LONG TERM BENEFITS OF ORAL AGENTS J. Robin Conway M.D. Diabetes Clinic Smiths Falls, ON www.diabetesclinic.ca

Long Term Benefits of Oral Agents Robin Conway M.D.

Physical Activity and Diabetes I would like to see a chart prior to this slide – see the page entitled Physical Activity I think this could replace this slide For people who have not previously exercised regularly and are at risk of CVD, an ECG stress test should be considered prior to starting an exercise program Testing is particularly important before, during and for many hours after exercise.

Nutrition Therapy People with diabetes should: Receive nutrition counseling by a registered dietitian Receive individualized meal planning Follow Canada’s Guidelines for Healthy Eating People on intensive insulin should also be taught to adjust the insulin for the amount of carbohydrate consumed Anna let me know what you think about changing to a table instead

Pharmacologic Management of Type 2 Diabetes Add anti-hyperglycemic agents if: Diet & exercise therapy do not achieve targets after 2-3 month trial or newly diagnosed and has an A1C of  9% A1C & BMI Suggested starting agent < 9% BMI  25 Biguanide alone or in combination BMI < 25 1 or 2 agents from different classes  9% -- 2 agents from different classes or insulin basal and/or preprandial Can remove the last column See flipchart pharmacological management of type 2, I like the simple chart as well describing A1C Intensify to reach targets in 6-12 months

Management of Hyperglycemia in Type 2 Diabetes Patients Clinical assessment and initiation of nutrition therapy and physical activity Mild to moderate hyperglycemia (A1C<9.0%) Marked hyperglycemia (A1C  9.0%) Basal and/or preprandial insulin Non-overweight Overweight 2 antihyperglycemic agents from different classes 1 or 2 antihyperglycemic agents from different classes Biguanide alone or in combination If not at target Add a drug from a different class or use insulin alone or in combination Add an oral antihyperglycemic agent from a different class or insulin Intensify insulin regimen or add antihyperglycemic agents Need to replace or add a different title such as Get to Target…quickly

Oral Agents for Type 2 Diabetes Combination at less than maximal doses result in more rapid improvement of blood glucose Counsel patients about hypoglycemia prevention and treatment SMBG is recommended at least once daily

Targets for Glycemic Control Under Normal range please change to – if it can safely be achieved I would suggest removing the recommendation, however mentioning #1 under the chart * Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors To achieve an A1C  7.0%, patients should aim for FPG, preprandial and postprandial PG targets

Burden of Poor Control - Cost The socioeconomic buden of diabetes can be documented in different ways: Burden of poor control established by assessing the relationship between glycemic control and diabetes health care cost Example of such a study is given above where Gilmer et al. Estimated the cost to health plans associated with different levels of glycemic control Lack of control in diabetes has a socioeconomic burden for all stakeholders in health care

Burden of Poor Control - Cost Estimate annual cost to health plans by level of glycemic control Determine effect of Improved Glycemic Control on Health Care Utilization and Costs The socioeconomic buden of diabetes can be documented in different ways: Burden of poor control established by assessing the relationship between glycemic control and diabetes health care cost Example of such a study is given above where Gilmer et al. Estimated the cost to health plans associated with different levels of glycemic control Lack of control in diabetes has a socioeconomic burden for all stakeholders in health care

Oral Antihyperglycemic Agents: Biguanides Decreases hepatic glucose production, enhances peripheral glucose uptake May reduce insulin resistance in the periphery e.g., Metformin Contraindicated in renal/hepatic insufficiency May cause GI side effects Not associated with hypoglycemia, may promote weight loss LIVER MUSCLE Oral Antihyperglycemic Agents: Biguanides The biguanide, metformin (Glucophage®) has no effect on endogenous insulin secretion. Its mechanism of action is not completely clear, but it is thought to act primarily to decrease hepatic glucose production and enhance insulin-mediated glucose uptake.1,2 Metformin may reduce insulin resistance by enhancing the effect of insulin on peripheral receptor sites. Metformin has been shown to decrease fasting glucose, glycosylated haemoglobin (HbA1C), fasting triglycerides, and total and LDL-C levels, and to increase HDL-C levels.2 Clinical trials with both diet and sulfonylurea-failure patients have demonstrated a further decrease HbA1C levels of 1.5-2% with the addition of metformin. Metformin is contraindicated in patients with renal insufficiency, hepatic disease, cardiac insufficiency, alcohol abuse, any hypoxic condition, or a history of lactic acidosis.2,3 Side effects include mild self-limiting diarrhea, nausea or anorexia and some patients have complained of a metallic taste. The only major systemic side effect is lactic acidosis. Metformin does not cause hypoglycemia when used alone, and it may promote weight loss. References: 1. Meltzer S, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159(Suppl):S1-S29. 2. Edelman SV. Type II diabetes mellitus. Adv Intern Med 1998;43:445-500. 3. Sheen AJ. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Drugs 1997;54:355-68. Meltzer et al CMAJ 1998;159(Suppl):S1-29.

Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs) Decrease insulin resistance Increase insulin-dependent glucose disposal, decrease hepatic glucose production e.g., Pioglitazone, rosiglitazone Pioglitazone has a positive effect on lipids Not associated with hypoglycemia Possible URI, headache, edema, weight gain and reduction in hemoglobin MUSCLE LIVER ADIPOSE TISSUE Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs) Key message: Thiazolidinediones decrease insulin resistance and pioglitazone may also positively effect lipid parameters. TZDs are the newest class of antihyperglycemic agents for type 2 diabetes and include rosiglitazone and pioglitazone. Troglitazone is no longer available due to concerns of hepatic toxicity. These agents enhance sensitivity to insulin in the liver, adipose tissue and muscle, which results in improved insulin-mediated glucose disposal.1,2 TZDs activate the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-), which is involved in adipose cell differentiation and insulin-mediated glucose uptake in peripheral tissues. They reduce the expression of leptin (a signalling factor that regulates appetite, body weight and energy balance), and increase the expression of a lipid binding protein that plays a key role in the facilitated transport of glucose into adipocytes and skeletal muscle.1,2 Studies have demonstrated a dose-dependent reduction of HbA1C, fasting blood glucose and plasma insulin levels. Pioglitazone may also improve lipid abnormalities, particularly hypertriglycidemia.1 Modest weight gain has been reported, but hypoglycemia is rare.1,2 Upper respiratory tract infections, edema, headache and reduction in hemoglobin have also been reported.1,2 References: 1. Plosker GL, Faulds D. Troglitazone. Drugs 1999;57:410-32. 2. Balfour JA, Plosker GL. Rosiglitazone Drugs 1999;57:921-30. Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.

Thiazolidinediones: Mechanism of Insulin Sensitization TZD INSULIN INSULIN RECEPTOR GLUCOSE TZD GLUT-4 Thiazolidinediones: Mechanism of Insulin Sensitization Thiazolidinediones cross the plasma membrane and pass through the cytoplasm to the nucleus where they bind with the nuclear receptors, peroxisome proliferator-activated receptor-gamma (PPAR-). These receptors are found in tissues involved in insulin action, including adipose tissue, skeletal muscle, and the liver. Activation of PPAR- nuclear receptors sends signals into the nucleus that augment the function and efficiency of insulin’s effect on transcription factor activation. This augmentation increases the nuclear based actions of insulin which include the signal for formation of proteins involved in enzymatic processes, cell growth, regulation of insulin receptor activity and glucose transport.1 TZDs, thus improve the cells insulin sensitivity by increasing the insulin signal in the nucleus, which results in an increased number of GLUT-4 transporters and increased glucose entry into the cell. Pioglitazone has also shown some activation of the PPAR- receptor, which has been linked to some aspects of lipid metabolism.2-4 This may account for pioglitazone’s beneficial effects on lipid parameters. References: 1. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996;45:1661-9. 2. Lehmann JM, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor  (PPAR-). J Biol Chem 1995;270:12953-6. 3. Forman BM, et al. 15 deoxy-12,14 prostaglandin J2 is a ligand for the adipocyte determination factor PPAR-. Cell 1995;83-803-12. 4. Henry RR. Thiazolidinediones. Endocrinol Metab Clin North Am 1997;26:553-73. PPAR DNA RNA Saltiel, Olefsky Diabetes 1996;45:1661–9.

Durability of Glycemic Control with Pioglitazone Long Term HbA1c (%) The durability of pioglitazone to maintain improved glycemic control was demonstrated by a sustained reduction in the HbA1c of –1.39% (mean change from baseline) throughout the 72 week follow up period. Einhorn D et al. Diabetes 2001;50 (suppl2):A111

Metformin & Pioglitazone Study - Open Label Extension In an open label extension to the double blind study, further reductions in HbA1c and fasting plasma glucose were observed. Patients treated with pioglitazone and metformin for 72 weeks had mean changes from baseline of 1.4% in HbA1c and 3.5 mmol/L in fasting plasma glucose. Change in HbA1c (%) Change in fasting glucose (mmol/L) Einhorn et al. Clin Therapeutics 2000;12:1395-1409

Oral Antihyperglycemic Agents: Sulfonylureas Stimulate pancreatic insulin release e.g., First-generation: tolbutamide, chlorpropamide, acetohexamide e.g., Second-generation: Glyburide, gliclazide Secondary failure a problem Weight gain, risk of hypoglycemia PANCREAS Oral Antihyperglycemic Agents: Sulfonylureas Sulfonylureas include the first generation compounds: acetohexamide(Dimelor®), chlorpropamide (Diabinese®), and tolbutamide (Orinase®), and the second-generation compounds, glyburide (DiaBeta®), and gliclazide (Diamicron®). These agents work primarily by stimulating pancreatic release of insulin.1 This reduces hepatic glucose output and facilitates peripheral glucose disposal. First generation and second generation compounds have similar efficacy, but the second generation drugs are more potent on a per milligram basis, tend to produce fewer side effects, interact less frequently with other drugs and allow for once a day dosing.2 HbA1C levels can be reduced by 1-2% in responsive patients, but only 60-70% of patients achieve glycemic targets.3 Patients with high fasting blood glucose levels and severe obesity often respond poorly to these compounds. About 5-10% of patients/year exhibit secondary failure to these agents. Most side effects are mild and infrequent, but one major complication of sulfonylurea agents is the potential to increase the occurrence of hypoglycemia.1-3 This has been more often associated with chlorpropamide and glyburide but all sulfonylureas have this adverse effect.3 Weight gain, sometimes of several kilograms, may occur and is undesirable in already overweight patients.3 References: 1. Meltzer S, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159(Suppl):S1-S29 2. Edelman SV. Type II diabetes mellitus. Adv Intern Med 1998;43:445-500. 3. Sheen AJ. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Drugs 1997;54:355-368. Meltzer et al CMAJ 1998;159(Suppl):S1-29.

Natural History of Type 2 Diabetes Prior to the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and postprandial insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to compensatory increases in circulating insulin, which prevents an increase in glucose levels. As time progresses, the insulin resistance reaches a peak and stabilizes while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal. Impaired Glucose Tolerance (IGT): However, at some point in time, either due to early -cell dysfunction or due to a natural limit of -cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, postprandial glucose levels become abnormal as a limitation in insulin response is reached. Type 2 Diabetes: Following the onset of -cell dysfunction, insulin levels can no longer overcome insulin resistance, and fasting and postprandial glucose levels increase progressively over time. References: 1. Henry RR. Type 2 diabetes care: the role of insulin-sensitizing agents and practical implications for cardiovascular disease prevention. Am J Med 1998;105(1A):20S-6S. Henry. Am J Med 1998;105(1A):20S-6S.

Oral Antihyperglycemic Agents: Alpha-glucosidase inhibitors Slows gut absorption of starch and sucrose Attenuates postprandial increases in blood glucose levels e.g., Acarbose GI side effects Not associated with hypoglycemia or weight gain INTESTINE Oral Antihyperglycemic Agents: Alpha-glucosidase Inhibitors The alpha-glucosidase inhibitor, acarbose (Prandase®) slow the absorption of starch and sucrose in the gut.1 This compound retards the breakdown of disaccharides, polysaccharides, and other complex sugars into monosaccharides on the brush border of the small intestine. The enzymatic generation and subsequent absorption of glucose are delayed, and the postprandial blood glucose values, which are typically high in people with type 2 diabetes, are improved.2 Several clinical trials have demonstrated the effectiveness of alpha-glucosidase inhibitors, both alone and in combination with other antihyperglycemic agents.2 Decreases in HbA1C of between 0.5-3% have been demonstrated, with no affect on the incidence of hypoglycemic episodes.3 The most common side effects of these agents include flatulence, soft stools, diarrhoea, and mild abdominal pain. These side effects are most likely due to the fermentation of undigested carbohydrates in the colon. Slow titration of acarbose is recommended to avoid or minimise the GI side effects.1,2 Acarbose has not been associated with body weight gain or hypoglycemic effects.1 References: 1. Salvatore T, Giugliano D. Pharmacokinetic-pharmacodynamic relationships of acarbose. Clin Pharmacokinet 1996;30:94-106. 2. Edelman SV. Type II diabetes mellitus. Adv Intern Med 1998;43:445-500. 3. Sheen AJ. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Drugs 1997;54:355-368. Salvatore, Giugliano Clin Pharmacokinet 1996;30:94-106.

Oral Agents for Type 2 Diabetes Combination at less than maximal doses result in more rapid improvement of blood glucose Counsel patients about hypoglycemia prevention and treatment SMBG is recommended at least once daily

Natural History of Type 2 Diabetes Metformin/Thiazolidinediones Lifestyle Insulin Secretagogues Natural History of Type 2 Diabetes Prior to the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and postprandial insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to compensatory increases in circulating insulin, which prevents an increase in glucose levels. As time progresses, the insulin resistance reaches a peak and stabilizes while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal. Impaired Glucose Tolerance (IGT): However, at some point in time, either due to early -cell dysfunction or due to a natural limit of -cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, postprandial glucose levels become abnormal as a limitation in insulin response is reached. Type 2 Diabetes: Following the onset of -cell dysfunction, insulin levels can no longer overcome insulin resistance, and fasting and postprandial glucose levels increase progressively over time. References: 1. Henry RR. Type 2 diabetes care: the role of insulin-sensitizing agents and practical implications for cardiovascular disease prevention. Am J Med 1998;105(1A):20S-6S. Henry. Am J Med 1998;105(1A):20S-6S.

Targets for Glycemic Control Under Normal range please change to – if it can safely be achieved I would suggest removing the recommendation, however mentioning #1 under the chart * Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors To achieve an A1C  7.0%, patients should aim for FPG, preprandial and postprandial PG targets