Type 2 DM

1. Type 2 DM LCDR Jason Daily Staff Endocrinologist 13 May 2013

2. Objectives • Pathogenesis • Diagnosis • Management • Standards of Care

3. Reference • 2013 - ADA Standards of Medical Care in Diabetes • http://care.diabetesjournals.org/content/36/Supplement_1/S11.full

4. Pathogenesis • Pathogenesis of Type II DM complex involves genetic and environmental factors particularly excessive caloric intake leading to obesity and a sedentary lifestyle • Resistance to the action of insulin in peripheral tissues include muscle and fat, but also liver • Present years before onset of diabetes • Insulin resistance rises as body fat content increases • Nutrient intake that exceeds expenditure must be stored and is usually in the form of triglyceride in adipose tissue. If the storage capacity is exceeded the lipids enter non-storage sites such as the liver and muscle leads to worsening insulin resistance • Defective insulin secretion, particularly in response to glucose stimulus • Increased glucose production of the liver • Accelerated lipolysis in the fat cell, incretin hormone deficiency (GLP-1, glucose-dependent insulinotropic polypeptide) and resistance, hyperglucagonemia, increased tubular reabsorption

5. Risk Factors • Age > 45 • 1st degree relatives (39% of patients with type 2 Dm will have at least one parent with type II DM) • Ethnicity (African American, Pacific-Islander, Native American 2-6 times more prevalent) • Gestational DM • Polycystic ovarian syndrome • Overweight • Metabolic Syndrome

6. Indications for testing • One-forth of all people with diabetes in the U.S. may be undiagnosed • Adults who are overweight (BMI ≥ 25 kg/m2) or obese and additional risk factor: • First-degrees relative with diabetes • High-risk race/ethnicity • Women delivered a baby weighing > 9 pounds or GDM • Hypertension (≥ 140/90 mm Hg or on therapy) • HDL < 35 mg/dl and/or triglyceride > 250 mg/dl • History of CVD

7. Diagnosis of Prediabetes • Prediabetes – high risk for the future development of diabetes • Impaired Fasting Glucose • FPG levels 100 to 125 mg/dl • Impaired Glucose Tolerance • 2-hour values in the OGTT of 140 to 199 mg/dl • A1c 5.7-6.4% • A1c between 5.5 – 6.0% increase 5 year incidence 9 to 25% • A1c between 6.0 – 6.5% had 5 year risk of developing diabetes between 25 to 50%

8. Management of Prediabetes • Patients with Prediabetes (IFG, IGT, or A1c 5.7-6.4%) should be counseled on life style changes • 7% weight loss • low-carbohydrate low-fat calorie restricted or Mediterranean diets may be effective in the short term • Encouraged 14 g fiber/1,000 kcal and foods containing whole grains • Limit intake sugar-sweetened beverages • Saturated fat intake should < 7% of total calories • Minimize trans fat (reducing intake lowers LD cholesterol and increased HDL cholesterol) • Moderate physical activity 150mins/week • DPP Trial demonstrated a 57% reduction in Diabetes • Metformin may be considered for the prevention of DM • More effective in patients with Prediabetes, BMI > 35 kg/m2 and age < 60 years • Women with prior GDM

9. Diagnosis of Diabetes • Diagnostic Criteria for Diabetes (any of the following) • A1c ≥ 6.5% • FPG ≥ 126 mg/dl (fasting for least 8 hours) • 2-hour plasma glucose ≥ 200 mg/dl during OGTT (75g glucose load) • Symptoms of hyperglycemia and random glucose ≥ 200 mg/dl

11. Metformin • Metformin initial pharmacological agent, A1c reduction 1.0-2.0% • Decreased hepatic glucose production • Weight neutral • No hypoglycemia • Side effects: diarrhea, abdominal cramping, lactic acidosis • Contraindicated: CKD, acidosis, hypoxia, dehydration

12. GLP-1 Receptor Agonists • A1c reduction 0.5-1.0% • Exenatide, Exenatide extended release, Liraglutide • Activates GLP-1 receptors • Increases insulin secretion (glucose-dependent) • Decreases Glucagon Secretion (glucose-dependent) • Slows Gastric Emptying • Increases Satiety • No hypoglycemia, Weight Reduction • Possible pancreatitis, C-cell hyperplasia in animals, Injectable

13. DPP-4 Inhibitors • A1c reduction 0.5-0.8% • Sitaglipitin (Januvia), Saxaglipitin • Inhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations that leads to increase insulin secretion (glucose-dependent) and decrease glucagon secretion (glucose-dependent) • No hypoglycemia • Modest A1c reduction, Possible pancreatitis, Urticaria/Angioedema, expensive

14. α-Glucosidase Inhibitors • A1c reduction 0.5-0.8% • Acarbose • Starting dose 25mg TID • Inhibits intestinal α-glucosidase that slows intestinal carbohydrate digestion/absorption • No hypoglycemia, decreases postprandial glucose excursions • GI side effects (flatulence, diarrhea)

15. Thiazolidinediones • A1c reduction 0.5-1.4% • Pioglitazone, Rosiglitazone • Activates the nuclear transcription factor PPAR-ϒ that increases insulin sensitivity and reduces hepatic glucose production • No hypoglycemia, Increases HDL, Decreases Triglycerides • Side effects: Weight Gain, Edema/heart failure, bone fractures • Increases MI in meta-analyses rosiglitazone • Increases bladder cancer pioglitazone

16. Sulfonylureas • A1c reduction 1.0-2.0% • 2nd Generation: Glyburide, Glipizide, Glimepiride • Closes KATP channels on β-cell plasma membranes that increases insulin secretion • Side effects: weight gain, hypoglycemia, blunts myocardial ischemic preconditioning

17. Meglitinides • A1c reduction 0.5-1.5% • Repaglinide, Nateglinide • Closes KATP channels on β-cell plasma membranes that increases insulin secretion • Decreases postprandial glucose excursions • Side effects: weight gain, hypoglycemia, blunts myocardial ischemic preconditioning, frequent dosing schedule

18. SGLT-2 • Sodium-Glucose Cotransporter 2 Inhibitor • Canagliflozin, A1c Reduction 0.91-1.16% (just approved by FDA) • Adverse Effects: GU infections female, Renal Insufficiency, Hypovolemia, Hyperkalemia, Hypoglycemia

19. Colesevelam • Bile acid sequestrantthat lowers LDL • Reduced A1c levels 0.5% • Thought mechanism of action to reduce glucose absorption • Side Effects: constipation, nausea, and dyspepsia

20. Bromocriptine • Dopamine Agonist • Minimally effective reducing A1c (0.4-0.5%) • Side effects: Nausea, Vomiting, Dizziness, and Headache

23. Standards of Care

24. A1c Goal • < 7% in most nonpregnant adults • If implemented soon after the diagnosis of diabetes associated with long-term reduction in macrovascular disease • DCCT in type I DM reduction in microvascular complications • EDIC Trial 57% reduction in nonfatal MI, stroke, CV death • Kumamoto Study and UKPDS showed reduction in microvascular complications in type II diabetes • 10 years after the UKPDS, patients randomized to intensive therapy significant reduction in MI and in all-cause mortality • Consider < 6.5% in selected individuals patients, if this can be achieved safely • < 8% may be appropriate in patients with sever hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions • ACCORD, ADVANCE, VADT – suggested no significant reduction in CVD outcomes with intensive glycemic control in participants who had more advanced type II diabetes

25. A1c • Average glycemia over several months and has strong predictive value for diabetes complications • Test two times a year in patients meeting treatment goals • Test quarterly in patients whose therapy has changed or who are not meeting treatment goals • Affected by red blood cell turnover • Falsely High Values – RBC turnover is slow (Iron, B12, Folate deficiency) • Falsely Low Values – Increased RBC turnover (hemolysis, anemia treated with iron, B12, Folate, EPO) • Hemoglobin variants may affect the A1c

26. A1c Mean plasma glucose • A1c (%) mg/dl mmol/l • 6 126 7.0 • 7 154 8.6 • 8 183 10.2 • 9 212 11.8 • 10 240 13.4 • 11 269 14.9 • 12 298 16.5

27. Hypertension • Goal systolic blood pressure < 140 mm Hg and diastolic blood pressure < 80 mm Hg • Lower targets such has < 130 mm Hg may be appropriate for certain individuals such as younger age or whom stroke risk is a concern • Treatment • Lifestyle changes • Weight loss • DASH style dietary pattern (reduce sodium intake to 1,500mg/day, increasing consumption fruits and vegetables (8-10 servings/day, avoiding excessive alcohol consumption) • Increase physical activity • Pharmacological Therapy • ACE Inhibitor or Angiotensin Receptor Blocker should be initial therapy (contraindicated in pregnancy) • If second agent is needed add HCTZ, amlodipine, or chlorthalidone, if eGFR < 30 ml/min/m2, a loop diuretic should be added instead of HCTZ or chlorthalidone

28. Lipid Management • Goals • Individuals without overt CVD, the goal LDL cholesterol < 100 mg/dl • Individuals with overt CVD, the goal LDL cholesterol < 70 mg/dl • Treatment • 1st priority is lower the LDL cholesterol • Patients with overt CVD or over the age of 40 with CVD risk factors should be treated with statin therapy • Contraindicated in pregnancy

29. Antiplatelet Therapy • Consider aspirin therapy (75-162mg/day) as primary prevention in patients with diabetes with increased cardiovascular risk (10-year risk > 10%) includes men greater 50 years of age and women greater 60 years of age with one additional major risk factor (FH of CVD, HTN, Smoking, HLD or albuminuria) • Not recommended in low risk patients (10-year risk < 5%) includes men less than age of 50 or women less than age of 60 with no additional major risk factors • Clinical judgment for 10-year risk between 5-10%

30. Nephropathy • Occurs in 20-40% with diabetes and single leading cause of ESRD • Reduce the risk or slow progression optimize glucose and blood pressure control • Screening • Annually test urine albumin excretion in Type I diabetes with duration ≥ 5 years and annually at the time of diagnosis of type II diabetes • Measure albumin-to-creatinine ratio • Annual serum creatinine • Treatment • Modestly elevated (30-299 mg/day) or higher levels (≥ 300 mg/day) of urinary albumin excretion should be on ACE inhibitors or ARB • Reduction of protein intake to 0.8-1.0 g/kg body wt per day in individuals with diabetes and the earlier states of CKD and to 0.8g/kg body wt per day in the latter stages of CKD

31. Retinopathy • Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20-74 years • Reduce the risk or slow the progression of retinopathy optimize glycemic and blood pressure control • Screening • Patients with type I DM should have initial dilated and comprehensive eye examination within 5 years after onset of DM then annually • Patients with type II DM should have initial dilated and comprehensive eye examination at the time of diagnosis and then annually • Women with pre-existing diabetes should have a comprehensive eye examination in the first trimester

32. Neuropathy • All patients should be screened for distal symmetric polyneuropathy starting at diagnosis of type II DM and 5 years after the diagnosis of type I DM • Pinprick sensation • Vibration perception (using a 128-Hz tuning fork) • 10-g monofilament pressure sensation • Loss of 10-g monofilament perception and reduced vibration perception predict foot ulcers • Screen for signs or symptoms of cardiovascular autonomic neuropathy at diagnosis of type II DM and 5 years after the diagnosis of type I DM • Symptoms include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, and potentially autonomic failure in response to hypoglycemia

33. Immunizations • Annual influenza vaccine • Pneumococcal polysaccharide vaccine to all diabetic patients, and one time revaccination is recommended at 65 years of age if the vaccine was administered greater than 5 years ago • Hepatitis B vaccination to all adults aged 19 through 59 years

34. Diabetic Emergencies • Hyperglycemia (DKA or Nonketotic Hyperglycemia) • Hypoglycemia

35. Diagnosis

36. Hypoglycemia • If blood sugar less than 70 • “15 Rule” • Ingest 15 grams of CHO and then repeat finger stick in 15 minutes

37. When to refer to endocrine? • Type 1 DM (DKA, BMI < 25, positive ab’s) • Poorly controlled type 2 requiring insulin therapy

38. Questions??