Glucose in Diabetes
Note: Numbers in parentheses refer to slide numbers of this presentation, which can be downloaded from this website by clicking here.

As family physicians it is no surprise (2) to us that we are looking at an epidemic of Type 2 Diabetes (3). We also know that the incidence of diabetes increases with age (4), that for every diagnosed case of diabetes there is another case that is undiagnosed and that there is another group even larger than the diabetics (diagnosed or undiagnosed), those with pre-diabetes who have all the cardiovascular (5) risks associated with diabetes. Type 2 diabetes (6) is a family practice disease (in contradiction to Type 1 Diabetes where 90% of care is given by specialists. We are not doing a great job of diabetes management. A recent Quebec study showed that of patients who had more than 2 risk factors, 79% had a glucose test done and of these, 20% had Diabetes or Pre-Diabetes but 74% of those diagnosed had no treatment advice. In Ontario, Dr. Stewart Harris (7) from the University of Western Ontario surveyed our standards of care as family physicians, 84% of patients had at least one A1c done in the past year and the average A1c was 7.9%. We were fairly good at screening for and treating macro vascular disease but poor in assessing micro vascular disease. Not only were we poor at identifying disease but there was also a gap between our practice and the current CDA treatment recommendations (8). Sub optimal control not only impacts on quality and quantity of life but also increases health care costs (9).

The Canadian Diabetes Association has up to date evidence based Clinical Practice Guidelines for Diabetes Mellitus (10), covering screening (10,11), prevention (12), diagnosis (13), and glycemic targets (14), as well as monitoring (15). Exercise (16) and nutrition therapy (17) remain the cornerstones of Type 2 Diabetes Treatment but in most cases, in order to achieve treatment goals (18) pharmacotherapy (19) is needed (and the UKPDS has shown us that in most cases combination therapy (20) is required.

The Pathophysiology of Type 2 Diabetes (21)

We discovered from the UKPDS that Type 2 Diabetes is a progressive disease (22) and that the reason for the progressive deterioration in A1c is the loss of Beta cell function over time (23). Initially in the individual who will develop Diabetes we see increasing insulin resistance which causes an increased need for insulin in order to achieve glucose control (24). As the insulin resistance progresses the pancreas becomes unable to provide the required amount of insulin to cover periods of greatest glycemic.stress such as after meals and we see postprandial hyperglycemia. This is the earliest blood glucose abnormality associated with pre-diabetes. Postprandial hyperglycemia increases cardiovascular risk almost as much as full blown Diabetes. The DCCT and the UKPDS have shown us that we can virtually eliminate microvascular complications if we can keep glucose levels (and A1c) below 7. If we are to make an impact on the macrovascular complications we must also control post prandial glucose.

In the non-diabetic, in response to meals there is a rapid and intense first phase of insulin secretion (25). This first phase is lost in the pre diabetic stage and as a consequence of the late insulin response to a glucose challenge, post prandial glucose increases. Through the progression of the disease (26) we need to remember that Diabetes is characterized by varying degrees of insulin resistance and insulin defect (27). If we are to successfully treat and avoid complications we need to take this into account.(28). The first abnormality is insulin resistance but in order to be Diabetic we must have. insulin deficiency it is the predominant defect that we want to address first with our treatment. (28).

The Importance of Post Prandial Hyperglycemia:

In Diabetes there is always insulin deficiency, which is manifested by hyperglycemia. In the early stages of the disease the hyperglycemia is seen predominantly in the postprandial period and then later we see the characteristic fasting hyperglycemia of diabetes. The type and relative frequency of hyperglycemia give us clues to the stage of the disease. While all hyperglycemia reflects an insulin deficiency, postprandial hyperglycemia tends to be associated with insulin resistance. Post Prandial Hyperglycemia is also strongly associated with cardiovascular risk (29). We have known for some time that Diabetics are at high risk for cardiovascular disease (30) the risk being at least twice that of the non-diabetic. The DECODE Study showed us that it is Post Prandial Glucose rather than fasting glucose that predicts cardiovascular mortality (31) so and numerous other studies have confirmed (32) the link between Post Prandial Hyperglycemia and cardiovascular disease. It is important that we consider post prandial glycemic control when formulating treatment plans(33).

Pharmacotherapy for hyperglycemia

We have a number of therapeutic options; Metformin reduces hepatic glucose production, the Thiazolidinediones (Avandia and Actos) improve insulin sensitivity, the Secretagogues (Sulphonylureas & Meglitinides) increase insulin secretion; Acarbose slows carbohydrate absorption and Orlistat blocks fat absorption (34), these drugs are used alone or in combination (35) and each class finds its best use at a particular time in the cycle of disease (36)

The CDA Guidelines (37) recommend choosing treatment appropriate to the individual (38) and in order to do this we need to consider the predominant defect (39). There are 4 arms to the CDA Hyperglycemia treatment algorithm (40) but we can simplify things by looking at the first arm (41) which is the most common, the obese, insulin resistant individual. We start treatment with Metformin to decrease hepatic production of glucose and decrease glucoses load; then; in the suitable individual we add an insulin sensitizer. Because most classes of oral medication lower A1c by 1-2% (42) (except Acarbose), if A1c is greater than 9% we should start 2 agents simultaneously (Our third line agent is an insulin secretagogue. In the slim elderly insulin sensitive individual , an insulin secretagogue would be our second line agent.

Insulin secretagogues work by stimulating insulin production by the pancreas (43). They address a fundamental defect in the diabetic, that of insulin deficiency, they work rapidly and are effective in most individuals. There are 2 classes of secretagogue, the Sulphonylureas (Glyburide, Gliclazide and Glimepiride) and the Meglitinides (Repaglinide or Gluconorm and Nateglinide or Starlix) (44). The Meglitinides (45) are very short acting with about a one hour half life, they increase insulin secretion but primarily in the first phase, they are given with meals and insulin production is to some extent glucose dependant.. Because insulin is selectively stimulated after meals and there is no long term beta cell stimulation, risk of hypoglycemia is low and there is no weight gain. Hypoglycemia is common in Sulphonylurea treated patients approaching 20% in a year (46) and may be particularly severe and dangerous in the elderly and those who do not get regular meals so a Meglitinide may be preferable in these individuals. For those on the Ontario Drug Benefit Plan a section 8 ICR is required for Gluconorm (Starlix is not covered).

The requirements for ICR to be granted are that the person must have been on maximum therapeutic (or tolerated) dose of Metformin and Glyburide and must have developed hypoglycemia on Glyburide. Repaglinide (Gluconorm (47) is given in a dose of 0.5 mg to 2 mg with meals. The usual Dose is 1 mg with each meal and it comes in 0.5, 1 mg and 2 mg tabs, The challenge is compliance, to get the patient to take a tablet with EVERY meal. Gluconorm has a particular application in Type 2 Diabetics in long term care facilities, especially those who may refuse their meals, they receive the Gluconorm only with the meals.

In the insulin treated patient, the use of a rapid acting insulin analogue (48) such as Insulin Aspart (Novorapid) or Insulin Lispro (Humalog) at mealtime decreases postprandial hyperglycemia and reactive hypoglycemia. These analogues are preferred over regular insulin or a pre-mix containing regular insulin.

In conclusion, type 2 Diabetes is a family practice disease that affects a large proportion of our patients. There has been a gap between ideal care and average care and this care gap has contributed to complications and mortality. The CDA Guidelines give us an evidence-based framework for treatment of Diabetes. Post Prandial glucose elevation contributes to Cardiovascular morbidity and mortality, effective treatment of Diabetes should affect both Fasting and Post Prandial Glucose.