|Dr. J. R. Conway, Diabetes Clinic, Smiths Falls, K7A 2H6
17 April 2003 Note: Numbers in parentheses refer to slide numbers of this presentation (click here to download).
Why is Diabetes important to us? Because (2) we are in the midst of a Diabetes Epidemic in which the number of Diabetics will double in the next 15 years. (3) 2 Million Canadians have known diabetes but a similar number have the disease but have not been diagnosed. Even more significant is the number of people with Impaired Glucose Tolerance or Pre-Diabetes which is almost twice the number of both diagnosed and undiagnosed diabetes. . The incidence of diabetes increases with age and in Canada we have an ageing population. (4) Diabetes is a cardiovascular disease and it is a killer, 80% of diabetics will die from an MI or stroke which is 2-4 times the rate in non diabetics. (5) Type 2 Diabetes is almost all treated by family practitioners and the Diascan Study by Dr. Leiter from Toronto has shown that almost 1 4 of all patients presenting in our offices have diabetes (though half of them do not know it). A Quebec study by Strychar demonstrates that 7-8% of the population have diabetes but twice that number have Impaired Glucose Tolerance, what is disturbing is that 74% of those with IGT or diabetes were not offered any treatment advice. (6) Stewart Harris from London, On has also looked at standards of treatment in family physician’s offices and demonstrated that while we are fairly good at treatment of macrovascular complications, we are missing the boat in diagnosis & treatment of microvascular complications.
The treatment of diabetes requires (7) a multidisciplinary approach with a health care team. The problem is that unless the approach to treatment is structured & formalized, the involvement of different care providers can lead to fragmented and incomplete care. It has been repeatedly demonstrated (8) that structured care improves outcomes. This approach allows the members of a multidisciplinary health care team to coordinate their efforts to achieve the desired outcomes. The central member of the team must always be the diabetic who needs to take ownership and control of the disease. An example of the structured care approach is in the GREACE (9) study in which post MI & Post-Angioplasty were randomized to either receive structured care from a team in a specialist care unit or were returned to usual care by their family physician. The structured care (10) approach reduced all end points by almost 50%.
Targets and Treatment Principles
CDA 2003 Guidelines give the targets for glycemic control (11) at A1c less than 7%, preprandial glucose 4-7 mmol/L and postprandial 5-10 mmol/L based on evidence. When possible we should try to achieve normal levels of glycemic control. Physical Activity (12) and Nutrition therapy (13) remain the cornerstones of treatment; but when these are insufficient to achieve glycemic targets pharmacotherapy (14) is required. In order to achieve success with our drug treatment we need to understand the pathophysiology of the disease and tailor our treatments to achieve the most benefit. From the UKPDS, we learned the progressive nature (15) of Type 2 Diabetes, both in the intensive and the conventional treatment groups, glycemic control deteriorated over time irrespective (16) of the treatment agent. The reason for this loss of control was the progressive loss of beta cell mass (17) leading to increasing insulin deficiency over time. If we want our treatment of diabetes to be successful we need to know where our patient is on the curves of insulin resistance (18a)and insulin deficiency. In the individual genetically predisposed to diabetes we first see increasing insulin resistance, insulin production initially parallels the insulin resistance so that glucose levels remain normal but gradually over time these curves diverge as the ability of the pancreas to produce ever increasing amounts of insulin is limited. 10 or 12 years after the process has started, we reach a point at which the pancreas can no longer increase insulin production and at this point we see early signs of pancreatic insufficiency with post prandial hyperglycemia developing after heavy carbohydrate loads. This is the stage of Impaired Glucose Tolerance or “Pre-Diabetes”. At this stage insulin resistance is still the predominant problem. As time goes on, insulin production becomes progressively more impaired and insulin deficiency becomes more marked, as this happens we see Fasting Hyperglycemia, then glucose levels continue to rise until Post Prandial glucose is greater than 11 or Fasting Glucose greater than 7 mmol/L and at this point we diagnose Diabetes although the disease process has been present & progressive for about 12 years. At the point when Diabetes is diagnosed the individual has lost 75% of insulin sensitivity and 50% of insulin producing ability. The UKPDS has shown us that it is all downhill from here until we reach pancreatic beta cell exhaustion in another 12-20 years. Knowing where out patient is in this continuum helps us to apply the most logical treatment. In the early stages of insulin resistance (frequently associated with obesity, dyslipidemia and hypertension (metabolic syndrome), life style interventions of weight loss, diet and increased physical activity are most helpful in slowing or preventing progression to IGT. At the stage of Pre-Diabetes (FBS 6.1-7 or PC glucose 8-11), lifestyle intervention (18b) was shown to be the most effective treatment in the Finish and US Diabetes Prevention studies but Metformin in the DPP showed a 30% reduction in conversion from IGT to Diabetes and Acarbose in the STOP NIDDM trial showed a 25% risk reduction so these medications should be considered. Troglitazone in the TRIPOD study as well as the Troglitazone arm of the DPP has also shown great promise in diabetes prevention and the potential of Rosiglitazone to prevent Type 2 Diabetes is currently being investigated in the DREAM trial.
At the time of diagnosis of diabetes (FBS>7 or RBS>11), the predominant defect is insulin resistance and so this is the target of our treatment with Metformin (18c) to decrease hepatic glucose production and the Thiazolidenediones (Avandia and Actos) to increase glucose disposal and decrease insulin resistance. Since Diabetes has components of both insulin resistance and insulin deficiency, if we still cannot achieve glycemic control we add in a Sulphonylurea (18d) to increase insulin production. As time goes on and beta cell dysfunction progresses, the sulphonylureas become less effective and we have to use insulin (18e) to correct the insulin deficiency.
The agents that we have available (19) have different and complementary sites of action; Metformin works predominantly by decreasing glucose production by the liver, Acarbose decreases glucose absorption, the insulin secretagogues both Sulphonylureas and Meglitinides increase pancreatic insulin secretion and the Thiazolidenediones increase glucose disposal in the muscles and fat. When single agents alone are insufficient to achieve goal glucose levels of fasting glucose <7 and post prandial glucose less than 11 (20) we add on another agent with a complementary method of action. The 2003 CDA Clinical Practice Guidelines recommend individualized treatment (21) , starting with Metformin in the obese patient as this is the only medication that is associated with weight loss. If initial A1c is greater than 9% then we should start with 2 agents since no single agent is likely to decrease A1c more than 1.5%. In the metabolically decompensated patient we should consider early insulin. The CDA treatment algorithm (22) starts with lifestyle therapy and early addition of medications as needed. While the algorithm looks complicated, in fact (23) all the arms are fairly similar, we generally start with Metformin (24) and if control is not achieved or if A1c is >9% we add a second agent from another class, usually an insulin sensitizer, followed by an insulin secretagogue, then insulin. The order of agents is suggested by the guidelines (25). The Alpha Glucosidase inhibitors (Acarbose) have only a modest effect on A1c and I feel that these are best used in the early stages of Diabetes when lifestyle measures alone are just not enough. The use of anorexiants may be considered in the obese individual but the effect on A1c is only modest (0.5%).We need to treat the predominant problem (26) and treat logically, the treatments will vary according to the needs of the individual. Most oral agents (27) are capable of giving a 1-1.5% decrease in A1c. Early combination therapy (28) is recommended. Individuals on Insulin Secretagogues or insulin need to be counseled about the possibility of hypoglycemia. All Type 2 Diabetics should be doing glucose monitoring (29) and can adjust treatment according to glucose results. We aim to achieve glycemic control within 6-12 months so we need to be aggressive in adding on agents. It is recalled from the UKPDS that most patients end up needing combination therapy (30). We generally get 75% of the maximum therapeutic effect of a medication with about 50% of the maximal dose (31). In the case of Metformin we see that with 1500 mg/day we are getting about 90% of the maximal effect and that doses above 2000 mg cause a deterioration of effect. Incidence of side effects increases dramatically at higher doses. There is no point in giving doses higher than those recommended by the product monograph. Unfortunately to get ODB approval for some medications we have to treat in an illogical manner with doses that are unlikely to be more beneficial than smaller doses.
In summary; (32) in order to lower glucose levels we can decrease glucose production in the body, increase glucose removal from the circulation, increase insulin production, retard carbohydratae absorption or correct insulin deficiency with insulin. In order to accomplish our goals we will use drugs with different mechanisms of action.
(33) Metformin primarily acts by decreasing insulin production by the liver which is a primary pathophysiologic problem in diabetes. It has been used (34) for over 30 years in Canada and has a good safety record. Most patients will respond and it has the advantage of not causing weight gain and indeed there is usually modest weight loss of the order of 2 kilograms. It does; however (35), often cause GI irritation manifested by diarrhea, abdominal cramps and flatulence. This can usually be overcome (36) by starting with a low dose (1/2 a 500 mg tablet) with supper and then gradually titrating up to 2 tablets twice daily. Although the maximum therapeutic dose is shown in the CPS to be 2500 mg, there is no point in going above 2000 mg because the drug becomes less effective. It comes as a generic 500 mg tablet and an 850 mg Glucophage tablet. It is a full ODB benefit in the 500 mg tablet.
Thiazolidinediones (Glitazones): (37)
These drugs act by decreasing insulin resistance by increasing uptake of glucose by muscle and fat tissue. They also decrease hepatic glucose production and there are animal studies showing preservation of islet cell function. These drugs decrease insulin resistance (38) which is a primary metabolic defect of diabetes. It may take weeks or months (39) to see the maximal effect on blood glucose because these drugs act on the nucleus to increase the production of glucose transporters on the cell membrane and this is a multi part process that takes some time. Some people simply do not respond to the drug class. These drugs cause sodium resorption and thereby increase extracellular fluid which may lead to edema or even congestive cardiac failure in patients with impaired myocardial function. About 5% of people develop unacceptable weight gain and stop taking the drug. There is a fat redistribution with intra abdominal fat being decreased while sub cutaneous fat is increased. Overall there is an improvement in lipids, particularly a decrease in small dense LDL. We have 2 members of this class available in Canada (40); Avandia (Rosiglitazone) and Actos (Pioglitazone). Avandia comes in tablets of 2, 4 and 8 mg, dosage range is 2-8 mg a day, the usual dose is 4 mg once a day it also comes combined with Metformin as Avandamet. Actos (Pioglitazone) comes in 15, 30 or 45 mg tablets. Both drugs have the same glucose lowering potential but Actos has some PPAR alpha activity a nd modestly lowers triglycerides. Rosiglitazone is currently being investigated for prevention of Type 2 Diabetes in the DREAM trial. The CDA Guidelines suggest these drugs as an add on after Metformin.ODB will give section 8 ICR only if the patient has failed treatment on full therapeutic doses of Metformin and Glyburide. While this restriction is neither logical nor appropriate and there have been numerous attempts to make ODB see reason, one has to demonstrate lack of efficacy before a TZD will be covered. This means that ODB clients may have delays of years before qualifying for the most appropriate treatment and with the progressive loss of beta cells over time, by the time these drugs are permitted they may be ineffective.
These drugs lower glucose by stimulating the pancreas to produce more insulin. The first generation sulphonylureas Tolbutamide and Chlorpropamide are no longer used because of their extremely long action and potential for severe hypoglycemia. Glyburide is the most commonly used and is fully covered by ODB. Dosage is from 1.25 mg daily to 20 mg daily (given as 10 mg BID). It comes in 2.5 mg and 5 mg tabs. These drugs improve a primary pathophysiologic impairment (42) of insufficient insulin secretion. They act very rapidly and most patients respond. They are associated with significant hypoglycemia (43) in about 15% of patients and this may be very severe and prolonged in the elderly. They are associated with weight gain and some patients allergic to sulpha drugs may not be able to take them. The newer third generation sulphonylureas Gliclazide (Diamicron & Diamicron MR) and Glimepiride (Amaryl) cause less hypoglycemia particularly in the elderly and less weight gain. Gliclazide (Diamicron) may be covered by ODB with a section 8 ICR if the patients has had documented hypoglycemia on Glyburide. Glimepiride (Amaryl) is not covered by ODB. Dosage range (44) for Glyburide is 1.25 to 20 mg a day, it comes in 2.5 and 5 mg tablets, doses greater than 5 mg a day are given as divided doses. Gliclazide (Diamicron) comes as an 80 mg tablet or a 30 mg MR (extended action) tablet which is therapeutically equivalent to the 80 mg regular dose. Dosage range is from one to 4 tablets a day, in the case of the MR tablets they can all be given at the same time. Glimepiride (Amaryl) is given once a day in a dose of 1-4 mg. It is supplied in 1, 2 & 4 mg tablets. It is not covered by ODB.
These are short acting insulin secretagogues (46)that are given with meals and cause a brief increase in insulin production by the pancreas. They are useful in the elderly (47) who frequently have hypoglycemia on sulphonylureas and in people who do not eat at regular mealtimes. There is a rapid response, (48) most people respond and the insulin production is somewhat glucose dependant (i.e. there is a greater response if glucose levels are high and little or no insulin response if glucose levels are low). Repaglinide (Gluconorm) is available in 0.5, 1, and 2 mg tablets. The dosage (49) range is 0.5 to 4 mg with each meal. The usual dose is 2 mg with each meal. ODB will give section 8 ICR for Gluconorm if there is documented hypoglycemia or intolerance with Glyburide. Nateglinide (Starlix) is similar in properties and comes as a 120 mg tablet. The dose is one tablet with each meal. There is no ODB coverage.
In order to have diabetes we must have insulin deficiency so this treatment corrects a primary pathophysiologic defect. In sufficient dose it will control all diabetics. It should be used when there is evidence of metabolic decompensation (ketoacidosis or weight loss). There are many different preparations with different action profiles to treat specific defects such as a short acting analogue for post prandial hyperglycemia or an intermediate acting insulin (such as NPH) to suppress glucose production by the liver overnight (bedtime insulin therapy). Overdoseage may cause hypoglycemia (50) , there may be weight gain and it has to be given by injection.
Alpha Glucosidase Inhibitors: (51)
Acarbose (Prandase) inhibits the enzyme that splits polysaccharides into glucose in the small intestine. Only the simple sugars can be absorbed across the wall of the intestine so the glucose peak is lowered and there is less post prandial hyperglycemia. Eventually the polysaccharides are split by other enzymes in the intestine so the absorption is retarded not blocked. Since Sucrose has to be split before it can be absorbed, Glucose should be used to treat hypoglycemia in the patient on Acarbose. Prandase comes in 50 & 100 mg tablets, the usual dose is 50-100 mg with the first bite of each meal. It is a safe drug (52) with no associated weight gain but it only has a modest effect (53) on A1c and has a high incidence of GI side effects. Dosage (54) should be started low (1/2 a 50 mg tab once a day) and titrated up gradually to an effective dose. It is paid for by ODB on a Limited Use form.
Orlistat (Xenical) (55) is an intestinal lipase inhibitor that causes mal-absorption of fat resulting in 30% of dietary fat being excreted in the feces. It is not absorbed into the body and there are no drug interactions. It may be helpful in the obese type 2 Diabetic. There is only a modest effect on A1c and it is expensive. It has shown a beneficial effect on prevention of diabetes in obese subjects with IGT. Dosage is 120 mg with each meal and it needs to be combined with a low fat diet to avoid the side effect of steatorrhea. It may be reimbursed by ODB under section 8 ICR.