Outpatient Management of Diabetes Mellitus Type 2: Oral Medications

1. Outpatient Management of Diabetes Mellitus Type 2:Oral Medications John Atlee “Jay” Snyder, D.O. Assistant Professor of Internal Medicine East Tennessee State University January 24th 2012

2. Today’s Goals • 1. To recognize the importance of knowledge of treatment of diabetics by reviewing the increasing prevalence of type 2 Diabetes • 2. To review the numerous classes of medicines currently used for oral management of Diabetes • 3. To recognize strategies used for treatment of Diabetes • 4. To discuss Diabetes & driving

3. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2004 Age-adjusted percent www.cdc.gov/diabetes

4. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2005 Age-adjusted percent www.cdc.gov/diabetes

5. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2006 Age-adjusted percent www.cdc.gov/diabetes

6. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2007 Age-adjusted percent www.cdc.gov/diabetes

7. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2008 Age-adjusted percent www.cdc.gov/diabetes

8. 2004 Age-Adjusted Estimates of the Percentage of Adults† with Diagnosed Diabetes in Tennessee Centers for Disease Control and Prevention: National Diabetes Surveillance System. Available online at: http://apps.nccd.cdc.gov/DDTSTRS/default.aspx. Retrieved 1/20/2012

9. 2005 Age-Adjusted Estimates of the Percentage of Adults† with Diagnosed Diabetes in Tennessee

10. 2006 Age-Adjusted Estimates of the Percentage of Adults† with Diagnosed Diabetes in Tennessee

11. 2007 Age-Adjusted Estimates of the Percentage of Adults† with Diagnosed Diabetes in Tennessee

12. 2008 Age-Adjusted Estimates of the Percentage of Adults† with Diagnosed Diabetes in Tennessee

13. Who will help us stop this destructive pattern? • The food industry???

17. http://www.foxnews.com/entertainment/2012/01/17/paula-deen-reveals-secret-struggle-with-diabetes-teams-up-with-drug-company/http://www.foxnews.com/entertainment/2012/01/17/paula-deen-reveals-secret-struggle-with-diabetes-teams-up-with-drug-company/

18. Diabetes vs. Obesity 2008 Centers for Disease Control and Prevention: National Diabetes Surveillance System. Available online at: http://apps.nccd.cdc.gov/DDTSTRS/default.aspx. Retrieved 1/20/2012

19. Treating Diabetes

20. First Line Classes • Sulfonylureas • Biguanides

21. Sulfonylureas (Second Generation) • Glipizide (Glucatrol, Glucatrol XL) • Glimepiride (Amaryl) • Glyburide (Diabeta, Micronase) • -ionized Glyburide (Glynase) also available • -ionized doses ≠ to regular Glyburide

22. Yes Virginia, there is a First generation Sulfonylurea Rarely used • Chlorpropamide (Diabinese) • Tolazamide • Tolbutamide

23. Preference for a specific Sulfonylurea? • Second generation? • Glipizide because of short half-life? • Glimeperide because of a study showing less hypoglycemia in the elderly?1 PMID: 19952550/PMID: 8675920

24. Biguanides • Metformin (Glucophage) • Metformin ER (Fortamet/Glumetza/Glucophage XR) • Riomet -liquid cherry flavored Metformin

25. Are there different “generations” of Biguanides? • Originally introduced in the 1950’s, the first biguanides (Phenformin) had a very high frequency of lactic acidosis & were removed from the market. • Some critics will argue there is not enough evidence of lactic acidosis1 • Metformin has a much lower incidence of lactic acidosis but still enough to warrant a Black Box warning. (9 cases per 100000 person years)2 1. PMID 20393934. 2. PMID:10372243

26. Are there other first line meds? • Sitagliptin (Januvia) is a DPP4 previously used as an adjunct that has now been approved as a monotherapy. • Insulin. Very poor control/renal failure/etc but that’s a “whole ‘nother presentation.”

27. So which medicine have we started in the past?? • Sulfonylurea or Metformin?

28. Cardiac concerns? • Old study (1970) with first generation sulfonylurea Tolbutamide showed increased cardiovascular mortality.1 • Some belief that this still persists with all sulfonylureas including second generation.2 1. PMID: 992232. 2. PMID :22250169

29. Are they Overweight/Obese? • Sulfonylureas increase insulin release from the pancreas & thus can cause weight gain

30. Are they Overweight/Obese? • Metformin helps with weight loss by: • -reduction of GI absorption of glucose. • -stimulation of anerobicglycolysis. (lactic acid) • -inhibition of gluconeogenesis. • -stimulation of glucose uptake in the liver. • -increasing insulin receptors.

31. Dosing=Start low & go slow. • Start Sulfonylureas at lower doses & increase slowly due to concern of hypoglycemia. • Start Metformin at lower doses & increase slowly due to concern of GI side effects. May even start with PM or HS dosing, then increasing to BID. (To sleep through the bloating sensation) Also consider the extended release formula. • Max dose Sulfonylurea varies medicine to medicine • Max daily dose Metformin… 2550mg/day

32. Renal failure? • Metformin contraindicated due to concerns of lactic acidosis. • Metformin should be held in anticipation of procedures when IVP dye is used. • Sulfonylureas are excreted by the kidneys & may build up in the bloodstream, thus causing hypoglycemia.

33. Rare adverse anemias • Metformin- Megaloblastic anemia • Sulfonylureas- Aplasticanema, hemolytic anemia & pancytopenia

34. Cost • Most first line options on $4/month $10/3month lists or even free depending on the pharmacy.

35. Example: Walmart $4 List • Diabetes • Chlorpropamide 100mg tab* . . . . . . . . . . . . . . 30 . . . . . 90 • Glimepiride 1mg tab . . . . . . . . . . . . . . 30 . . . . . 90 • Glimepiride 2mg tab . . . . . . . . . . . . . . 30 . . . . . 90 • Glimepiride 4mg tab . . . . . . . . . . . . . . 30 . . . . . 90 • Glipizide 5mg tab . . . . . . . . . . . . . . . . 30 . . . . . 90 • Glipizide 10mg tab* . . . . . . . . . . . . . . . 60 . . . . . 180 • Glyburide 2.5mg tab . . . . . . . . . . . . . . . . . . . . 30 . . . . . 90 • Glyburide 5mg tab (blue) . . . . . . . . . . . .30 . . . . . 90 • Glyburide 5mg tab (green) . . . . . . . . . . . 30 . . . . . 90 • Glyburide, micronized 3mg tab . . . . . . . . . . . . 30 . . . . . 90 • Glyburide, micronized 6mg tab . . . . . . . . . . .. 30 . . . . . 90 • Metformin 500mg tab . . . . . . . . . . . . . . . . . . . . 60 . . . . . 180 • Metformin 850mg tab . . . . . . . . . . . . . . . . . . . . 60 . . . . . 180 • Metformin 1000mg tab* . . . . . . . . . . . . . 60 . . . . . 180 • Metformin 500mg ER tab* . . . . . . . . . . . 60 . . . . . 180 • *Prices may be higher in CA, HI, MN, MT, PA, TN and WI.

36. Example: Target $4 List • Diabetes • CHLORPROPAMIDE 100 MG* - Tablet 30 90 • GLIMEPIRIDE 1 MG - Tablet 30 90 • GLIMEPIRIDE 2 MG - Tablet 30 90 • GLIMEPIRIDE 4 MG - Tablet 30 90 • GLIPIZIDE 5 MG - Tablet 30 90 • GLIPIZIDE 10 MG* - Tablet 60 180 • GLYBURIDE 2.5 MG - Tablet 30 90 • GLYBURIDE 5 MG - Tablet 30 90 • GLYBURIDE MICRO 3 MG - Tablet 30 90 • GLYBURIDE MICRO 6 MG - Tablet 30 90 • METFORMIN 500 MG - Tablet 60 180 • METFORMIN 850 MG - Tablet 60 180 • METFORMIN 1000 MG* - Tablet 60 180 • METFORMIN ER 500 MG* - Tablet 60 180

37. More on strategy later…

38. Second-line/Add on Therapy • Alpha-glucosidase inhibitors • Beta cell stimulators • TZD’s • GLP-1’s • DPP4’s • Others

40. Alpha-glucosidase inhibitors • Acarbose (Precose) • Miglitol (Glyset) • Prolong digestion of carbohydrates & reduce peak glucose levels by blocking oligosaccharide binding to the brush border. • Taken with first bite of the meal & has additive effects when combined with sulfonylurea. • Side effects: -GI related. Worse with Acarbose (including elevated LFT’s & ileus)

41. Oral Beta cell stimulators • Repaglinide (Prandin) technically a Meglitinide • Nateglinide (Starlix) technically amino acid derivative • Action similar to sulonylureas, working in a glucose dependent fashion but still with the risk of hypoglycemia. • Have a very short half-life & must be taken with meals. • Some consideration as first line therapy in renal failure • Side effects: - URI symptoms & GI side effects. Rare cardiac ischemia with Prandin & rare accidental injury with Starlix

42. Thiazolidinediones (TZD’s/Glitazones) • Pioglitazone (Actos) • Rosiglitazone (Avandia) • Very good for additional control. • Agonists of PPAR–gamma. • Work at the tissue level to increase insulin sensitivity. • Side effects: -may cause or worsen heart failure -rare hepatotoxicity -fractures (in women only)1 -Bladder cancer2 1. PMID: 17363747. 2. PMID: 21515844.

44. Incretin Mimetics (GLP-1’s) • Exanatide (Byetta) • Liraglutide (Victoza) • Lixisenatide (Lyxumia) soon to be released • Works as a glucogon-like peptide (GLP-1) to increase glucose dependent insulin secretion, decrease excessive glucagon secretion, slow gastric emptying & decrease appetite. • $$$ & bid injections. If willing to do injections why not just do insulin?? • Side effects: -Suppresses appetite -Associated with pancreatitis -Rarely associated with acute renal failure -Injection site concerns?

45. Dipeptidyl peptidase-4 inhibitors(DPP4’s) • Sitagliptin (Januvia) • Saxagliptin (Onglyza) • Linagliptin (Tradjenta) recently released • By blocking DPP4, incretins including GLP-1 are increased & effect is similar to incretin mimetics. • Side effects: -URI symptoms -pancreatitis

46. Cancers with GLP-1’s/DPP4’s • With known risk for pancreatitis in Exanatide & Sitagliptin, a review also found an increased risk for pancreatic cancer with these medicines • Also thyroid cancer in Exanatide PMID: 213343333

47. PMID: 213343333

48. Bile acid sequestrants • Colesevelam (Welchol) • Cholesterol medicine shown to improve glucose control/lower A1C. • Side effects: • -GI (including obstructions starting at the esophagus & ending with fecal impaction) • -Oral blisters/severe rash

49. Amylin analogues • Pramlintide (Symlin) • Increased risk of hypoglycemia (especially with insulin)

50. The elephant in the room… • INSULIN