1. Diabetes Medications: An Overview Eric L. Johnson, M.D. Assistant Professor Department of Community and Family Medicine University of North Dakota School of Medicine and Health Sciences Assistant Medical Director Altru Diabetes Center Altru Health System Grand Forks, ND

2. Objectives Assess knowledge of usual diabetes medications Implement proper medication use per guideline management Improve knowledge of side effects and contraindications of diabetes medications

3. Diabetes Mellitus Type 1: Usually younger, insulin at diagnosis Type 2: Usually older, often oral agents at diagnosis Type “1.5” (Latent Autoimmune), mixed features Gestational: Diabetes of Pregnancy

4. U.S. Prevalence of Diabetes 2010 Diagnosed: 26 million people—8.3% of population (90%+ have Type 2) Undiagnosed: 7 million people 79 million people have pre-diabetes CDC 2011

5. Diabetes Diagnosis Category FPG (mg/dL) 2h 75gOGTT A1C Normal <100 <140 <5.7 Prediabetes 100-125 140-199 5.7-6.4 Diabetes >126** >200 >6.5 Or patients with classic hyperglycemic symptoms with plasma glucose >200 ** On 2 separate occasions Diabetes Care 34:Supplement 1, 2011

6. *IFG=impaired fasting glucose. Copyright ® 2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission. Natural History of Type 2 Diabetes Years of Diabetes Glucose (mg/dL) 50 – 100 – 150 – 200 – 250 – 300 – 350 – 0 – 50 – 100 – 150 – 200 – 250 – -10-5051015202530 Relative Function (%) Fasting Glucose Postmeal Glucose ObesityIFG*Diabetes Uncontrolled Hyperglycemia Insulin Resistance  -cell Function  -Cell Failure

7. The Ominous Octet Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect

8. Targets for glycemic (blood sugar) control in most non-pregnant adults ADAAACE A1c (%) <7*≤6.5 Fasting (preprandial) plasma glucose 70-130 mg/dL<110 mg/dL Postprandial (after meal) plasma glucose <180 mg/dL<140 mg/dL American Diabetes Association. Diabetes Care. 2010;33(suppl 1) Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement at http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed January 6, 2006. AACE Diabetes Guidelines – 2002 Update. Endocr Pract. 2002;8(suppl 1):40-82. *<6 for certain individuals Goals of Glucose Management

9. A1C ~ “Average Glucose” American Diabetes Association A1C eAG % mg/dL mmol/L 61267.0 6.51407.8 71548.6 7.51699.4 818310.1 8.519710.9 921211.8 9.522612.6 1024013.4 Formula: 28.7 x A1C - 46.7 - eAG

10. Diabetes Medications

11. Many new medications in last decade Three main categories –Oral agents (pills)- many different kinds old and new –Insulin- newer, more modern insulins –Newer, non-insulin injectable medications Choices allow individualization of treatment plan Different medications, different indications, different situations

12. Glucose-lowering Potential of Diabetes Therapies* Treatment FPG  HbA1C  Sulfonylureas50-60 mg/dl1-2% Metformin50-60 mg/dl1-2%  -Glucosidase Inhibitors (Precose) 15-30 mg/dl0.5-1% Repaglinade (Prandin)60mg/dl1.7% Thiazolidinediones40-60 mg/dl1-2% Gliptins (Januvia,Onglyza)targets ppd0.5 - 0.8% *based on package insert data as monotherapy

13. Glucose-lowering Potential of Injection Diabetes Therapies* Treatment FPG  HbA1C  Exenatide (Byetta) targets ppd1-1.5% Liraglutide (Victoza) targets ppd 1-1.5% Pramlintide (Symlin) targets ppd1-2% InsulinLimited by1.5-3.5% hypoglycemia *based on package insert data as monotherapy

14. ADA/EASD consensus algorithm to manage type 2 MET: metformin; SU: sulfonylurea. Nathan et al. Diabetes Care 2009;32(1): 193-203 a SU other than glyburide or chlorpropamide. b Insufficient clinical use to be confident regarding safety. No No hypoglycemia Weight loss Nausea/vomiting Lifestyle and MET + intensive insulin Lifestyle and MET + basal insulin Lifestyle and MET+ SU a At diagnosis: Lifestyle + MET Step 1Step 2Step 3 Lifestyle and MET + pioglitazone NoNo hypgglycemia edema/CHF Bone loss Lifestyle and MET + GLP-1 agonist b Lifestyle and MET + pioglitazone + SU a Lifestyle and MET + basal insulin Tier 2: Less well-validated studies Tier 1: Well-validated core therapies Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%.

16. Key Points of Medication Selection in Type 2 Metformin at diagnosis unless a contraindication Second line agents- basal insulin or many other meds

17. Oral Diabetes Medications

18. Sulfonylureas Oldest oral medications Stimulate pancreas to secret more insulin Effective, inexpensive Glyburide, Glipizide, Glimiperide

19. Caveats with Sulfonylureas Hypoglycemia (particularly in elderly) Premature B-cell exhaustion? Caution in liver disease, renal disease Weight gain Rash Avoid if anaphylactic to sulfa

20. Metformin Improves insulin resistance Reduced Hepatic Glucose production Effective, inexpensive Extremely low incidence of hypoglycemia Weight neutral or weight loss Positive effects on lipid profiles Long term use may result in better CVD outcomes Can be combined with virtually all other DM meds

21. Caveats with Metformin Liver Disease Renal Disease GI upset Heavy Alcohol Use Intravascular Dye Studies (IVP, Angio,etc) CHF Not for persons over 80 Can result in B12 deficiency

22. Thiazolidinediones (TZD’s) Pioglitazone (Actos) Rosiglitazone (Avandia) Improves insulin resistance Extremely low incidence of hypoglycemia

23. Caveats with TZD’s CHF (or if hx/risk?) Patients already dealing with edema Potential weight gain Renal disease-fluid overload Current TZD’s rare liver disease, not recommended in active liver disease Heart disease risk? (Rosiglitazone-new restrictions)

24. Gliptins(DPP-IV) DPP-IV inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza) Oral agents Weight neutral or weight loss Can use with Metformin, Sulfonylurea, TZD, or insulin (sitagliptin)

25. Gliptins’ Caveats, Benefits Caveats: Hypoglycemia if used with sulfonyurea or insulin Nausea, rash Benefits: Few drug interactions; can be renally dosed

26. “Niche” Drugs Colesevelam (Welchol) - adjunct to lower A1c and LDL - limited efficacy, cost Repaglinide (Prandin), Nateglinide (Starlix) - may replace SU if sulfa allergy - Prandin may be useful in CKD Acarbose (Precose), Miglitol (Glyset) - limited efficacy, GI intolerance, cost Bromocriptine (Cycloset) - limited efficacy? Will be marketed Salsalate -older NSAID, may lower blood sugar, no indication yet

27. Non-Insulin Injectable Medications

28. Glucagon-like Peptide-1 (GLP-1) Gut hormone Stimulates pancreas to secret insulin Suppresses glucagon action Many target organs Weight regulation Caution in renal or hepatic impairment

29. GLP-1 Exenatide (Byetta) GLP-1 mimetic Liraglutide (Victoza) GLP-1 analog Both available in pen injectors (easy) Modest weight loss Combined with other agents except DPP-IV inhibitors or insulin (exenatide has basal insulin data)

30. GLP-1 Caveats Nausea, vomiting Pancreatitis Medullary thyroid carcinoma in rodents (liraglutide) Hypoglycemia combined with sulfonyurea

31. Pramlintide-Synthetic Amylin (Symlin) Amylin secreted by normal pancreas along with insulin to regulate blood glucose Enhances Postprandial control. Used in Type 1 and Type 2 patients Used as adjunct to insulin Available in pen injector Possible significant hypoglycemia

32. Combination Drug Therapy Consider early if failing monotherapy Generally additive or synergistic effects Triple or quadruple non-insulin drug therapy -limited benefit in many -safe for many Insulin is often a better,more potent choice

33. Insulin Therapies

34. Insulin Therapy All Type 1 patients at diagnosis All type 2 patients will require insulin if they live long enough -7 to 10 years post diagnosis -A1C >9% -Function of many non-insulin meds based on presence of native insulin

35. Beta-cell function declines as diabetes progresses Beta-cell function (%) Beta-cell decline exceeds 50% by time of diagnosis 4­4­4­12­8­80812 0 50 100 75 25 Type 2 Diabetes IGT Years from diagnosis Postprandial Hyperglycemia Diagnosis Insulin initiation Beta-cell function decline over time Lebovitz H. Diabetes Rev 1999;7:139-153.

36. Insulin Therapy Modern insulins safer and more predictable Most insulin types come in pen injectors Pen injectors easy to use, to teach, less cumbersome than vials/syringes

37. Rapid Acting Insulin Aspart (Novolog) Lispro (Humalog) Glulisine (Apidra) (Human Regular) Taken with meals and snacks “Bolus” insulin

38. Long-Acting Insulin Detemir (Levemir) Glargine (Lantus) Human NPH (N) Taken 1 or 2 times daily “Basal” insulin

39. Insulin Time Action Curves 0 20 40 60 80 100 120 140 0246810121416 Insulin Effect Hours 1820 Intermediate (NPH) Long (Detemir,Glargine) Short (Regular) Rapid (Lispro,Glulisine, Aspart) adapted from R. Bergenstal, IDC

40. Basal Insulin in Type 2 Diabetes Glargine (Lantus), Detemir (Levemir) Good, potent add-on for improved A1C Second line agent for many patients A1C >9, diabetes longer than 5 to 7 years AACE: ? Weight benefit with Detemir Pen injectors easy

41. Basal Insulin in Type 2 Diabetes Some oral meds may be continued -metformin, maybe TZD, maybe SU, maybe gliptin (sitagliptin) Glargine (Lantus) or Detemir (Levemir) started at 10 units at HS Increase 3 units every 3 to 5 days until fasting blood sugars <110 (or <140) Most type 2 on 50-80+ units/day

42. Adding Bolus Insulin in Type 2 Diabetes Lispro (Humalog) Aspart (Novolog) Glulisine (Apidra) Pen injectors Why is bolus insulin important in Type 2?

43. Fasting and Postprandial Glycemic Excursions as a Function of A1C Monnier L et al. Diabetes Care. 2003;26:881-885. 0 20 60 80 2 (7.3–8.4) 3 (8.5–9.2) 4 (9.3–10.2) 5 (>10.2) 1 (<7.3) 40 Contribution (%) A1C (%) Quintiles Postprandial hyperglycemia Fasting hyperglycemia

44. Adding Bolus Insulin in Type 2 Diabetes 1 injection basal/1 injection bolus good 2 injection program- better than split basal 90/10 rule (90% basal, 10% bolus) Start with largest meal of the day Add other meal doses later Usually stop TZD, always stop SU Easy with pens

45. Premix Insulins 70/30, 75/25, 50/50 Combine R or rapid acting with NPH or an “NPH-like” component Certain applications may be appropriate Limitation: change 2 insulins at once

46. Case Studies

47. Case #1 42 y/o Hispanic female with hx of GDM 6 years ago, term 10 lb 5 oz male infant Not seen for follow-up in 3 years FBS done at annual pap/px is 149 Does this patient have type 2 diabetes? What next?

48. Case #1 Diagnosis of diabetes generally requires two abnormal values Patient at high risk for type 2 GDM is a pre-diabetes condition Repeat FBS three days later…….

49. Case #1 Repeat FBS 135 Dx: type 2 diabetes (FBS >126 on two separate occasions) What should be done next for this patient?

50. Case #1 Patient had tubal ligation after last delivery Start metformin 500mg BID, advance to 850-1000 mg BID Most newly-diagnosed patients should start metformin (current ADA recommendation)

51. Case #1 Diabetes Educator and Dietician SBGM with appropriate targets Check fasting lipids, monitor Blood Pressure

52. Case Study#2 54 y/o white male Diagnosed with type 2 diabetes after 2 fasting blood sugars of 154 and 142 Also has high blood pressure and cholesterol disease (common in type 2)

53. Case Study #2 Metformin 500 mg prescribed twice daily, titrated to 1000mg BID ASA 81 mg daily Referred to Diabetes Educator and Dietician for meal planning Recommend developing graduated exercise plan (exercise prescription) Six months after diagnosis, A1C = 6.8% (target <7%)

54. Case Study #2 Three years later, patient’s A1C has risen to 8.4% (target <7%) Blood pressure and cholesterol effectively treated Now what?

55. Case Study #2 Choices include –Adding a basal insulin once daily –Adding any other oral agent –Adding exenatide twice daily or liraglutide once daily Any of these are good choices Choice may be made on individual factors

56. Case Study #2 Patient chose additional oral agent (sitagliptin), but others would be OK A1C:  6 months later = 7.4% (target <7%)  3 years later = 8.1% (target <7%) Now what?

57. Case Study #2 Sitgliptin, metformin continued Basal insulin started with titration Eventually added bolus insulin with largest meal (90/10 rule) Likely will add bolus with other meals over time

58. Medication Combinations Sulfonylureas: Virtually any in type 2 Metformin: Virtually any in type 2 TZD: Virtually any in type 2 Gliptins: metformin, TZD, insulin (sitagliptin) Insulin: metformin, TZD, sulfonylurea, amylin, sitagliptin Amylin: only in insulin regimens Exenatide/Liraglutide: metformin, sulfonyureas, TZD

59. Medication Indications Type 1 Diabetes: Insulin, amylin (amylin only in combination with insulin) Type 2 Diabetes: All oral agents, exenatide, liraglutide, amylin, insulin (amylin only in combination with insulin) Prediabetes: none (yet), case by case, i.e., PCOS

60. Summary Diabetes is common Understand Medications and Indications Type 1 diabetes: Insulin regimen (pumps) Type 2 diabetes: Lots of choices, but nearly all will need insulin eventually

61. Acknowledgements North Dakota Department of Health, Karalee Harper Centers for Disease Control Office of Continuing Medical Education, UNDSMHS, Mary Johnson Department of Family and Community Medicine, UNDSMHS, Melissa Gardner Brandon Thorvilson, UNDSMHS IT Disclosure: Novo Nordisk Speaker’s Bureau

62. Contact Info/Slide Decks/Media e-mail eric.l.johnson@med.und.edu ejohnson@altru.org Phone 701-739-0877 cell Slide Decks (Diabetes, Tobacco, other) http://www.med.und.edu/familymedicine/slidedecks.html http://www.med.und.edu/familymedicine/slidedecks.html iTunes Podcasts (Diabetes) (Free downloads) http://www.med.und.edu/podcasts/ or iTunes>> search UND Medcast (updated soon) http://www.med.und.edu/podcasts/ WebMD Page: (under construction) http://www.webmd.com/eric-l-johnson http://www.webmd.com/eric-l-johnson Diabetes e-columns (archived): http://www.ndhealth.gov/diabetescoalition/DrJohnson/DrJohnson.htm http://www.ndhealth.gov/diabetescoalition/DrJohnson/DrJohnson.htm