Long Term Benefits
of Oral Agents
Dr. J. R. Conway, Diabetes Clinic, Smiths Falls, K7A 2H6

Note: Numbers in parentheses refer to slide numbers of this presentation (click here to download).

In the 2003 Canadian Diabetes Assoc Clinical Practice Guidelines, there are a range of options for the treatment of Type 2 Diabetes. One should always remember that the cornerstone of treatment is the lifestyle modifications of 150 minutes per week of exercise (3), appropriate diet choices for the Diabetic (4) and weight loss where relevant. The lifestyle modifications have benefit at all stages of from Pre-Diabetes with early elevations of post prandial glucose through to the late stages where beta cell dysfunction predominates and there is profound insulin resistance. If A1c levels are below 9% (5) we may start lifestyle measures, wait a short period to assess the effect and then start monotherapy with a hypoglycemic agents. If A1c is greater than 9% (6) then we should start treatment with lifestyle changes and 2 pharmacologic agents at the same time since each agent alone will normally only lower A1c by 1-1.5% (7). It is critically important to achieve glycemic targets (8) because if we can maintain Average Glucose and A1c values below 7 then microvascular complications of diabetes just do not occur. For many patients, the cost of treating their disease is a significant factor. The lower the A1c, (9) the lower the direct cost of treatment, we see here that in Canada the average cost of medications and diabetic supplies is about $4,700 at an A1c of 6% but if A1c is 10%, this direct treatment cost rises to $6,100. Even more dramatic are the hidden costs for treatment of complications (10), loss of earnings etc which are about $10,000 per year at an A1c of 6 rising to $25,000 a year at an A1c of 10. Good glycemic control makes good economic sense both for the person with diabetes and for society.

Metformin, the first line choice of oral agent works by decreasing hepatic glucose production (11), this medication has been shown in the American Diabetes Prevention Program to prevent the progression of Impaired Glucose Tolerance to Type 2 Diabetes by 30%. Metformin alone does not caused hypoglycemia and can be used all the way through the stages of diabetes from pre-diabetes to profound insulin sufficiency. In the United Kingdom Prospective Diabetes Study, those people treated with Metformin had the lowest rate of cardiovascular complications of all the drugs studied.

Thiazolidenediones (12) the usual second line agent according to CDA Guidelines lower glucose by increasing glucose disposal in liver fat and muscle. The way they do this is (13) They are approved treatment after the diagnosis of diabetes has been made although early studies on Troglitazone in the Tripod Study and the Troglitazone arm of the DPP suggest that this class of drug may have a role in diabetes prevention and this is currently being investigated in the DREAM study. Since these drugs directly reduce insulin resistance, they are most useful in the early stages after diagnosis when insulin resistance is the predominant defect. In the late stages when there is profound insulin deficiency they may be less effective. Since these drugs have only been available in Canada for the past 3 years we don’t have data on long term benefit but 72 month data from Einhorn et all has shown persistence of glucose reductions both in monotherapy (14) and in combination with metformin (15) . Studies by Hanefeld et al reported in the Jan 2004 issue of Diabetes Care also show durability foe a year of glucose lowering effect of Pioglitazone in combination both with either Metformin or Sulphonylurea. This class of drug has also shown beneficial effects on lipids as well as anti-inflammatory qualities as measure by CRP reductions.

Sulphonylureas: (16) lower glucose by stimulating release of insulin from the pancreas. The new CDA Guidelines put this class of drugs in third line after Metformin & Thiazolidenediones. In common with Insulin & Thiazolidenediones they may be associated with weight gain and the UKPDS has shown us that secondary failure may occur over time. A common side effect is hypoglycemia, particularly in the elderly, although this is less of a problem with Gliclazide or Glimepiride than with Glyburide. Maximum effective dose of Glyburide is 20 mg a day and doses above this may decrease the efficacy. In the early stages after diagnosis when there is minimal beta cell dysfunction these drugs are effective(17) to increase insulin production but as beta cell dysfunction progresses over time, there is less response to stimulation and the sulphonylureas are replaced by giving insulin.

Alpha Glucosidase Inhibitors: (18) act by slowing carbohydrate absorption in the gut and lowering post prandial glucose. They are very useful in the stage of Impaired Glucose Tolerance and in the STOP NIDDM study they reduced progression from IGT to Type 2 Diabetes by 25% but they only have the ability to lower A1c by about .5% (19) while other classes of drugs can lower A1c by up to 1.5% so in the treatment of Type 2 Diabetes they usually have to be used in combination. They have a fairly high rate of GI side effects.

In Summary: As the disease process progresses from early insulin resistance, through Pre-Diabetes into Diabetes and finally pancreatic beta cell exhaustion, our therapeutic choices in medications change; lifestyle changes have benefits across the entire spectrum (20a), Metformin shows long term benefit from the stage of IGT to beta cell exhaustion (20b) while the Thiazolidenediones are most valuable from the early stage after diagnosis through to the stage of beta cell exhaustion. There are early indications that they may be of value in prevention and that they have durability of effect with possible beta cell protection, improve lipid parameters and have anti inflammatory effects but the studies on these are ongoing. The Sulphonylureas (20c) are most effective while there is still beta cell function ant their benefits decrease as beta cell function declines, while the benefits of insulin increase (20d) with declining beta cell function.

The aim (21) of drug therapy is to use the most effective medications as tools to reach glycemic targets that will minimize the complications of diabetes improving and maintaining quality of life. Our aim is to keep Fasting Glucose levels below 7, to maintain post prandial glucose below 11 and A1c below 7%.