Dr. J. R. Conway, Diabetes Clinic, Smiths Falls, K7A 2H6
Toronto May 2003 Note: Numbers in parentheses refer to slide numbers of this presentation (click to download).
We know that the incidence of Diabetes throughout the world is increasing (2) and that in Canada we expect to see a doubling of the number of cases by 2016; moreover, since incidence increases with age (3)and we have an ageing population, we will be seeing more morbidity and mortality from the complications of Diabetes (4).
The UKPDS (5) investigated whether an intensive glucose control policy (6) would reduce the risk of Diabetic complications and whether sulphonylureas, metformin or insulin had any specific advantage (7). The subjects in the study has characteristics typical of many of the Diabetic patients that we see in practice (8). 70% of subjects were randomized to Intensive Therapy aimed at a fasting glucose below 6 and A1c below 7% (9). In order to achieve these goals most subjects needed treatment with multiple agents (10). The study looked at Diabetes Related Endpoints (11) and showed a 25% risk reduction for Microvascular complications (12) with a 0.9 (% absolute) decrease in A1c in the intensive treatment group.
One of the most significant findings of the UKPDS was that there was a progressive deterioration in Glycemic control (13) no matter what treatment or treatment combination was used. Why is this? Because no matter what treatment was used there was a progressive deterioration in Beta cell functioning and progressive insulin deficiency (14).
Prior to the UKPDS, treatment was easy (15), we used Glyburide, Metformin or a combination of the two and when these failed we added insulin (16). The UKPDS has shown us that all these therapies fail with time (16) and that A1c increases at the rate of about 0.3%/year (17). After 9 years of treatment no monotherapy regime gave control in more than 25% of subjects except insulin and even this failed in more than 50% of subjects (1). Combination therapy (19) was more effective but still yielded unacceptably poor results. Why is this?
The pathophysiology of Type 2 Diabetes shows an interplay of Insulin Resistance and Insulin Deficiency (21). Increased hepatic Gluconeogenesis contributes to glucose load while increased Insulin Resistance in the muscles and fat tissue decreases glucose disposal (22). As glucose levels rise, the need for insulin rises but because of beta cell failure, the pancreas cannot supply the increased need. Insulin Resistance is central to the development of the Metabolic Syndrome (23) which increases risk of Macrovascular Disease and explains why the improvement in Microvascular Disease endpoints seen in the UKPDS was not seen in the Macrovascular Disease endpoints. So what is the major problem? (24) Insulin Resistance or Insulin Deficiency?
In fact Type 2 Diabetes has aspects of both Insulin Resistance and Insulin Deficiency, the predominant problem depends which stage the patient is at (25).
The UKPDS has shown us that with metformin, sulphonylurea or insulin; beta cell deterioration continues. The traditional “Step-Wise” treatment recommended by the CDA 1998 guidelines is doomed to failure and despite our efforts fully half of Diabetics in Canada are not adequately controlled (27). We have been too slow to change our treatments when they are not working (28). What is needed is a way to slow or stop the Beta Cell decline.
A novel new class of agents, the Glitazones or Thiazolidenediones have been released in Canada in the past 3 years; Rosiglitazone (Avandia) and Pioglitazone (Actos) (29). An earlier member of the class; Troglitazone (Rezulin) was approved but never marketed in Canada and was subsequently removed from the market because of idiosyncratic hepatotoxicity. The Glitazones act as PPAR-Gamma agonists by increasing production of glucose transporter substances and decreasing insulin resistance (30). These drugs have demonstrated glucose lowering effects similar to the sulphonylureas (31) but without the relentless upward drift in glycemia that was shown in the UKPDS (32). We now have over 3 years of experience in Canada with the Glitazones and the reductions in A1c have been persistent (33).
The Glitazones have proven most effective when Insulin Resistance is the predominant defect as in subjects with elevated BMI (34) and they have shown durability of glucose lowering effect (35) both in Monotherapy (36) as well as in Combination Therapy with Metformin (37) or Sulphonylurea (38).
What has changed subsequent to the publication of the UKPDS? We know that we have to control the multiple aspects of the Metabolic Syndrome controlling not only glucose levels but also blood pressure and lipids (39). We have to consider both insulin resistance and insulin deficiency and direct our treatment toward the predominant defect. With most oral agents we get 85% of the full therapeutic dose with 50% of the full therapeutic dose (40); and further dose increases over the maximum result may actually worse control (41). We may need to start combination therapy from the outset of treatment (42). We need to consider where the patient is in the progression of the disease and consider the Glitazones where Insulin Resistance is the predominant defect.