Diabetes Clinic, Smiths Falls

Teleconference 12 June 2008

Suggestions: Print out this script, then use it to follow along and change slides.

Slide 1: Intro

Slide 2: For those of us in front line practice, we don’t have to be told about the increasing prevalence of Type 2 Diabetes, we see it in our waiting rooms.

Slide 3: We didn’t need the UKPDS to show us that diabetes is a progressive disease, we see it daily in the struggle to maintain glycemic control.

Slide 4: We are constantly battling to get our patients to target and despite our best efforts we only achieve target half the time.

Slide 5: Ann represents a fairly typical patient, she is an overweight, sedentary middle-aged lady diagnosed 5 years ago. She was referred for diet counseling & diabetes education. It goes without saying that she is on full dose of ACE, statin and ASA . Blood pressure is at target of <130/80 and she does not have complications. A year after diagnosis she was started on metformin and is now taking 1000 mg twice a day. Fasting glucose levels are increasing and her A1c is now >7%

Slide 6: How do we decide the target value for her A1c? CDA Guidelines give us a target A1c of less than 7% which corresponds to an Average Glucose of 8.5 mmol/L

Slide 7: Why is A1c important? Because the UKPDS has shown that each 1% reduction in A1c reduces the risk of microvascular complications by 37% and reduces the risk of heart attack by 14%

Slide 8 a: Why has Anne’s A1c deteriorated? In the UKPDS no matter which treatment was used, either Insulin, Sulphonylurea or Metformin, the pancreatic beta cell function declined.

Slide 8 b: and this decline in beta cell function was paralleled by increasing glucose levels. So here we see one of the fundamental defects in Type 2 Diabetes; declining beta cell function leads to decreasing insulin production and increasing glucose levels

Slide 9: In order to help us make make rational treatment choices, we need to know what is going on in the progression of Type 2 Diabetes. We know that in the progression of type 2 diabetes, we get an initial period of increasing insulin resistance. This insulin resistance is another fundamental defect of Type 2 diabetes. This increase in insulin resistance is paralleled by an increase in insulin production which compensates to keep glucose levels normal. As time progresses, the pancreas reaches it maximal ability to produce insulin and then production of insulin starts to decrease and we get a relative insulin deficiency. As insulin production increasingly fails to meet needs, glucose levels start to rise, at first in the stressed or post-prandial state and then across the board.

Slide 10: When fasting levels exceed the normal of 6mmol/L we say that the person has impaired fasting glucose or pre-diabetes and when the fasting level reaches 7mmol/L we diagnose diabetes. Similarly when post meal glucose is above 8mmol/L we make a diagnosis of Impaired Glucose Tolerance or Pre-Diabetes and when greater than 11mmol/L we diagnose diabetes. While we have traditionally thought of diabetes as an interplay between insulin needs (insulin resistance) and insulin supply; there are other factors involved.

Slide 11 a: We now realize that Type 2 Diabetes involves 3 main factors. Pancreatic insulin deficiency, insulin resistance in the fat and muscle cells as well as overproduction of glucose by the liver.

Slide 11 b: The beta cell produces less insulin, while the alpha cell of the islet overproduces Glucagon.

Slide 11 c: The diminished insulin and the increased glucagon levels cause the liver to produce excess glucose.

Slide 11 d: The excess glucose production by the liver, contributes to the insulin resistance in muscle & fat (which decreases glucose removal from the blood) and the diminished insulin secretion by the pancreas to cause the hyperglycemia of diabetes.

Slide 12: So to review; glucagon increases blood glucose levels by creating more glucose in the liver and increasing glucose levels by breaking down glycogen from muscle & fat.

Slide 13: What Are The Incretin Hormones: Glucagon action is in turn determined by the Incretin Hormones

GLP-1 and GIP.

Slide 14: The one that we are concerned with in Diabetes is GLP-1 which is secreted by the gut in response to food.

Slide 14: The action of GLP-1 is to increase satiety, to slow gastric emptying, to decrease glucagon secretion (thereby reducing liver glucose production) and to enhance beta cell response by increasing glucose dependant insulin secretion. This system gives us another means of therapeutic intervention.

Slide 14: The incretins are small polypeptide hormones secreted by the gut in response to food intake, there are 2 hormones, GLP-1 and GIP.

Slide 15: GLP-1 is the hormone that we are interested in in diabetes. The effects of this hormone are to increase satiety, slow gastric emptying, reduce glucagon secretion and increase glucose dependant pancreatic insulin output.

Slide 16 a: We can see “incretin effect” on insulin production when we compare the insulin output stimulated by the same amount of glucose given orally or intravenously; on the left we see that glucose levels rise the same amount whether the glucose is given orally in green or intravenously in purple

Slide 16 b: but on the right side we see that the insulin secretion is much higher if the glucose is given orally in green than intravenously in purple, we call this increased insulin output “the incretin effect” and it may be responsible for up to 60% of insulin output.

Slide 17: The loss of the incretin effect is responsible for the loss of first phase insulin secretion that we see early in diabetes.

Slide 18: Impaired insulin secretion is a fundamental defect of Type 2 Diabetes, together with Insulin Resistance and Insulin Deficiency. The Incretin deficiency results in further decreased insulin output as well as excess glucagon formation leading to excess glucose formation through gluconeogenesis and glycogenolysis.

Slide 19: So GLP-1 looks like a potential therapy for type 2 diabetes; but GLP-1 has a very short life, it is inactivated in seconds by the enzyme Dipeptyl Peptidase 4. We could continuously infuse GLP-1 intravenously but this would be impractical. We could use a compound that has the action of GLP-1 but is not broken down by DPP-4.

Slide 20 a: Knowing that GLP-1 is inactivated by DPP 4

Slide 20 b: we could inhibit the DPP-4 enzyme, reducing breakdown and inactivation of GLP-1; thereby increasing levels of GLP-1 and take advantage of its favourable actions on glucose control.

Slide 21: Another possibility is to use a compound that has the action of GLP-1 but is not metabolized by DPP-4. Such a compound is exenatide (Byetta) which is found in the saliva of the Gila Monster. Another synthetic GLP-1 mimetic is Liraglutide. These compounds can deliver higher levels of GLP-1 activity and have been associated with weight loss and nausea. They need to be injected once or twice daily, are not yet available in Canada and longer acting versions are currently under development.

Slide 22: As we can see, GLP-1 deficiency is a fundamental defect of Type 2 Diabetes, we can correct this defect by giving a GLP-1 analogue which has to be done by injection or by inhibiting GLP-1 inactivation by giving a DPP-4 inhibitor. The DPP-4 inhibitors are oral compounds.

Slide 23: Januvia (Sitagliptin) is the first of the DPP-4 inhibitors to be available in Canada, it comes in a 100 mg tablet.

Slide 24: It has shown efficacy in reducing glycemia in monotherapy.

Slide 25: And improves Beta Cell Function

Slide 26: The degree of A1c lowering depends on the starting A1c but in the rang of A1c 7-8 we are likely to see a 0.5-0.7% Aic reduction.

Slide 27: It does not cause weight gain (the GLP-1 analogues when available also cause significant weight loss but at the expense of increased nausea and vomiting)

Slide 28: Sitagliptin is comparable in effect to a sulphonylurea when added to Metformin.

Slide 29: It also gives additional glucose lowering in combination with a TZD.

Slide 30: It appears to be most effective when working synergistically with metformin. This is the indication that is approved in Canada. The only contraindication is renal impairment.

Slide 31: Back to Ann – metformin monotherapy failed, what do we do next?

Slide 32: These are key points when treating type 2 diabetics.

Slide 33: What drugs are we going to use?

Slide 34: We used to be able to consult CDA Guidelines and get a pretty good road map. The new Guidelines will suggest Metformin as the first agent and then ask us to use our clinical judgment for medications to add on

Slide 35: These are our options.

Slide 36: 75% of type 2 diabetes patients will require combination therapy within 9 years of diagnosis. The new guidelines will say to start with metformin monotherapy, then add another agent, the choice of agent should be individually tailored to the patient.

Slide 37: Considering most type 2 diabetics are already overweight, weight-gain is a real cause for concern when treating with pharmacologic agents. Insulin and Suphonylureas led to weight gain in the UKPDS

Slide 38: As did Sulphonylureas and TZD in the ADOPT Study

Slide 38: Metformin actually results in a weight decrease.

Slide 39: The pharmacologic agents work on different parts of the body.

Slide 40: We could add a TZD which would increase insulin sensitivity, increase glucose disposal

Slide 41: One of the major advantages of TZDs is that they preserve beta-cell function and as a result they can slow the progression of type 2 diabetes.

Slide 42: The disadvantage is that it is expensive, takes time to have full effect and is associated with weight gain and fluid retention. It is recalled that Ann is concerned about weight gain

Slide 43: We could use a Sulphonylurea to increase insulin output

Slide 44: The advantage is that they are effective and cheap.

Slide 45: Disadvantages are hypoglycemia and weight gain.

Slide 46: Add Acarbose to slow glucose absorption.

Slide 47: Advantages are a good safety profile and no weight gain.

Slide 48: Disadvantages, GI side effects and only a 0.5% A1c decrease.

Slide 49: Add Insulin. Advantages of insulin.

Slide 50: Disadvantages of insulin, hypoglycemia, weight gain.

Slide 51: With Anne, a DPP-4 inhibitor was added and A1c decreased to target 3 months later.

Slide 52: Summary

Slide 53 a: Conclusions

Slide 53 b:

Slide 53 c:

Slide 53 d:

Slide 54: Questions

Slide 55: Thanks, for more information refer to the Clinical Focus Supplement in the May 6 2008 issue of the Medical Post