1. Diabetes Mellitus Oral Hypoglycemic Agents Dr. A. ghanei endocrinologist

2. Non-Insulin Hypoglycemic Agents Oral  Biguanides  Sulfonylureas  Meglitinides  Thiazolidinediones  Alpha Glucosidase inhibitors  Incretin Enhancers (DPP- IV inhibitors)  Resin binder Parenteral  Amylin analogs  Incretin mimetics

3. Sulfonylureas : stimulate β cells to produce more insulin  1 st generation –(1) Orinase (tolbutamide) –(3) Tolinase (tolazamide) –(6) Diabinese (chlorpropamide)  2 nd generation –(75) Glucotrol (glipizide) –(150) Glucotrol XL (ex. rel. glipizide) –(150) Micronase, Diabeta (glyburide) –(250) Glynase (micronized glyburide)  3 rd generation –(350) Amaryl (glimepiride) 2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD) was used in treatment of typhoid fever in 1940’s  hypoglycemia Currently > 12,000  may become dislodged  delayed activity *Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway *Hydroxylated derivatives have much lower hypoglycemic activity

4.  Mechanism of action: –presence of functional pancreatic beta cells is must –SUs imitate the effects of glucose on beta cells –SUs bind to SURs at the beta-cell potassium channels > this closes the channels and blocks potassium ions from leaving the cell > The membrane then becomes depolarized and calcium channels open > Calcium ions enter the cell and trigger the release of insulin > The increased insulin concentration lowers blood glucose levels Mechanism of action Glimepiride(Amaryl)1, 2, 4 mgtablets Glipizide(Glucotrol, Glucotrol XL) (2.5), 5, 10 mg (XL)tablets Glyburide(DiaBeta)1.25, 2.5, 5 mgtablets

5. Pharmacology - Sulfonylureas Compound Glibenclamide/Glyburide Glipizide Gliclazide Glimepiride Mechanism Closes K ATP channels on β -cell plasma membranes Action(s)  Insulin secretion Advantages Generally well tolerated Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages Relatively glucose-independent stimulation of insulin secretion: Hypoglycemia, including episodes necessitating hospital admission and causing death Weight gain Primary and secondary failure

6. Biguanides : improves insulin’s ability to move glucose into cells (esp. muscle)  Metformin - Glucophage®, Fortamet®, Riomet® *only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with diabetes (UKPDS 1998). - Metformin was first described in the scientific literature in 1957 (Unger et al). - It was first marketed in France in 1979 but did not receive FDA approval for Type 2 diabetes until 1994. - mechanism improves insulin sensitivity by increasing peripheral glucose uptake and utilization. - Zhou et al (2001) showed that metformin stimulates the hepatic enzyme AMP-activated protein kinase Metformin is a widely used monotherapy, and also used in combination with the sulfonylureas in treatment of type 2 diabetes

7. Biguanides  Metformin is a biguanide that works mainly by:  Suppressing excessive hepatic glucose production  Increasing glucose utilization in peripheral tissues to a lesser degree  It may also improve glucose levels by reducing intestinal glucose absorption

8. MetforminGlucophage500, 850, 1000 mgtablets (Glucophage XR)500, 750 mg XRtablets

9. Pharmacology - Biguanides MechanismActivates AMP-kinase Action(s) Hepatic glucose production  Intestinal glucose absorption  Insulin action  Glucose Lowering Effect Fasting Post Prandial Advantages No weight gain No hypoglycemia Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages Gastrointestinal side effects (diarrhea, abdominal cramping) Lactic acidosis (rare) Vitamin B 12 deficiency Contraindications: reduced kidney function

10. Thiazolidinediones (TZD’s) : make cells more sensitive to insulin (esp. fatty cells)  Pioglitazone - Actos®, Avandia® - binds to and activates (PPARγ). - PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta PPAR - γ - upon activation of this nuclear receptor by a ligand such as a TZD, PPARγ–ligand complex binds to a specific region of DNA and thereby regulates the transcription of many genes involved in glucose and fatty acid metabolism. - Marketed in USA in August of 1999

11. Pioglitazone(Actos)15, 30, 45 mgtablets Rosiglitazone(Avandia)2, 4, 8 mgtablets

12. Pharmacology – Thiazolidinediones (TZD) CompoundRosiglitazone (Avandia®) Mechanism Activates the nuclear transcription factor PPAR-  Action(s) Peripheral insulin sensitivity  AdvantagesNo hypoglycemia Disadvantages LDL cholesterol  Weight gain Edema Heart failure (CI with stages III and IV) Bone fractures Increased cardiovascular events (mixed evidence) FDA warnings on cardiovascular safety ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.

13. Α lpha – glycosidase inhibitors : Block enzymes that help digest starches  slowing the rise in BS.  AGI’s - Precose ® (acarbose), - Glyset ® (miglitol)

15. Pharmacology – Alpha-Glucosidase Inhibiters Compound Acarbose Miglitol Mechanism Inhibits intestinal α -glucosidase Action(s)Intestinal carbohydrate digestion and absorption slowed Advantages Nonsystemic medication Postprandial glucose  Disadvantages Gastrointestinal side effects (gas, flatulence, diarrhea) Dosing frequency ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.

16. Meglitinides : Stimulate more insulin production ; dependant upon level of glucose present  Meglitinides - Prandin ® (repaglinide) - Starlix ® (nateglinide)

17. Meglitinides  Examples: repaglinide, nataglinide  It is a benzoic acid derivative and a short-acting insulin releaser.  It stimulates the release of insulin from the pancreatic beta cells by closing ATP-sensitive potassium channels.  It has no significant effect on plasma lipid levels  Rapid onset and short duration of action make multiple daily doses necessary (take it immediately before each meal!).

18. Pharmacology – Meglitinides Compound Repaglinide (Prandin®) Nateglinide (Starlix®) Mechanism Closes K ATP channels on β -cell plasma membranes Action(s) Insulin secretion  AdvantagesAccentuated effects around meal ingestion Disadvantages Hypoglycemia, weight gain Dosing frequency ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.

19. Diabetes – Oral Medications Summary 5 Classes :  Sulfonylureas stimulate β cells  Biguanides improves insulin’s ability to move glucose  Thiazolidinediones cells more sensitive to insulin  Alpha-glycosidase inhibitors Block enzymes that help digest starches  Meglitinides stimulate β cells (dependant upon glucose conc.)

20. Pharmacology – Bile Acid Sequestrants CompoundColesevelam (Welchol®) MechanismBinds bile acids/cholesterol Action(s)Bile acids stimulate receptor on liver to produce glucose Results Lowers fasting and post prandial glucose Advantages No hypoglycemia LDL cholesterol  Disadvantages Constipation Triglycerides  May interfere with absorption of other medications ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University.

21. Drug Pearls MedicationPROCON MetforminLow cost, A1c lowering, + CV effects, weight loss, PCOS Renal or hepatic impairment SulfonylureaLow cost, A1c loweringHypoglycemia, treatment failure MeglitinidesErratic meals, renal insufficiency Hypoglycemia, treatment failure PioglitazoneInsulin resistance, decrease in adipose tissue, TG reduction Edema, wt gain, CI with HF class III and IV α -glucosidase inhibitors Patients with constipationLong duration of T2DM, patients with GI problems DPP-4Well tolerated? long term safety

22. Typical A1c Reductions MonotherapyRoute of AdministrationA1c (%) Reduction SulfonylureaPO1.5-2.0 MetforminPO1.5 GlitazonesPO1.0-1.5 MeglitinidesPO0.5-2.0 α -glucosidase inhibitors PO0.5-1.0 DPP-4PO0.5-0.7 InsulinInjectableOpen to target Unger J et al. Postgrad Med 2010; 122: 145-57

23. Fasting vs. Postprandial Effect Mostly targets FASTING hyperglycemia Mostly targets POSPRANDIAL hyperglycemia Insulin (long and intermediate action) Insulin (regular, rapid-action) Colesevelam α -glucosidase inhibitors MetforminMeglitinides Pramlinitide DPP-4 inhibitors GLP-1 agonist

24. PHARMACOLOGIC MANAGEMENT  The stepwise approach described in the 1998 CDA Clinical Practice Guidelines implied that it was acceptable to wait for up to 8 to 16 months before implementing aggressive therapy to treat hyperglycemia.

25.  It is now recommended that the management regimens of patients with type 2 diabetes be tailored to the individual patient, aiming for glycemic targets as close to normal as possible and, in most people, as early as possible.

26.  Multiple therapies may be required to achieve optimal glycemic control in type 2 diabetes.  The choice of antihyperglycemic agent(s) should be based on the individual patient.  Target A1C should be attainable within 6 to 12 months.

27. Type 2 Diabetes Recommendations  Metformin + lifestyle changes at diagnosis providing no contraindication –Medications are ALWAYS to be used in combination with healthy meal planning and regular physical activity (150 minutes per week )  If marked elevation of A1c /blood glucose and/or symptomatic consider insulin (+ or – other agents) from the onset  If noninsulin monotherapy at maximal tolerated dose does not achieve /maintain the A1c goal over 3 – 6 months, add a second oral agent, a GLP-1 receptor agonist, or insulin ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S21

28. Considerations When Selecting Therapy  How long has the patient had diabetes (duration of disease – preservation of β-cell function)?  Which blood glucose level is not at target (fasting, postprandial, or both)?  The degree of A1c lowering effect required to achieve goal?  Side effect profile and the patients tolerability?  Co – existing conditions ( CVD, osteoporosis, obesity, etc)?  Patient preference for route of administration (oral, injection)?