Volume 1 number 1 Summer 2003
Special issue for the abstracts of the 7th Pan Arab Conference on Diabetes
PACD7 , 25 – 28 March 2003 Cairo

Abstract Number : 68
Intensive Management of Type 2 Diabetes: Risks, Benefits, and Techniques

John B. Buse, MD, PhD, CDE , USA

The American Diabetes Association glycemic treatment goals have been well supported by the Stockholm Diabetes Intervention Study, the Diabetes Control and Complications trial, the Kumamoto study and most recently by the United Kingdom Prospective Diabetes Study. In each, a more intensively treated group achieved a hemoglobin A1c (A1c) of approximately 7% and in each there was an associated reduction in microvascular endpoints and trends towards improvement in macrovascular endpoints. In each the more stringently controlled group had a higher incidence of hypoglycemia, greater weight gain, and increased costs, though the net benefit with respect to endpoint reduction was felt to adequately compensate for these adverse effects. In the Veterans Association Cooperative Study of Diabetes Mellitus there was insufficient power to determine the effects of the interventions on events, though a similar level of A1c was observed in the more intensively treated group. However, in this one study of modest size and short duration, there was a non-statistically significant increase in cardiovascular events in the intensive treatment group. Thus, it remains uncertain whether more intensive glycemic control is associated with cardiovascular benefit though the preponderance of information suggests a benefit of approximately 15-20% reduction in macrovascular endpoints for every 1% lowering of A1c. In the epidemiological analysis of the UKPDS, there was a linear reduction in vascular events into the normal range. In each of the studies in which microvascular events were reported, there was a curvilinear relationship of risk to average A1c, with a relatively low absolute risk of complications at an A1c of approximately 7% and a fairly flat curve in the relationship of microvascular complications to A1c below 7%. The risk of hypoglycemia and weight gain is similarly curvilinear with a relatively high risk at lower levels of A1c and a steep relationship of further lowering of A1c with increasing risk of hypoglycemia.

As these studies generally aimed for normalization of glucose, it has been argued that this justifies setting an A1c goal of even <6% (i.e. within the normal range). From an evidence-based approach, since only an average A1c of 7% was achieved in each of the outcomes studies, arguably we do not robustly understand the true risk of hypoglycemia and the true benefit in the form of microvascular and macrovascular risk reduction below an A1c of 7%. We can be certain that the risk of adverse treatment related effects will be higher, particularly the risk of hypoglycemia, but could also contemplate if there would be adverse effects related to long-term exposure to poorly studied combinations of medications, greater expense, life disruption caused by greater attention and effort to achieve lower glycemic targets as well as the potential that if extreme efforts are expended in achieving very stringent glycemic goals that it will result in lesser attention to other health risks by patient or provider. Similarly it is certain that the absolute benefit vis-à-vis microvascular events will be modest as a result of pursuing lower A1c targets. With the advent of improvements in the oral antidiabetic agents, insulin analogs and glucose monitoring technology, achieving lower glycemic targets is easier in the 21st century than in the previous decade and thus these advances could mitigate some of the risks. That said, we do not know the risks or the benefits of these technologies in long-term studies and it remains possible that there are predictable (excessive weight gain with thiazolidinediones or altered rates of retinopathy related to possibly greater IGF-1 mediated effects of insulin analogs) or unpredictable adverse events that have just not been evaluated in long-term studies. 

Perhaps the most realistic approach to counseling regarding glycemic control is to suggest that we should pursue A1c levels as low as possible as limited by unacceptable adverse events and to use glucose monitoring to guide therapeutic adjustments and ensure the safety of such approaches by assessing symptoms consistent with hypoglycemia and evaluating for asymptomatic hypoglycemia both of which would require treatment adjustment. The apparent controversy regarding the actual glucose targets recommended by various experts is greater than the obvious consensus that many patients are not adequately controlled by any standards and that treatment approach should be individualized. 

There are inadequate clinical trial data to allow dogmatic statements regarding optimal approaches to the management of type 2 diabetes. A generally reasonable (e.g. opinion based) overall approach is to first work on lifestyle issues (diet and exercise) with patients, preferably with the help of a dietitian and/or diabetes educator. The major tenets of lifestyle management are to promote consistent carbohydrate intake in the context of a diet low in saturated and trans-unsaturated fats as well as regular aerobic exercise. The initial goal should generally be to aim for premeal blood glucose levels of around 100 mg/dl (5.5 mM). In-patients with higher levels of glucose, a single pharmacological agent should be administered to reduce plasma glucose expeditiously. In general, metformin monotherapy has the greatest evidence in the form of outcome studies to support its use as monotherapy, though there are a number of contraindications to its use that must be carefully considered. Sulfonylureas are very effective glucose lowering agents and quite inexpensive. The thiazolidinediones (sometimes referred to as glitazones) hold tremendous promise to reduce cardiovascular risk as well as the progression of beta-cell dysfunction, but there are no outcomes studies available to help guide their use. Long-acting insulin – primarily NPH and glargine – are also very effective agents to lower premeal glucose levels. If a single agent is inadequate to achieve fasting and premeal glucose targets, additional agents can be added sequentially. There is some evidence to suggest that monitoring and specifically treating to achieve postprandial glucose targets may be associated with greater overall control and perhaps lower risk of weight gain and hypoglycemia than approaches targeting fasting and premeal glucose more exclusively. Most patients can achieve the glucose targets above using combinations of agents that improve insulin sensitivity (metformin and the thiazolidinediones) with agents that increase insulin levels (Sulfonylureas, “glinides” and insulin) as well as combinations of agents that primarily lower fasting and premeal glucose levels (metformin, glitazones, Sulfonylureas and long-acting insulin) with agents that lower postprandial glucose (alpha glycosides inhibitors, glinides and monomeric insulin analogues). The “kitchen sink” approach to maximal diabetes therapy would thus be: metformin + glitazone + lifestyle management (the combination to maximize insulin sensitivity) + long-acting insulin in the evening to normalize fasting glucose + meal related monomeric insulin analogs combined with carbohydrate counting and insulin dose self-adjustment; this is an approach that is being tested in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial with an aim to achieve an A1C of < 6%.

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