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Oral Anti-diabetic Medications

Oral Anti-diabetic Medications. Mario Skugor, MD FACE Endocrine and Metabolic Institute Cleveland Clinic. CLASSES OF ORAL ANTIDIABETIC MEDICATIONS. CLASSES OF ORAL ANTIDIABETIC MEDICATIONS. Canagliflozin just approved. METFORMIN. French lilac – used in folk medicine for centuries.

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Oral Anti-diabetic Medications

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  1. Oral Anti-diabetic Medications Mario Skugor, MD FACE Endocrine and Metabolic Institute Cleveland Clinic

  2. CLASSES OF ORAL ANTIDIABETIC MEDICATIONS

  3. CLASSES OF ORAL ANTIDIABETIC MEDICATIONS Canagliflozin just approved.

  4. METFORMIN French lilac – used in folk medicine for centuries. Synthesized in 1920s In 1950 Metformin was used to treat influenca and noted to lower blood glucose to physiologic levels.

  5. METFORMIN • In 1957 first clinical trial of diabetes treatment was published in France • Approved in 1958 in UK, 1972 in Canada and in 1995 in US.

  6. METFORMIN • Suppression of hepatic gluconeogenesis through activation AMP-activated protein kinase (AMPK). • Improves glucose uptake in muscle and fat. • Causes weight loss in some individuals. • Improves menstrual cycle and fertility in PCOS • May improve NASH. • May reduce risk of range of different carcinomas

  7. METFORMIN • Comes in 500, 850 and 1000 mg pills. • Extended release pills are available (but more expensive) • Usual dose is 1000 mg twice a day. • Main side effects is abdominal cramping and diarrhea • Metformin extended release is better tolerated by some patients • Even mild renal failure (Cr>1.4 in males and >1.5 in females) is contraindication for use

  8. Metformin – Bottom line • Clearly the first line. • Cheap • Improves physiology • Has other benefits. • Unfortunately, significant proportion of patients has contraindications or cannot tolerate it.

  9. SULPHONYLUREAS • Marcel Janbon and co-workers discovered hypoglycemic effect of sulfonylurea in 1942. • They were studying sulfonamide antibiotics and discovered that the compound sulfonylurea induced hypoglycemia in animals

  10. Sulphonylureas First sulfonylurea for treatment of DM introduced in 1955. General structure:

  11. Sulphonylurea • First generation – Binds to the proteins in the blood. • Tolbutamide • Chlorpropamide • Tolazamide • Acetohexamide • Carbutamide

  12. Sulphonylurea • Second generation – Not bound to serum proteins. • Glipizide • Glyburide (glibenclamide) • Gliclazide • Glibornuride • Gliquidone • Glisoxepide • Glyclopyramide

  13. Sulphonylurea • Third generation • Glimepiride

  14. SUFONYLUREAS

  15. Sulfonylurea • Advantages • Fast acting • Once a day dosing • Gliclazide may be particularly beneficial • Disadvantages • Risk of hypoglycemia • Weight gain • Possible problems with ischemic preconditioning

  16. Glicilizide • Inhibits platelet aggregation • Associated with lower mortality from malignant neoplasms. • Improves repair of DNA damage caused by oxidative stress in tissue cultures.

  17. Sulfonylureas – Bottom line • Fast acting • Older ones are cheap • Do not improve physiology • Hypoglycemia is significant risk • Require strict regime of diet

  18. Meglitinides • Nategelinde • Repaglinide • Act on same potassium channel as sulfonylurea but bind to different part of the molecule. • Short acting – taken 0-30 min before meal. • Risk of hypoglycemia is small

  19. Meglitinides – Bottom line • Useful in small number of patients for relatively short period of time. • Allow for some flexibility in timing of the meals.

  20. TZD-s – actually Pioglitazone • The proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α agonist in the muscle, adipose tissue, and the liver. • Pioglitazone reduces insulin resistance in the liver and peripheral tissues. • Pioglitazone decreases the level of triglycerides and increases HDL without changing LDL and total cholesterol.

  21. Pioglitazone • Pioglitazone - 15 - 30 - 45 mg pills • Peripheral edema is main side effect. • More hospitalizations for CHF in studies with all • TZD-s • Effect is maintained when combined with metformin and incretin based therapies.

  22. Thiazolidinediones and bladder cancer. Colmers IN, et al. CMAJ 2012I:10.1503

  23. TZD-s and fracture risk Toulis KA, et al. CMAJ, 2009, 180 (8) 841-842

  24. TZD-s and fractures TZD-s are associated with fractures in females over 50 years of age. In men risk is increased if TZD-s are used with loop diuretic Bilik D, et al. JCEM. 2010 (10) 1210.

  25. Bottom line on Pioglitazone • Benefits are still higher than risks. • There is some evidence that lower dose is not associated with risk of bladder cancer. • However – at this time Metformin and PPD-4 inhibitors are clearly ahead of Pioglitazone as choices for treatment.

  26. Incretins Gut-derived hormones, secreted in response to nutrient ingestion, that potentiate insulin secretion from islet cells in a glucose-dependent fashion, and lower glucagon secretion from islet  cells Two predominant incretins: Glucagon-like peptide–1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP) (also known as gastric inhibitory peptide) Incretin effect is impaired in type 2 diabetes Known as GLP-1 deficiency

  27. Incretin system and DPP-4 physiologic action

  28. Native GLP-1 is rapidly degraded by DPP-IV Human ileum, GLP-1 producing L-cells Capillaries, DPP-IV (Di-Peptidyl Peptidase-IV) Double immunohistochemical staining for DPP-IV (red) and GLP-1 (green) in the human ileum Adapted from: Hansen et al. Endocrinology 1999;140:5356–5363.

  29. Glucagon-Like Peptide–1 Normalizes Postprandial Hyperglycemia in Patients with Type 2 Diabetes Healthy subjects T2DM patients Infusion Infusion 300 300 Liquid meal Liquid meal 250 250 Placebo 200 200 150 150 Placebo Plasma glucose (mg/dl) Plasma glucose (mg/dl) 100 100 50 50 GLP-1 [7-36 amide] 1.2 pmol/kg/min GLP-1 [7-36 amide] 1.2 pmol/kg/min 0 0 –1 –1 0 0 1 1 2 2 3 3 4 4 Time (h) Time (h) Nauck MA et al. Acta Diabetol. 1998;35:117-129.

  30. 0 1 6 Continuous Glucagon-Like Peptide–1 Infusion Reduces Appetite over 6 Weeks *Satiety *Fullness Mean (SE) AUC for Visual Analogue Score (mm) vs Time (h) Time (wk) *Prospective food intake *Hunger *p<.05 Time (wk) All data for patients treated with glucagon-like peptide–1 (n = 10). No changes in these parameters were observed in the saline group. Zander M et al. Lancet. 2002;359:824–830.

  31. Glycemic Control with GLP-1 Receptor Agonists in Head-to-Head Clinical Trials *Significant difference vs comparator GLP-1 receptor agonist 1Buse JB et al. Lancet. 2009;374:39-47 | 2Drucker DJ et al. Lancet. 2008;372:1240-1250 | 3Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310 | 4Buse JB et al. Presented at 47th EASD Annual Meeting, Lisbon, Portugal, 14 September 2011. LIRA EXN QW EXN BID Trial: Size (N): Study length (weeks): LEAD-61 464 26 DURATION-12 303 30 DURATION-53 254 24 DURATION-64 912 26 * * *

  32. Comparison of Incretin Modulators GLP-1=glucagon-like peptide–1; DDP-4=dipeptidyl peptidase–4

  33. DPP – 4 inhibitors • Sitagliptin • Saxagliptin • Linagliptoin • Alogliptin • Vildagliptin – marketed in EU • More in development • Gemigliptin

  34. DPP4 inhibitors • All taken once a day • Sitaglipitin 100 mg daily • 50 mg if Cr 1.7-3.0 for men and 1.5-2.5 for women • 25 mg in ESRD • Saxagliptin 5 mg per day • 2.5 mg in renal impairment • 2.5 if taken with cytochrome P450 inhibitors (ketoconazole) • Linagliptin 5 mg daily

  35. Sitagliptin - example

  36. DPP-4 inhibitors • Side effects are minimal • Acute pancreatitis is seen • Linagliptin 15.2/10.000 patients • Placebo 3.7/10,000 patients • Saxaglipin – No data but some postmarketing cases are reported • Sitagliptin – There is 88 cases in 2.5 years in postmarketing reporting.

  37. DDP-4 inhibitors – Bottom Line • Very well tolerated • Improve physiology • Expensive • So far, no serious adverse effects with long term use. • No increased risk of pancreatic caner.

  38. Alpha-Glucosidase inhibitors • Acarbose - 25, 50 or 100 mg tablets • Miglitol - 25, 50 and 100 mg tablets • They block intestinal enzyme breaking sugars to monosaccharides. • This slows down and blocks some of carbohydrate absorption. • Postprandial peak is diminshed and Hba1c improves.

  39. Alpha-Glucosidase inhibitors

  40. Alpha-glucosidase inhibitors • Taken with each meal. • Side effects are flatulence and diarrhea • This can be diminished with low carb, high fiber diet and slow titration of the dose form 25 mg to 100 mg per day. • Very low risk of hypoglycemia

  41. Alpha-glucosidase inhibitors – Bottom line • Very useful if tolerated • Relatively cheap.

  42. Bromocriptine • Bromocriptine mesylate given within 2 hours of waking up in the morning improves glycemic control by unknown mechanism. • It is given in escalating dose starting with 0.8 mg and increasing by 0.8 mg every week to maximal tolerated dose. • Therapeutic dose is between 1.6 to 4.8 mg per day. • Very low risk of hypoglycemia. • About 25% of patients experience some nausea.

  43. Bromocriptine

  44. Bromocriptine

  45. Bromocriptine – Bottom line • Useful if tolerated. • Still expensive • Many patients are discuoraged by need to use 2-6 pills at once (In US only 0.8 mg pill is available).

  46. Bile acid sequestrants • Colesevelam • Cholestyramine • Colestid • Mechanism is unknown • In db/db mice these drugs increase metabolic utilization of glucose in peripheral tissues which corelates with decrease in muscle long chain acylcarnitine content Meissner M, et al. PLOS 2011 (6)11 e24564.

  47. Coleselavam

  48. Cholestyramine

  49. Colesevalam

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