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  1. 1. Diabetes Mellitus: A Review
  2. 2. Objectives <ul><li>Review the criteria for the diagnosis of Diabetes and Pre-Diabetes </li></ul><ul><li>Review treatment goals in diabetes mellitus </li></ul><ul><li>Review therapeutic options to achieve treatment goals </li></ul>
  3. 3. Diabetes Mellitus <ul><li>Group of metabolic diseases characterized by: </li></ul><ul><ul><li>Hyperglycemia resulting from defects in insulin secretion, insulin action or both </li></ul></ul><ul><ul><li>Long term damage, dysfunction and organ failure associated with long term hyperglycemia especially in the following organs: eyes, nerves, kidneys, heart and blood vessels </li></ul></ul>
  4. 4. Classification <ul><li>Type 1 diabetes </li></ul><ul><ul><li>results from β-cell destruction, usually leading to absolute insulin deficiency </li></ul></ul><ul><li>Type 2 diabetes </li></ul><ul><ul><li>results from a progressive insulin secretory defect on the background of insulin resistance </li></ul></ul><ul><li>Other specific types of diabetes due to other causes </li></ul><ul><ul><li>e.g., genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced (such as in the treatment of AIDS or after organ transplantation) </li></ul></ul><ul><li>Gestational diabetes mellitus (GDM) </li></ul><ul><ul><li>diabetes diagnosed during pregnancy </li></ul></ul>
  5. 5. Criteria for Diagnosis of Diabetes <ul><li>HbA1C ≥ 6.5% </li></ul><ul><li>The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay </li></ul><ul><li>FPG ≥ 126 mg/dl (7.0 mmol/l) </li></ul><ul><li>Fasting is defined as no caloric intake for at least 8 hours </li></ul>
  6. 6. Criteria for Diagnosis of Diabetes <ul><li>2-hour Plasma Glucose ≥ 200 mg/dl (11.1 mmol/l) during OGTT </li></ul><ul><li>The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water </li></ul><ul><li>Random Plasma Glucose ≥ 200 mg/dl </li></ul><ul><li>In patients with classic symptoms of hyperglycemia or in hyperglycemic crises. </li></ul>
  7. 7. Categories for Increased Risk of Diabetes <ul><li>Impaired Fasting Glucose </li></ul><ul><ul><li>FPG = 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) </li></ul></ul><ul><li>Impaired Glucose Tolerance </li></ul><ul><ul><li>2-h plasma glucose = 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) </li></ul></ul><ul><li>HbA1c = 5.7–6.4% </li></ul>
  8. 8. Criteria for Testing Asymptomatic Individuals <ul><li>Testing should be considered in all adults who are overweight ( BMI ≥ 25 kg/m2 *) and have additional risk factors : </li></ul><ul><ul><li>physical inactivity </li></ul></ul><ul><ul><li>first-degree relative with diabetes </li></ul></ul><ul><ul><li>members of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, and Pacific Islander) </li></ul></ul><ul><ul><li>women who delivered a baby weighing >9 lb or were diagnosed with GDM </li></ul></ul><ul><ul><li>hypertension ( 140/90 mmHg or on therapy for hypertension) </li></ul></ul><ul><ul><li>HDL cholesterol level <35 mg/dl (0.90 mmol/l) and/or a triglyceride level >250 mg/dl (2.82 mmol/l) </li></ul></ul><ul><ul><li>women with polycystic ovarian syndrome (PCOS) </li></ul></ul><ul><ul><li>IGT or IFG on previous testing, A1C 5.7%, </li></ul></ul><ul><ul><li>other clinical conditions associated with insulin resistance (e.g., severe obesity and acanthosis nigricans) </li></ul></ul><ul><ul><li>history of CVD </li></ul></ul>
  9. 9. Criteria for Testing Asymptomatic Individuals <ul><li>In the absence of the above criteria, testing for pre-diabetes and diabetes should begin at age 45 years </li></ul><ul><li>If results are normal, testing should be repeated at least at 3-year intervals , with consideration of more frequent testing depending on initial results and risk status. </li></ul>
  10. 10. Criteria for Testing in Asymptomatic Children <ul><li>Overweight (BMI 85th percentile for age and sex, weight for height, 85th percentile, or weight 120% of ideal for height) </li></ul><ul><ul><li>Family history of type 2 diabetes in first- or second-degree relative </li></ul></ul><ul><ul><li>Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) </li></ul></ul><ul><ul><li>Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small for gestational age birthweight) </li></ul></ul><ul><ul><li>Maternal history of diabetes or GDM during the child’s gestation </li></ul></ul>
  11. 11. Criteria for Testing in Asymptomatic Children <ul><li>Age of initiation </li></ul><ul><ul><li>10 years or at onset of puberty, if puberty occurs at a younger age </li></ul></ul><ul><li>Frequency </li></ul><ul><ul><li>Every 3 years </li></ul></ul>
  12. 12. Screening for and Diagnosis of GDM <ul><li>Carry out risk assessment on the first prenatal visit </li></ul><ul><li>Criteria for very high risk of developing DM: </li></ul><ul><ul><li>Severe obesity </li></ul></ul><ul><ul><li>Prior history of GDM or LGA infants </li></ul></ul><ul><ul><li>Presence of glycosuria </li></ul></ul><ul><ul><li>Diagnosis of PCOS </li></ul></ul><ul><ul><li>Strong family history of type 2 diabetes </li></ul></ul>
  13. 13. Screening for and Diagnosis of GDM <ul><li>Criteria for low risk of developing GDM: </li></ul><ul><ul><li>Age < 25 years old </li></ul></ul><ul><ul><li>Weight normal before pregnancy </li></ul></ul><ul><ul><li>Member of an ethnic group with a low prevalence of diabetes </li></ul></ul><ul><ul><li>No known diabetes in first-degree relatives </li></ul></ul><ul><ul><li>No history of abnormal glucose tolerance </li></ul></ul><ul><ul><li>No history of poor obstetrical outcome </li></ul></ul><ul><ul><li>*does not require GDM screening </li></ul></ul>
  14. 14. GDM Screening at 24-28 weeks <ul><li>Two-step Approach: </li></ul><ul><ul><li>Perform initial screening by measuring plasma or serum glucose 1 h after a 50-g load; 140 mg/dl identifies 80% of women with GDM, while the sensitivity is further increased to 90% by a threshold of 130 mg/dl. </li></ul></ul><ul><ul><li>Perform a diagnostic 100-g OGTT on a separate day in women who exceed the chosen threshold on 50-g screening. </li></ul></ul>
  15. 15. GDM Screening at 24-28 weeks <ul><li>One-step approach (may be preferred in clinics with high prevalence of GDM): </li></ul><ul><ul><li>Perform a diagnostic 100-g OGTT in all women to be tested at 24–28 weeks. </li></ul></ul><ul><ul><li>To make a diagnosis of GDM, at least two of the following plasma glucose values must be found: </li></ul></ul><ul><ul><ul><li>Fasting: 95 mg/dl </li></ul></ul></ul><ul><ul><ul><li>1-hour: 180 mg/dl </li></ul></ul></ul><ul><ul><ul><li>2-hour: 155 mg/dl </li></ul></ul></ul><ul><ul><ul><li>3-hour :140 mg/dl </li></ul></ul></ul>
  16. 16. Prevention and Delay of Type 2 DM (Pre-Diabetic Patients) <ul><li>Weight loss of 5-10% of TBW </li></ul><ul><li>Increase in physical activity of 150 mins/week of moderate exercise </li></ul><ul><li>For very high-risk individuals, Metformin may be added </li></ul><ul><li>Monitoring for development of DM should be done yearly </li></ul>
  17. 17. Initial Evaluation
  18. 18. History <ul><li>Age, Characteristic of onset </li></ul><ul><li>Eating patterns, physical activity habits, nutritional status and weight history </li></ul><ul><li>Growth and development in children and adolescents </li></ul><ul><li>Diabetes education history </li></ul><ul><li>Review of previous treatment regimens and response to therapy </li></ul><ul><li>Current treatment of diabetes </li></ul><ul><ul><li>including medications, meal plan, physical activity patterns, and results of glucose monitoring and patient’s use of data </li></ul></ul>
  19. 19. History <ul><li>DKA frequency, severity, and cause </li></ul><ul><li>Hypoglycemic episodes </li></ul><ul><ul><li>Hypoglycemia awareness, frequency and cause </li></ul></ul><ul><li>History of diabetes-related complications </li></ul><ul><ul><li>Microvascular: retinopathy, nephropathy, neuropathy (sensory, including history of foot lesions; autonomic, sexual dysfunction and gastroparesis) </li></ul></ul><ul><ul><li>Macrovascular: CHD, CVD, PAD </li></ul></ul><ul><li>Other: psychosocial problems, dental disease </li></ul>
  20. 20. Physical Examination <ul><li>Height, weight, BMI </li></ul><ul><li>Blood pressure determination, including orthostatic measurements when indicated </li></ul><ul><li>Fundoscopic examination </li></ul><ul><li>Thyroid palpation </li></ul><ul><li>Skin examination (for acanthosis nigricans and insulin injection sites) </li></ul>
  21. 21. Physical Examination <ul><li>Comprehensive foot examination </li></ul><ul><ul><li>Inspection </li></ul></ul><ul><ul><li>Palpation of dorsalis pedis and posterior tibial pulses </li></ul></ul><ul><ul><li>Presence/absence of patellar and Achilles reflexes </li></ul></ul><ul><ul><li>Determination of proprioception, vibration, and monofilament sensation </li></ul></ul>
  22. 22. Laboratory Evaluation <ul><li>HbA1C, if results not available within past 2–3 months </li></ul><ul><li>If not performed/available within past year: </li></ul><ul><ul><li>Fasting lipid profile, including total, LDL and HDL cholesterol and triglycerides </li></ul></ul><ul><ul><li>Liver function tests </li></ul></ul><ul><ul><li>Test for urine albumin excretion with spot urine albumin/creatinine ratio </li></ul></ul><ul><ul><li>Serum creatinine and calculated GFR </li></ul></ul><ul><ul><li>TSH in type 1 diabetes, dyslipidemia, or women over age 50 years </li></ul></ul>
  23. 23. Referrals <ul><li>Annual dilated eye exam </li></ul><ul><li>Family planning for women of reproductive age </li></ul><ul><li>Registered dietitian for nutritional therapy </li></ul><ul><li>Diabetes self-management education </li></ul><ul><li>Dental examination </li></ul><ul><li>Mental health professional, if needed </li></ul>
  24. 24. Glycemic Control
  25. 25. Glucose Monitoring <ul><li>Self-monitoring of Blood Glucose (SMBG) for patients on insulin therapy </li></ul><ul><ul><li>Three or more times daily </li></ul></ul><ul><li>HbA1c </li></ul><ul><ul><li>At least twice a year in patients meeting glycemic goals </li></ul></ul>
  26. 26. Summary of Glycemic Recommendations Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals., taken 1-2 hours after beginning the meal. HbA1c < 7.0% Preprandial Capillary Blood Glucose 70-130 mg/dl (3.9 – 7.2 mmol/L) Peak Postprandial Capillary Blood Glucose < 180 mg/dl (< 10.0 mmol/L)
  27. 27. Key Concepts in Setting Glycemic Goals <ul><li>HbA1C is the primary target for glycemic control </li></ul><ul><li>Goals should be individualized based on: </li></ul><ul><ul><li>duration of diabetes </li></ul></ul><ul><ul><li>age/life expectancy </li></ul></ul><ul><ul><li>comorbid conditions </li></ul></ul><ul><ul><li>known CVD or advanced microvascular complications </li></ul></ul><ul><ul><li>hypoglycemia unawareness </li></ul></ul><ul><ul><li>individual patient considerations </li></ul></ul><ul><li>More or less stringent glycemic goals may be appropriate for individual patients </li></ul>
  28. 28. Glycemic Control for Women with GDM <ul><li>Preprandial Capillary Glucose = 95 mg/dl (5.3 mmol/l) and either </li></ul><ul><li>1-h postmeal = 140 mg/dl (7.8 mmol/l) </li></ul><ul><li>OR </li></ul><ul><li>2-h postmeal = 120 mg/dl (6.7 mmol/l) </li></ul>
  29. 29. Glycemic Control for Pregnant Women with Pre-existing DM <ul><li>Premeal, bedtime, and overnight glucose </li></ul><ul><ul><li>60–99 mg/dl (3.3–5.4 mmol/l) </li></ul></ul><ul><li>Peak postprandial glucose </li></ul><ul><ul><li>100 –129 mg/dl (5.4 –7.1 mmol/l) </li></ul></ul><ul><li>HbA1C = 6.0% </li></ul>
  30. 30. Goals of Treatment Summary of Recommendations for Glycemic, Blood Pressure and Lipid Control HbA1c < 7.0% Blood Pressure < 130/80 mm Hg LDL Cholesterol < 100 mg/dl (2.6 mmol/L) Triglycerides < 150 mg/dl (3.7 mmol/L) HDL Cholesterol > 40 mg/dl (1.1 mmol/L) ♂ > 50 mg/dl (1.3 mmol/L) ♀
  31. 31. Diabetes Management
  32. 32. Pharmacologic Treatment <ul><li>Patients with diabetes and hypertension should be treated with a regimen that includes either an ACE inhibitor or an ARB . </li></ul><ul><li>Statin therapy for diabetic patients: </li></ul><ul><ul><li>With overt CVD </li></ul></ul><ul><ul><li>Without CVD who are over the age of 40 and have risk factors for CVD </li></ul></ul>
  33. 33. Pharmacologic Treatment <ul><li>Aspirin therapy (75-162 mg) for </li></ul><ul><ul><li>Patients with history of CVD </li></ul></ul><ul><ul><li>Patients > 40 years old or who have additional risk factors such as: </li></ul></ul><ul><ul><ul><li>Family history of CVD </li></ul></ul></ul><ul><ul><ul><li>Hypertension </li></ul></ul></ul><ul><ul><ul><li>Smoking </li></ul></ul></ul><ul><ul><ul><li>Dyslipidemia </li></ul></ul></ul><ul><ul><ul><li>Albuminuria </li></ul></ul></ul>
  34. 34. Pharmacologic Treatment <ul><li>Annual influenza vaccination. Provide at least one lifetime pneumococcal vaccination. </li></ul><ul><li>Achieve blood sugar control with oral hypoglycemic agents and/or insulin. </li></ul>
  35. 35. Oral Hypoglycemic Agents
  36. 36. Major Classes of Medications <ul><li>1. Drugs that sensitize the body to insulin and/or control hepatic glucose production </li></ul><ul><li>2. Drugs that stimulate the pancreas to make more insulin </li></ul><ul><li>3. Drugs that slow the </li></ul><ul><li>absorption of starches </li></ul><ul><ul><li>Thiazolidinediones </li></ul></ul><ul><ul><li>Biguanides </li></ul></ul><ul><ul><li>Sulfonylureas </li></ul></ul><ul><ul><li>Meglitinides </li></ul></ul><ul><ul><li>Alpha-glucosidase inhibitors </li></ul></ul>
  37. 37. Thiazolidinediones/Glitazones <ul><li>Thiazolidinediones decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production. </li></ul><ul><li>Efficacy </li></ul><ul><ul><li>Decrease fasting plasma glucose ~35-40 mg/dl (1.9-2.2 mmol/L) </li></ul></ul><ul><ul><li>Reduce HbA1C ~0.5-1.0% </li></ul></ul><ul><ul><li>6 weeks for maximum effect </li></ul></ul><ul><li>Other Effects </li></ul><ul><ul><li>Weight gain, edema </li></ul></ul><ul><ul><li>Hypoglycemia (if taken with insulin or agents that stimulate insulin release) </li></ul></ul><ul><ul><li>Contraindicated in patients with abnormal liver function or CHF </li></ul></ul><ul><ul><li>Improves HDL cholesterol and plasma triglycerides; usually LDL neutral </li></ul></ul><ul><li>Medications in this Class: pioglitazone, rosiglitazone </li></ul>
  38. 38. Biguanides <ul><li>Biguanides decrease hepatic glucose production and increase insulin-mediated peripheral glucose uptake. </li></ul><ul><li>Efficacy </li></ul><ul><ul><li>Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L) </li></ul></ul><ul><ul><li>Reduce HbA1C 1.0-2.0% </li></ul></ul><ul><li>Other Effects </li></ul><ul><ul><li>Diarrhea and abdominal discomfort </li></ul></ul><ul><ul><li>Lactic acidosis if improperly prescribed </li></ul></ul><ul><ul><li>Cause small decrease in LDL cholesterol level and triglycerides </li></ul></ul><ul><ul><li>No specific effect on blood pressure </li></ul></ul><ul><ul><li>No weight gain, with possible modest weight loss </li></ul></ul><ul><ul><li>Contraindicated in patients with impaired renal function (Serum Cr > 1.4 mg/dL for women, or 1.5 mg/dL for men) </li></ul></ul><ul><li>Medications in this Class: metformin, metformin hydrochloride extended release </li></ul>
  39. 39. Sulfonylureas <ul><li>Sulfonylureas increase endogenous insulin secretion </li></ul><ul><li>Efficacy </li></ul><ul><ul><li>Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L) </li></ul></ul><ul><ul><li>Reduce HbA1C by 1.0-2.0% </li></ul></ul><ul><li>Other Effects </li></ul><ul><ul><li>Hypoglycemia </li></ul></ul><ul><ul><li>Weight gain </li></ul></ul><ul><ul><li>No specific effect on plasma lipids or blood pressure </li></ul></ul><ul><ul><li>Generally the least expensive class of medication </li></ul></ul><ul><li>Medications in this Class: </li></ul><ul><ul><li>First generation sulfonylureas : chlorpropamide, tolazamide, acetohexamide, tolbutamide </li></ul></ul><ul><ul><li>Second generation sulfonylureas: glyburide, glimepiride glipizide </li></ul></ul>
  40. 40. Meglitinides <ul><li>Meglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose. </li></ul><ul><li>Efficacy </li></ul><ul><ul><li>Decreases peak postprandial glucose </li></ul></ul><ul><ul><li>Decreases plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L) </li></ul></ul><ul><ul><li>Reduce HbA1C 1.0-2.0% </li></ul></ul><ul><li>Other Effects </li></ul><ul><ul><li>Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule) </li></ul></ul><ul><ul><li>Weight gain </li></ul></ul><ul><ul><li>No significant effect on plasma lipid levels </li></ul></ul><ul><ul><li>Safe at higher levels of serum Cr than sulfonylureas </li></ul></ul><ul><li>Medications in this Class: repaglinide, nateglinide </li></ul>
  41. 41. Alpha-glucosidase Inhibitors <ul><li>Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine </li></ul><ul><li>Efficacy </li></ul><ul><ul><li>Decrease peak postprandial glucose 40-50 mg/dl (2.2-2.8 mmol/L) </li></ul></ul><ul><ul><li>Decrease fasting plasma glucose 20-30 mg/dl (1.4-1.7 mmol/L) </li></ul></ul><ul><ul><li>Decrease HbA1C 0.5-1.0% </li></ul></ul><ul><li>Other Effects </li></ul><ul><ul><li>Flatulence or abdominal discomfort </li></ul></ul><ul><ul><li>No specific effect on lipids or blood pressure </li></ul></ul><ul><ul><li>No weight gain </li></ul></ul><ul><ul><li>Contraindicated in patients with inflammatory bowel disease or cirrhosis </li></ul></ul><ul><li>Medications in this Class: acarbose </li></ul>
  42. 42. Dipeptidyl Peptidase 4 Inhibitors <ul><li>Increase glucose-mediated insulin secretion </li></ul><ul><li>Suppress glucagon secretion </li></ul><ul><li>Efficacy </li></ul><ul><ul><li>Lowers HbA1c by 0.6-0.9% </li></ul></ul><ul><ul><li>Weight neutral </li></ul></ul><ul><ul><li>Well-tolerated </li></ul></ul><ul><li>Other effects </li></ul><ul><ul><li>Does not cause hypoglycemia </li></ul></ul><ul><ul><li>Increase in upper respiratory tract infections </li></ul></ul><ul><li>Medications in this class: sitagliptin, vidagliptin </li></ul>
  44. 46. Titration of Metformin <ul><li>Low-dose metformin (500 mg) once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day </li></ul><ul><li>After 5 to 7 days, if with no GI side effects, increase dose to 850 or two 500 mg tablets twice per day (to be taken before breakfast and/or dinner) </li></ul><ul><li>If with GI side effects, decrease to previous lower dose. Increase dose at later time. </li></ul><ul><li>Maximum dose: 1000 mg twice per day </li></ul>
  45. 47. Combination Therapy for Type 2 Diabetes Sulfonylureas Thiazolidinediones Alpha Glucosidase Inhibitors Meglitinide Biguanides Insulin
  46. 48. Combination Therapy: Fixed Dose Pills <ul><li>Glucovance (Glibenclamide + Metformin) </li></ul><ul><li>Eugloplus (Glibenclamide + Metformin) </li></ul><ul><li>Norsulin (Gliclazide + Metformin) </li></ul><ul><li>Avandamet (Rosiglitazone + Metformin) </li></ul><ul><li>Janumet (Sitagliptin + Metformin) </li></ul>
  47. 49. Contraindications for Use of OHAs Drug Class Contraindications Sulfonylureas Known allergies to SUs, Pregnancy, Hepatic & Renal insufficiency Meglitinides Known allergies, Pregnancy Biguanides Clinical states involving hypoxia Alpha Glucosidase Inhibitors Known allergies, GI disturbances Glitazones Known or suspected liver disease,  liver enzymes