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

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Presentation on theme: "Oral Anti-diabetic Medications Mario Skugor, MD FACE Endocrine and Metabolic Institute Cleveland Clinic."— Presentation transcript:

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

2 Insulin secretaguages Insulin sensitizers Incretin based therapies Alpha- glucosidase inhibitors CNS acting Long acting Sulphonylureas Liver Metformin PPD-4 inhibitors AcarboseBromocriptine Short acting Meglitinides Muscle and Fat Thiazolidinediones Miglitol Other Bile acid sequestrants Orlistat CLASSES OF ORAL ANTIDIABETIC MEDICATIONS In development Dual PPAR gamma agonists SGLT-2 antagonists

3 Insulin secretaguages Insulin sensitizers Incretin based therapies Alpha- glucosidase inhibitors CNS acting Long acting Sulphonylureas Liver Metformin PPD-4 inhibitors AcarboseBromocriptine Short acting Meglitinides Muscle and Fat Thiazolidinediones Miglitol Other Bile acid sequestrants Orlistat CLASSES OF ORAL ANTIDIABETIC MEDICATIONS In development Dual PPAR gamma agonists SGLT-2 antagonists 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 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 – 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 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. Pioglitazone

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

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

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 (10) 1210.

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26 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.

27 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

28 Incretin system and DPP-4 physiologic action

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

30 Slide Source: Lipids Online Slide Library Glucagon-Like Peptide–1 Normalizes Postprandial Hyperglycemia in Patients with Type 2 Diabetes Nauck MA et al. Acta Diabetol. 1998;35: Time (h) Plasma glucose (mg/dl) –1 Infusion GLP-1 [7-36 amide] 1.2 pmol/kg/min Placebo Liquid meal –1 Infusion GLP-1 [7-36 amide] 1.2 pmol/kg/min Placebo Liquid meal Plasma glucose (mg/dl) Healthy subjects T2DM patients Time (h)

31 Slide Source: Lipids Online Slide Library Continuous Glucagon-Like Peptide–1 Infusion Reduces Appetite over 6 Weeks All data for patients treated with glucagon-like peptide–1 (n = 10). No changes in these parameters were observed in the saline group. Mean (SE) AUC for Visual Analogue Score (mm) vs Time (h) Time (wk) 610 Zander M et al. Lancet. 2002;359:824–830. Time (wk) *Prospective food intake *Hunger *Satiety *Fullness *p<.05

32 Slide Source: Lipids Online Slide Library Glycemic Control with GLP-1 Receptor Agonists in Head-to-Head Clinical Trials *Significant difference vs comparator GLP-1 receptor agonist 1 Buse JB et al. Lancet. 2009;374:39-47 | 2 Drucker DJ et al. Lancet. 2008;372: | 3 Blevins T, et al. J Clin Endocrinol Metab. 2011;96: | 4 Buse JB et al. Presented at 47th EASD Annual Meeting, Lisbon, Portugal, 14 September Trial: Size (N): Study length (weeks): LEAD DURATION DURATION DURATION * * * EXN BID LIRA EXN QW

33 Slide Source: Lipids Online Slide Library Comparison of Incretin Modulators GLP-1 AnaloguesDPP-4 Inhibitors Administration routeInjectionOral  GLP-1SustainedMeal-related Effect on A1C  Effects on body weight     Side effects Nausea, Rare: pancreatitis (Well tolerated) Nasopharyngitis, skin rashes, Stevens-Johnson syndrome -cell function  GLP-1=glucagon-like peptide–1; DDP-4=dipeptidyl peptidase – 4

34 DPP – 4 inhibitors Sitagliptin Saxagliptin Linagliptoin Alogliptin Vildagliptin – marketed in EU More in development – Gemigliptin

35 DPP4 inhibitors All taken once a day – Sitaglipitin 100 mg daily – 50 mg if Cr for men and 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

36 Sitagliptin - example

37 DPP-4 inhibitors Side effects are minimal Acute pancreatitis is seen – Linagliptin 15.2/ 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.

38 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.

39 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.

40 Alpha-Glucosidase inhibitors

41 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

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

43 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.

44 Bromocriptine

45

46 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).

47 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.

48 Coleselavam

49 Cholestyramine

50 Colesevalam

51

52 Orlistat

53 Effect on weight

54 Effects on Hba1c

55 Chao EC, et al. Nat Rev Drug Discovery. 2010;9: Targeting the Kidney

56 Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9: Renal Glucose Transport

57 Rationale for SGLT2 Inhibitors SGLT2 is a low-affinity, high capacity glucose transporter located in the proximal tubule and is responsible for 90% of glucose reabsorption Mutation in SGLT2 transporter linked to hereditary renal glycosuria, a relatively benign condition in humans Selective SGLT2 inhibitors have a novel & unique mechanism of action reducing blood glucose levels by increasing renal excretion of glucose Decreased glycemia will decrease glucose toxicity leading to further improvements in glucose control Selective SGLT2 inhibition, would also cause urine loss of the calories from glucose, potentially leading to weight loss Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7):

58 Canagliflozin *P˂.001 vs. placebo calculated using LS meansRosenstock J, et al. Abstract 77-OR. ADA Metformin + Canagliflozin Dose-Ranging Study Mean Baseline A1C (%) * * * * * *

59 Changes from Baseline in Body Weight in Phase 3 Dapagliflozin Studies Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10): ; Bailey CJ, et al. Lancet. 2010;375(9733):

60 Canagliflozin Trials Symptomatic genital infections in 3-8% canagliflozin arms – 2% placebo – 2% SITA Urinary tract infections in 3-9% canagliflozin arms – 6% placebo – 2% SITA Hypoglycemia in 0-6% canagliflozin arms – 2% placebo – 5% SITA Rosenstock J, et al. Abstract 77-OR. ADA 2010.

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62 Treatment and cancer risk metformin sulphonylurea metformin + sulpha insulin No treatment

63 Treatment and colorectal cancer risk metformin sulphonylurea metformin + sulpha insulin

64 Treatment and pancreatic cancer risk metformin sulphonylurea metformin + sulpha insulin

65 ADOPT and RECORD Trials

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68 METFORMIN

69

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71 Are all sulphonylureas the same? Retrospective cohort study Glibenclamide treated N-378 Gliclizide treated N year follow up Cancer mortality higher for glibenclamide after adjustments for age and sex, BMI, metformin and insulin treatment- HR 3.56 ( )

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73 Are all sulphonylureas the same? Matched case-control study 195 diabetic patients with incident malignancy 195 matched diabetic patients with no malignancy Matched for sex, age, BMI, duration of diabetes, Hba1c, smoking and alcohol abuse Exposure to antidiabetic drugs over last 10 years was analyzed.

74 Are all sulphonylureas the same?

75 Possible mechanism

76 New Classes Presently in Development Long-acting GLP-1 receptor agonists Ranolazine 11 Hydroxysteroid Dehydrogenase (HSD)- 1 inhibitors Fructose 1,6-bisphosphatase inhibitors Glucokinase activators G protein-coupled Receptor (GPR)- 40 & -119 agonists Protein Tyrosine Phosphatase (PTB)- 1b inhibitors Camitine- Palmitoyltransferase (CPT)- 1 inhibitors Acetyl COA Carboxylase (ACC)- 1 & -2 inhibitors Glucagon receptor antagonists Salicylate derivatives


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