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Current Management of Type 1 and Type 2 Diabetes

Current Management of Type 1 and Type 2 Diabetes. Thomas Donner, M.D. Division of Endocrinology & Metabolism. Objectives. After attending this session, the participant should be able to: Describe the pathogenesis of type 1 and type 2 diabetes

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Current Management of Type 1 and Type 2 Diabetes

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  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. Good Glycemic Control Reduces the Incidence of Complications Complications DCCT1,2 Kumamoto3 UKPDS4,5 of A1C 9% 7% 9% 7% 7.9% 7% Retinopathy 63% 69% 17%-21% Nephropathy 54% 70% 24%-33% Neuropathy 60% – – Macrovascular disease 57%* – 15%-33% *After 17 years of follow-up 1DCCT Research Group. N Engl J Med. 1993;329:977; 2DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653 3Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103; 4UKPDS Group. Lancet. 1998;352:837; Horman R et al. N Engl J Med. 2008;359:1577-1589

  8. Good Glycemic Control Reduces the Incidence of Complications Complications DCCT1,2Kumamoto3 UKPDS4,5 of A1C 9% 7% 9% 7% 7.9% 7% Retinopathy 63% 69% 17%-21% Nephropathy 54% 70% 24%-33% Neuropathy 60% – – Macrovascular disease 57% – 15%-33%* *Sulfonylurea/Insulin – metformin, after 20 years of follow up 1DCCT Research Group. N Engl J Med. 1993;329:977; 2DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653 3Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103; 4UKPDS Group. Lancet. 1998;352:837; Horman R et al. N Engl J Med. 2008;359:1577-1589

  9. A1C and Relative Risk of Microvascular Complications: DCCT Retinopathy 15 Nephropathy 13 Neuropathy Microalbuminuria 11 9 Relative Risk 7 5 3 1 6 7 8 9 10 11 12 A1C (%) Adapted with permission from Skyler J. Endocrinol Metab Clin North Am. 1996;25:243 DCCT Research Group. N Engl J Med. 1993;329:977

  10. Goals for Glycemic Control • Biochemical IndexNormalGoal • 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

  12. Treatment of Type 2 Diabetes

  13. 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)

  14. 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

  15. 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

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

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

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

  19. Relative HbA1c-Lowering Efficacy of Established Oral Diabetes Medications 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. 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

  20. Sulfonylureas: Available agents • First Generation • Tolbutamide • Chlorpropamide • Tolazamide • Second Generation • Glyburide • Glipizide • Glimepiride

  21. 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

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

  23. 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

  24. 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

  25. 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

  26. a-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

  27. 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

  28. 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

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

  30. GLP-1 Secretion and Inactivation Meal Intestinal GLP-1 release GLP-1 t½ = 1 to 2 min ActiveGLP-1 DPP-4 GLP-1 inactive (>80% of pool) GLP-1 = glucagon-like peptide–1; DPP-4= dipeptidyl-peptidase–4 Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

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

  32. 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

  33. 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

  34. Natural History of Type 2 Diabetes Postmeal glucose Plasma Glucose Fasting glucose 126 mg/dL Insulin resistance Relative -Cell Function Insulin secretion 20 10 0 10 20 30 Years of Diabetes Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota. 6-6

  35. 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

  36. 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

  37. Intensive Insulin Therapyin Type 1 and Type 2 Diabetes

  38. Insulin and Glucose Patterns in Normals and in Type 2 Diabetes Normal Type 2 Diabetes Glucose Insulin 400 120 100 300 80 mg/dL U/mL 200 60 40 100 20 0600 1000 1400 1800 2200 0200 0600 0600 1000 1400 1800 2200 0200 0600 B L S B L S Time of Day Time of Day Polonsky, et al. N Engl J Med. 1988;318:1231-1239. 6-17

  39. 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

  40. Insulin Onset of Duration ofPreparations Action Peak (h) Action (h) Lispro/Aspart/Glulisine 5-15 min 1-2 3-6 Human Regular 30-60 min 2-4 6-10 Human NPH 1-2 h 4-8 10-20 Glargine 1-2 h flat ~24 Detemir 1-2 h flat 18-24 Comparison of Human Insulins and Analogs 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

  41. 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

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

  43. 0600 1800 0800 0600 1200 2400 Basal-Bolus Insulin Treatmentwith Insulin Analogues Lispro, glulisine, or aspart U/mL 100 Glargine or detemir B L D 80 60 Normal pattern 40 20 Time of day B=breakfast; L=lunch; D=dinner

  44. Diabetes Self Management • 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

  45. 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

  46. 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

  47. 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

  48. Continuous Glucose Monitoring

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

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