The prevalence of Type 2 Diabetes is increasing worldwide with a doubling of cases by 2016. This will increase the burden on the health care delivery system. The incidence of Diabetes increases with age and by 2010 it is estimated that 16% of individuals over the age of 40 will have Diabetes . In the Geriatric pupolation 1 in 4 has Diabetes (50% of cases are undiagnosed) and 1 in 2 has impaired glucose tolerance so we need to have a high index of suspicion in Geriatric patients. The Diascan Study published by Larry Leiter in Diabetes Care in 2000 showed that the burden of disease is much higher than the number of cases, that Diabetics (diagnosed or not) have greater care needs and utilize significantly more medical resources, usually because of Diabetic Complications. The cost per year of medical care for Canadians is about $2,500:00, the cost for Diabetics is four times that at $10,000:00 per patient per year. Diagnosis and appropriate treatment for prevention of complications in the elderly is therefore very important.
Less than 50% of Diabetics are optimally treated to the standards of the Canadian Diabetes Association Guidelines. 90% of Type 2 Diabetics are Hypertensive but only 16% of Hypertensives are treated to the goals of the Canadian Hypertension Society. 40% of Type 2 Diabetics have Dyslipidemias, the Framingham Studies have shown that a 1% increase in Cholesterol levels leads to a 2% increase in Cardiovascular mortality yet most Diabetics have not achieved goal levels for lipids despite the fact that effective pharmacological treatment is available today. The time between onset of Microalbuminuria as a marker of Diabetic Nephropathy and end stage renal failure is estimated at less than 8 years. We have effective treatment for Diabetic Nephropathy with ACE inhibitors yet most Diabetics have not had a microalbumen determination done. Treatment with ASA to reduce risk of thrombotic events reduces risk of Myocardial Infaction or Thrombotic Stroke by 25% for minimal cost or risk yet most Diabetic patients have not been advised to take ASA.
There is a large gap between guideline recommendations and average standards of care, this gap leads to excess morbidity and mortality for Diabetic patients as well as increasing the burden on the health care system.
Type 2 Diabetes has both Genetic & Environmental factors. The abnormal state starts up to decades before the clinical diagnosis of diabetes is made. The first abnormality is increasing insulin resistance. As insulin resistance increases, insulin production also increases so that a normal glucose level can be maintained. After a period of time (years or decades), the insulin production can no longer keep up with insulin needs in times of stress and the early signs of glucose control impairment are seen with post prandial hyperglycemia. When post prandial glucose levels are between 7.8 and 11 we say that the patient has developed Impaired Glucose Tolerance (IGT). Later as the beta cell starts to deteriorate and insulin production ability starts to fall off, fasting hyperglycemia develops and as fasting glucose levels rise above 6.1 but less than 7 mmol/L we diagnose Impaired Fasting Glucose (IFG). Finally when fasting glucose levels are greater than 7 and post prandial levels greater than 11 mmol/L we diagnose Type 2 Diabetes Mellitus (T2DM). The disease is characterized by a dual defect of Insulin Resistance and Insulin Deficiency. By the time that Diabetes is diagnosed Insulin Sensitivity is only 30% of normal and Insulin secretion is down to 50% of normal. As time goes on, insulin secretory ability continues to decline with progressive destruction of pancreatic beta cells while insulin resistance tends to level off. The position of the patient on the time scale is important because it influences our therapeutic choices. Our most effective treatment aim is to treat the predominant deficiency. In the early stages of disease (IGT of IFT), insulin resistance predominates and so we wish to treat insulin resistance with lifestyle measures or Thiazolidenediones (Actos or Avandia). As we progress to early diabetes we have loss of the first phase of insulin secretion which suppresses hepatic glucose production and thus we have excess hepatic glucose production. At this point an effective treatment would be a biguanide (Metformin) to decrease glucose production. With further passage of time, insulin deficiency becomes the predominant defect and treatment is directed toward increasing insulin output with Sulphonylureas (Glyburide, Gliclazide or Glimepiride) or short acting insulin secretagogues (Repaglinide, Nateglinide).
Geriatric patients tend to be further along in the natural evolution of disease and insulin deficiency tends to be the predominant factor, thus Sulphonylureas and insulin secretagogues tend to be a logical choice. Other factors in choice of therapeutic agent are Body Mass Index (degree of obesity) and the glucose record which will show at what time of the day the highest glucose levels are found. The use of a glucose meter and diary is very helpful in determining which therapeutic agent is likely to be most helpful. The obese patient usually has predominantly insulin resistance. The lean patient (particularly if losing weight) usually has insulin deficiency. If the highest glucose of the day is the fasting glucose then there is usually inadequate regulation of hepatic glucose output overnight.
Insulin Resistance treatment: Wt loss, exercise, TZD, Metformin
Fasting Hyperglycemia treatment: Metformin Post Prandial Hyperglycemia with normal fasting Repaglinide or Nateglinide with meals Insulin deficiency, constant glucose elevation Sulphonylurea, (Glyburide) Hypoglycemia (on Glyburide) Gliclazide (Diamicron MR), Glimepiride (Amaryl)
Diabetic patients have multiple comorbidities and end up taking multiple medications. In my practice of over three thousand Diabetics, the average number of medications taken to treat Diabetes and comorbidities is 7.2 medications per patient. The HOT trial showed us that optimum BP control requires an average of 3.2 drugs, for Glycemic control we usually need 2 or more drugs to address the dual deficiency of Insulin Resistance and Insulin Deficiency, a statin for lipid control and an aspirin; it is easy to see how the numbers add up. We know that the more frequently a medication is given, the more often the dose is missed so to enhance compliance we try to make the medication regime as simple as possible and wherever practical give medications once a day. We should try to choose medications that have a long duration of action. In the elderly, missed doses are a frequent problem and often assistance is needed to see that meds are prepared. A once a day dose is much easier to control.
- Sulphonylureas: Diamicron MR 30-120 mg, take once daily. (Each 30 mg MR tab is the equivalent of one Diamicron 80 mg (Gliclazide) tab
- Glimepiride (Amaryl) 1 mg to 8 mg once daily
- Avoid Glyburide as it needs to be taken twice daily
- ACE Coversyl 2-8 mg OD, long duration of action instead of Enalapril which needs to be given BID
- CCB Non Dihydropyridine, Chronovera, Cardizem CD or Tiazac given once a day instead of Diltiazem 30 mg QID
- Dihydropyridine, Adalat XL or Norvasc instead of Adalat
- Beta Blockers Monocor OD instead of Propranolol QID
The mechanism of action of the Thiazolidenediones, Metformin and Acarbose is such that hypoglycemia is very rarely caused by these agents alone. Hypoglycemia is cause by the insulin secretagogues as a result of overproduction of insulin. Hypoglycemia is uncommon with the use of the short acting secretagogues used to treat post prandial hyperglycemia. This is because these agents are taken only with meals when there is a need for insulin production. Both Repaglinide and Nateglinide have some degree of glucose dependant insulin release so insulin secretion is less if blood glucose is low. Hypoglycemia does still occasionally occur.
These drugs need to be given with each meal so compliance may be a problem. The Sulphonylureas are associated with the most frequent incidence of hypoglycemia. Because of the very long action and danger of hypoglycemia particularly in the elderly we no longer use Chlopropamide or Tolbutamide. Glyburide is the most frequently used sulphonylurea in a dosage range of1.25 mg to 20 mg a day. The pharmacodynamics are such that the drug is normally given twice a day. In the UKPDS there was a 17% incidence of hypoglycemia on Glyburide. The elderly and those with renal compromise are particularly at risk for hypoglycemia, the hypoglycemia may be prolonged and severe, particularly in the presence of dehydration. Gliclazide (Diamicron) and Glimepiride (Amaryl) have been demonstrated to cause less hypoglycemia than glyburide and may therefore be the drug of choice in the elderly, particularly those living alone. The decreased incidence of hypoglycemia may reflect the more specific nature of the binding of these drugs. Gliclazide has a high affinity for pancreatic beta cell receptors but less of an affinity for the sulphonylurea receptors in the heart and muscle than dose Glyburide. In addition the beta cell interaction is rapidly reversible so the effect of the drug is not as persistent on insulin release as is Glyburide. Gliclazide has also been shown to restore the biphasic (first phase) insulin response as opposed to the late monophasic response of Glyburide. Insulin secretion in glucose dependant. Both Gliclazide and Glimepiride have dual methods of elimination and therefore are safer than Glyburide in renal failure.
Provincial Formulary Considerations:
- Metformin full coverage
- Glyburide full coverage
- Diamicron MR Ont: Expedited Section 8 ICR Que: Special authorization if patient has a history of hypoglycemia on Glyburide
- Amaryl No Coverage
- Gluconorm Ont: Section 8 ICR, Que: Special Authorization for post prandial hyperglycemia or hypoglycemia on Glyburide, do not use with SU
- Starlix No Coverage
- Avandia ON: Section 8 ICR Que: Special Authorization for therapeutic failure on full doses of Metformin (2 gm) and Glyburide (20 mg) or intolerance
- Actos ON: Section 8 ICR Que: Special Authorization for therapeutic failure on full doses of Metformin (2 gm) and Glyburide (20 mg) or intolerance
- Xenical ON: Section 8 ICR as an adjunct in the obese patient uncontrolled on other meds Que: No coverage
Send Section 8 ICR requests to Linda Tennant, Director, Drug Programs
Branch, MOHLTC, Fax: 416-327-7526