1. John Atlee “Jay” Snyder, D.O. Assistant Professor of Internal Medicine East Tennessee State University January 24 th 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. www.cdc.gov/diabetes Age-adjusted percent County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2004

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

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

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

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

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 1/20/2012http://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/

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 1/20/2012http://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 acidosis 1 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 anerobic glycolysis. (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- Aplastic anema, 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 cancer 2 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

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

51. Combination meds Too many to count!!!! If on multiple medicines, see if there is an option. Only Sulfonylureas & Beta cell stimulators (& insulin/amylin) can cause hypoglycemia. However, additional medicines may enhance the hypoglycemia caused by sulfonylureas.

52. Future medicine options Weekly/Depot Byetta shots. More “me too” drugs such as DPP4 meds Vildagliptin & Alogliptin. Bromocriptine mesylate (Cycloset) is a dopamine agonist on the market with unknown mechanism of improved diabetic control. More meds like this soon? Other PPAR agonists. PPAR alpha, beta, or combinations with gamma. (TZD’s only gamma)

53. Future medicine options Dapaglifozin Works as a SGLT2 inhibitor. Works at sodium-glucose cotransporter 2 in kidneys to prevent glucose being reabsorbed & thus to be lost to the urine. Increased incidence of UTI’s Increased incidence of bladder cancer ?Increased incidence of breast cancer PMID: 22262072

54. Even more combination meds Juvisync (Januvia & Simvastatin) approved recently

55. Which medicine do we start?

56. Recent systematic review in the Annals of Internal Medicine “..overall guideline quality was poor with respect to the rigor of the guideline development process, particularly in use of systematic methods to identify evidence. In addition, most guidelines were susceptable to bias because they lacked a description of editorial independence from funders and guideline developers failed to report potential conflicts of interest.” PMID: 22213492

57. Recent systematic review in the Annals of Internal Medicine “11 guidelines met the inclusion criteria. Seven guidelines agreed with the conclusion that metformin is favored as the first-line agent” The American Diabetes Association has also recently clarified its preference for metformin

58. Which medicine to add on? New England Journal of Medicine interactive clinical decisions survey January 2008 Patient on Metformin & Glipizide with fasting morning glucose of 110-140 & HbA1C of 8.1% Adding Pioglitazone, NPH before bedtime or Exanatide twice daily PMID: 18272888

59. Results 6455 votes cast Pioglitazone 1625 votes Exanatide twice daily 1587 votes NPH before bedtime 3243 votes

60. Staying up to date Don’t forget to check the American Diabetes Association’s website in the beginning of every January for updates on recommendations.

61. Question A patient with poorly controlled DM2 comes in the office for a follow-up & yearly physical. The patient notes that if they were placed on insulin, they would no longer be able to work in their current profession & they would be fired…

62. What is your patient’s job? A. Nurse B. Teacher C. Carpenter D. Truck driver E. Chef

63. Answer D. Truck driver

64. Diabetes & driving

65. But wait a minute!! From the “Instructions for the Medical Examiner” section of the Medical Examination Report for Commercial Driver Fitness Determination: “CMV drivers who do not meet the Federal diabetes standard may call (202) 366-1790 for an application for a diabetes exemption” Diabetes Exemption Team (202) 366-4001

66. Insulin & Truckers Timeline 1986: ADA & others petitioned to grant waivers on a case- by-case basis 1993: Waiver program granted for those with safe driving history & endocrinologist/ophthalmologist approval. 1996: Appeals court ruled the program illegal (Advocates for Highway and Auto Safety v Federal Highway Administration) 2003: Federal waiver process established with an exemption for for interstate commerce Now: Most states are adopting similar process to Federal rule for their CDL’s http://www.fmcsa.dot.gov/facts-research/research-technology/tech/TB-02-01-1.htm

67. ADA Guidelines An entire section for Diabetes & Driving “...people with diabetes should be assessed individually, taking into account each individual's medical history as well as the potential related risks associated with driving.” Potential medical-legal ramifications

68. 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

69. Thank You!