; so the most important point is that the multifactorial risk reduction in the ACCORD Trial dramatically reduced risk of death by over 80% and that the target A1c of 7% seems to give the highest risk reduction.

ACCORD is consistent with other landmark studies which confirmed short term pain for long term gain.

In most countries of the world target for A1c is  <7% as above this level there is rapid increase in microvascular complications. Gradually the <7% target has been squeezed lower, first to 6.5% by the AACE and more recently the ADA & the CDA ; who set the official target at <7% but suggest a target of <6% if it can safely be achieved. ACCORD has shown that in their high risk patient cohort an A1c of 6.4% (which is the actual A1c achieved) is too low and the cardiovascular mortality risks outweigh the benefits (at least in the period of the study). Somewhat ironically, the intensively managed group showed increased mortality but there was a 10% decrease in non fatal MI, demonstrating benefits as well as risks to intensive glucose lowering. It may be that if this study had gone on longer we would have seen increased benefit in the intensively managed group.

We have excellent Class 1 evidence of benefit for a target A1c < 7%, there is less evidence for lower targets. The A1c achieved in the intensive arm of ACCORD was 6.4% and this level of glycemia resulted in an increased rate of death, this has answered one of the questions to be resolved by this study; whether lowering A1c below the currently recommended target of 7% decreases complications of diabetes? The answer is no; while there may be some benefits, there are also increased risks.

Other studies such as ADVANCE have not confirmed increased risk and studies such as ORIGIN are ongoing. We need to understand; however, that each of these studies is looking at a particular patient cohort and results from one group may not apply to another.

Until we have the results of these trials we should follow the Clinical Practice Guidelines of the ADA & CDA which recommends targeting A1c less than 7%.

The lesson may be that if tight glucose control doesn't kill you, it will make you stronger.