1. Current Management of Type 1 and Type 2 Diabetes Thomas Donner, M.D. Division of Endocrinology & Metabolism

2. Objectives After attending this session, the participant should be able to: Describe the pathogenesis of type 1 and type 2 diabetes Recognize glucose, lipid and blood pressure targets for patients with diabetes Understand the actions of insulins, and other injectable and oral anti-hyperglycemic agents

3. Disclosures I have no relevant disclosures

4. Diabetes 8% of the US population affected In the US, the leading cause of: –Adult blindness –End stage renal failure –Non-traumatic amputations A leading cause of heart attacks and strokes –Risk 2-fold in men and 4-fold in women with DM These complications are largely preventable –Aggressive control of glucose, lipids and BP

5. Pathogenesis of Type 1 Diabetes About 5% of all diabetes Autoimmune destruction of pancreatic islet cells Lifelong requirement of insulin to stay out of ketoacidosis Genetic and environmental causes –If an identical twin has type 1 diabetes the other twin has a 50% chance of developing the disease

6. Pathogenesis of Type 2 Diabetes Strongly correlated with obesity, especially visceral fat Hormones and cytokines released from fat cells contribute to both insulin resistance and defective insulin secretion –Insulin resistance Decreased uptake of glucose in muscle, fat and liver Excessive hepatic glucose output Worsened by physical inactivity –Insulin deficiency Loss of beta cells appears due to fatty infiltration of the pancreas among other causes If an identical twin has type 2 diabetes the other twin has nearly a 100% chance of developing the disease

7. Complications DCCT 1,2 Kumamoto 3 UKPDS 4,5 of A1C 9% 7% 9% 7% 7.9% 7% Retinopathy63%69%17%-21% Nephropathy54%70%24%-33% Neuropathy60%–– Macrovascular disease 57%*–15%-33% Good Glycemic Control Reduces the Incidence of Complications *After 17 years of follow-up 1 DCCT Research Group. N Engl J Med. 1993;329:977; 2 DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653 3 Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103; 4 UKPDS Group. Lancet. 1998;352:837; Horman R et al. N Engl J Med. 2008;359:1577-1589

8. Complications DCCT 1,2 Kumamoto 3 UKPDS 4,5 of A1C 9% 7% 9% 7% 7.9% 7% Retinopathy63%69%17%-21% Nephropathy54%70%24%-33% Neuropathy60%–– Macrovascular disease 57%–15%-33%* Good Glycemic Control Reduces the Incidence of Complications *Sulfonylurea/Insulin – metformin, after 20 years of follow up 1 DCCT Research Group. N Engl J Med. 1993;329:977; 2 DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653 3 Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103; 4 UKPDS Group. Lancet. 1998;352:837; Horman R et al. N Engl J Med. 2008;359:1577-1589

9. Adapted with permission from Skyler J. Endocrinol Metab Clin North Am. 1996;25:243 DCCT Research Group. N Engl J Med. 1993;329:977 Relative Risk Retinopathy Nephropathy Neuropathy Microalbuminuria A1C (%) 15 13 11 9 7 5 3 1 6789101112 A1C and Relative Risk of Microvascular Complications: DCCT

10. Goals for Glycemic Control Biochemical Index Normal Goal fasting/preprandial <100 <130 blood glucose (mg/dl) postprandial <140 <180 bedtime <100 100-140 HbA1c (%) <5.7 <7* American Diabetes Association: Clinical practice Recommendations 2014 * More stringent goals (<6%) can be considered in individual patients, and less stringent goals in older patients, those with advanced complications, or with recurrent hypoglycemia

11. Diabetes Prevention Program: Treatment Protocol Overweight patients with impaired glucose tolerance Metformin –850 mg QD for 1 month –850 mg BID after 1 month Lifestyle Intervention –Moderate exercise for at least 150 minutes/week –Weight loss of > 7% –16 lesson curriculum taught on one-to-one basis Placebo Follow-up –Average 2.8 years (range 1.8-4.6) Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403

13. Treatment of Type 2 Diabetes

14. Meal Planning Decrease fat content and total calories –weight reduction in obese patients –decrease saturated fat –increase fiber induces satiety, lowers postprandial glucose Reduce foods high in simple sugars to reduce postprandial hyperglycemia For patients on prandial insulin –try to keep carbohydrate calories constant for the same meal if on set insulin dosages or: –adjust pre-meal insulin for alterations in carbohydrate calories (insulin:carb ratios)

15. Benefits of Exercise Decreases insulin resistance which lowers blood glucose Improves weight, blood pressure, LDL and HDL cholesterol May increase risk of hypoglycemia in patients on insulin or insulin secretogogues Patients at risk should be pre-screened for coronary artery disease

16. Benefits of Modest Weight loss  Glucose and insulin levels  Blood pressure  LDL and triglycerides, increase HDL  CRP and IL-6  Cardiovascular risk  Severity of sleep apnea

17. Oral Pharmacologic therapy Monotherapy –Insulin secretogogues: sulfonylureas, nateglinide and repaglinide –Biguanides: metformin –Alpha-glucosidase inhibitors –Thiazolidinediones –DPP-4 inhibitors –SGLT-2 inhibitors Combination therapy

18. ↓ GLUCOSE PRODUCTION Insulin Metformin DPP-4 inhibitors (Thiazolidinediones) MUSCLE ↑ PERIPHERAL GLUCOSE UPTAKE Insulin Thiazolidinediones (Metformin) Sites of Action of Antihyperglycemic Agents PANCREAS ↑ INSULIN SECRETION Sulfonylureas Meglitinides Nateglinide DDP-4 inhibitors ADIPOSE TISSUE LIVER SLOW GLUCOSE ABSORPTION Alpha-glucosidase inhibitors Modified from: Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5 INTESTINE

19. RENAL TUBULES SGLT-2 Inhibitors MUSCLE Sites of Action of Antihyperglycemic Agents PANCREAS ADIPOSE TISSUE LIVER Modified from: Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5 INTESTINE ↑ INSULIN SECRETION Sulfonylureas Meglitinides Nateglinide DDP-4 inhibitors ↑ PERIPHERAL GLUCOSE UPTAKE Insulin Thiazolidinediones (Metformin) GLUCOSE PRODUCTION Insulin Metformin DPP-4 inhibitors (Thiazolidinediones) SLOW GLUCOSE ABSORPTION Alpha-glucosidase inhibitors

20. Relative HbA 1c -Lowering Efficacy of Established Oral Diabetes Medications AgentNo. Studie s No. Patients Studied HbA 1c Reduction Range (%) Median (%) Metformin92,8760.8-3.01.3 Sulfonylureas75,6830.9-2.51.8 Meglitinides62,4560.4-1.91.0-1.1 TZD’s72,6630.9-2.91.3-1.4 DPP-4 inhibitors611,2670.4-1.20.6-0.7  -Glucosidase inhibitors 163,2300.6-1.30.7-0.8 SGLT-2 inhibitors 134,0630.5-0.70.5-0.6 Kendall DM, et al. Diabetes Care. 2005;28:1083-1091. Richter B, et al. Vasc Health Risk Manag. 2008;4: 753–768. Musso G, et al. Ann Med. 2012 Jun;44(4):375-93 Kimmel B, Inzucchi SE. Clin Diabetes. 2005;23:64-76. DeFronzo R, et al. Presented at: ADA 2004 Scien Sess. Buse JB, et al. Diabetes Care. 2004;27:2628-2635.

21. Sulfonylureas: Available agents First Generation –Tolbutamide –Chlorpropamide –Tolazamide Second Generation –Glyburide –Glipizide –Glimepiride

22. Sulfonylureas Inexpensive Risk for significant hypoglycemia is 1-3%/year –glyburide carries the highest risk Small weight gain Long-term failure with monotherapy is a common problem

23. Nateglinide and Repaglinide Shorter-acting insulin secretogogues Given just before meals Lesser risk of hypoglycemia with prolonged fasting

24. Metformin Often leads to a modest weight loss Lowers total and LDL cholesterol, and triglycerides Lowers clotting factors: plasminogen activating inhibitor-1 (PAI-1), fibrinogen Reduced risk of myocardial infarction, stroke and diabetes-related deaths in overweight patients more than sulfonylureas or insulin in the UKPDS

25. Metformin and Cancer Mortality Cancer mortality is increased in those with diabetes (HR 1.09) Metformin reduces the risk of colon and pancreas cancer Mortality is increased relative to nondiabetes in those on monotherapy with sulfonylureas (HR 1.13) or insulin (HR 1.13) but reduced in those on metformin monotherapy (HR 0.85) Metformin carries a 0.75 HR for breast cancer c/w other diabetes medications Currie et. al. Diabetes Care. 2012;35(2):299-304. Chlebowski RT at al. J Clin Oncol. 2012

26. Metformin GI side effects most common –Diarrhea is most common but typically mild to moderate and self-limited –Nausea, vomiting, bloating, flatulence and anorexia are less common –Minimize by slow titration, dosing with meals, extended release formulation Lactic acidosis –Very rare complication –Typically occurs in at risk patients in whom it should be avoided: Kidney failure (decreased drug clearance) Liver failure (decreased lactate clearance) Other conditions associated with lactic acidosis

27.  -Glucosidase Inhibitors: Acarbose and Miglitol Slow carbohydrate digestion Lower postprandial glucose GI side effects –Flatulence and diarrhea are common –Nausea and vomiting uncommon –Start with low dosages (25 mg with meals) and titrate up slowly to max dose of 100 mg with meals –Acarbose in combination with a sulfonyurea or insulin may lead to hypoglycemia; if hypoglycemia occurs, treat with glucose PO or IV, not sucrose, the digestion of which is blocked by these agents

28. Thiazolidinediones: Pioglitazone (Actos) and Rosiglitazone (Avandia) Effective as monotherapy, or in combination with all other oral agents Do not cause hypoglycemia when used as monotherapy Increase HDL Change dense LDL cholesterol into a less atherogenic “fluffy” LDL particle

29. Thiazolidinediones Cardiovascular effects appear to be agent-specific –Pioglitazone has more favorable lipid effects –Long-term treatment with pioglitazone has been shown to reduce cardiovascular events –Studies of rosiglitazone show either no CV benefit or an small increased risk of myocardial infarction Adverse effects –Weight gain –Peripheral edema –CHF exacerbation in those with more advanced heart failure –Increased osteoporotic fractures in post-menopausal women –Bladder cancer

30. Glucagon-like Peptide-1 (GLP-1) Actions Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169 Stomach: Helps regulate gastric emptying Promotes satiety and reduces appetite Liver:  Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Alpha cells:  Postprandial glucagon secretion GLP-1: Secreted upon the ingestion of food - diminished in type 2 diabetes

31. Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131. GLP-1 Secretion and Inactivation GLP-1 inactive (>80% of pool) Active GLP-1 Meal DPP-4 Intestinal GLP-1 release GLP-1 t ½ = 1 to 2 min GLP-1 = glucagon-like peptide–1; DPP-4= dipeptidyl-peptidase–4

32. Intestinal GLP-1 release Mixed Meal Drucker DJ. Diabetes Care. 2003;26:2929-2940. DPP-4 – dipeptidyl peptidase-4 Inhibition of DPP-4 to Increase Active GLP-1 Sitagliptin/Saxagliptin/ Linagliptin: DPP-4 Inhibitors DPP-4 inhibitors - oral DPP-4

33. DPP-4 Inhibitors Very low risk of hypoglycemia due to glucose- dependent insulin secretion Neutral effect on body weight Most agents need to be renally dosed as most are renally cleared

34. GLP-1 Agonists Exenatide (Byetta, Bydureon) and liraglutide (Victoza) Resistant to DPP-IV inactivation –overcome the 1-2 minute half life of GLP-1 Given as subcutaneous injections Mimic the actions of endogenous GLP-1 –Glucose-responsive insulin secretion – no hypoglycemia –Suppress hepatic glucose production –Suppress appetite Weight loss of 4-12 lbs commonly seen

35.  20  10 0102030 Natural History of Type 2 Diabetes Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota. Years of Diabetes Relative  -Cell Function Plasma Glucose Insulin resistance Insulin secretion 126 mg/dL Fasting glucose Postmeal glucose 6-6

36. Insulin Therapy in Type 2 Diabetes Compensates for decreased endogenous insulin Improves B-cell function by reducing glucotoxicity A bedtime intermediate or long-acting insulin may be added to oral agents to suppress nocturnal hepatic glucose production and improve fasting glucose levels Multiple insulin injections may be required with progressive B-cell failure to optimize control

37. Insulin Therapy: Indications in Type 2 Diabetes Very symptomatic: weight loss, polyuria, polydipsia Marked hyperglycemia (glucose >300 mg/dl) Pregnancy Inadequate glycemic control with combination oral agent therapy

38. Intensive Insulin Therapy in Type 1 and Type 2 Diabetes

39. Insulin and Glucose Patterns in Normals and in Type 2 Diabetes Polonsky, et al. N Engl J Med. 1988;318:1231-1239. 100 200 300 400 GlucoseInsulin 0600100018001400020022000600 Time of Day 0600100018001400020022000600 Time of Day 20 40 60 80 100 120 BLSBLS Normal Type 2 Diabetes mg/dL  U/mL 6-17

40. Insulin Pharmacology “Basal” insulins (long-acting glargine, detemir and intermediate-acting NPH ) suppress hepatic glucose production in the post-absorptive state “Bolus” insulins (short-acting regular, ultra short-acting lispro, aspart and glulisine) promote uptake of ingested carbohydrates by peripheral cells

41. Comparison of Human Insulins and Analogs Insulin Onset ofDuration of Preparations Action Peak (h)Action (h) Lispro/Aspart/Glulisine 5-15 min1-2 3-6 Human Regular 30-60 min2-4 6-10 Human NPH1-2 h4-8 10-20 Glargine1-2 h flat ~24 Detemir1-2 hflat18-24 Time course of action of any insulin can vary in different people or at different times in the same person; thus, time periods indicated here should be considered general guidelines only. Adapted from Mudaliar S et al. Endocrinol Metab Clin North Am. 2001;30:935-982. J Plank et al. Diabetes Care 2005;28(5):1107-12

42. Rapid-acting Analogs: Insulin aspart, lispro and glulisine Rapidly absorbed and can be taken shortly before the meal –better postprandial glucose control than regular insulin –injection15-20 minutes before the meal is optimal to time insulin action with food absorption More rapidly cleared than regular insulin –less late, postprandial hypoglycemia

43. Insulin Effect B D LHS Bolus insulin Basal insulin Physiologic Insulin Replacement: Basal-Bolus Insulin Therapy Endogenous insulin Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193

44. 0600 0800 1800 12002400 0600 Time of day 20 40 60 80 100 BLD Basal-Bolus Insulin Treatment with Insulin Analogues B=breakfast; L=lunch; D=dinner Glargine or detemir Lispro, glulisine, or aspart Normal pattern  U/mL

45. Adjust insulin based on: –Meal content Insulin:Carb ratio, usually 1:10 to 1:15 500/Total daily insulin dose; ie 500/50 = 1ns:carb 1:10 –Glucose level correction factor: usually 1 unit to reduce BG 30-50 mg/dl to a target of 100-120 mg/dl 1800/Total daily dose; ie 1800/60 = CF of 1:30 –Physical activity (downwardly adjust pump basal rate, long-acting insulin, or meal bolus) To achieve target glucose ranges –80-130 mg/dl pre-meal, 100-160 after meals, 100-140 at bedtime Diabetes Self Management

46. Insulin pump therapy Most physiologic insulin replacement modality. Continuous subcutaneous infusion catheter delivers aspart, lispro or glulisine insulin - Basal insulin - pre-programmed - can be varied hourly - temporary basal rates can be programmed for inactivity, exercise or illness - Bolus insulin - pump is commanded to give bolus insulin before meals or to correct elevated glucose levels - can give 0.1 unit bolus increments

47. Home Glucose Monitoring Critical for intensive diabetes control with insulin Frequency of testing correlates with better control Should be performed: –before meals, at bedtime, before and after exercise, and periodically 2 hours after meals and at 3am

48. Subcutaneous Continuous Glucose Monitors MiniMed and DexCom Alarms for high and low glucose readings Useful for catching periods of hypoglycemia (especially overnight) of which patients are unaware Useful to observe BG trends to assist with basal and bolus insulin dosage adjustments Shown in adults with type 1 DM to reduce the incidence of severe hypoglycemia and reduce HbA1c levels

49. Continuous Glucose Monitoring

50. Combined Insulin Pump and Glucose Sensor Use A - Paradigm Pump B - Infusion Set C - Continuous Glucose Monitor D - Transmitter

51. Most Patients with Diabetes Die of Cardiovascular Disease 2- to 4-fold more likely to have heart disease 2- to 4-fold more likely to have a stroke 2- to 8-fold more likely to have heart failure ~ 70% of all diabetes-related deaths are associated with vascular disease

52. Cardiovascular Risk Factor Goals Blood Pressure –< 130/80 Lipids –LDL: <100 mg/dl, < 70 in those with CAD –HDL: > 40 mg/dl in men and > 50 mg/dl in women –Triglycerides: < 150 mg/dl Stop smoking Aspirin 81 mg daily in those with known CV disease or men > age 50, women > age 60

53. Thank you