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Ambulatory: Diabetes Mellitus

Ambulatory: Diabetes Mellitus. April 9, 2007. Subtypes. Insulin dependent (Type 1 /IDDM) Abrupt onset, < 30 yrs Autoimmune insulin deficiency due to islet cell destruction Prone to ketoacidosis Non-insulin dependent (Type 2/NIDDM) Gradual onset, > 30 yrs Obesity Insulin resistance

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Ambulatory: Diabetes Mellitus

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  1. Ambulatory:Diabetes Mellitus April 9, 2007

  2. Subtypes • Insulin dependent (Type 1 /IDDM) • Abrupt onset, < 30 yrs • Autoimmune insulin deficiency due to islet cell destruction • Prone to ketoacidosis • Non-insulin dependent (Type 2/NIDDM) • Gradual onset, > 30 yrs • Obesity • Insulin resistance • Impaired insulin secretion (beta cell dysfunction)

  3. Type I DM • Insulin deficiency secondary to β-cell destruction usually by autoimmune process • Insulin and C-peptide levels low • May have islet cell autoantibodies, Autoantibodies to insulin, or antibodies to glutamic acid decarboxylase or tyrosine phosphatases. • 20% risk of other autoimmune diseases • Typically will present with DKA due to absolute lack of insulin

  4. Type II • Insulin resistance and relative insulin deficiency - β-cell mass preserved, but decreased secretion and response to insulin. • Strong genetic component with 100% concordance in monozygotic twins. • Ketoacidosis is rare – though it can occur if concurrent infection. Also there are a small group of mainly African American patients in whom insulinopenia leads to a tendency to DKA. • Usually hyperglycemia in Type II develops gradually and pt may be undiagnosed for years.

  5. Subtypes • Gestational Diabetes • Dysfunction of glucose metabolism with presentation in pregnancy • Increased fetal morbidity • Up to 63% will develop non-gestational DM in 5-16 years • MODY (maturity-onset diabetes of the young) • Subset of Type 2 DM • Family history, early age of onset (teens, 20’s) • At least 5 subtypes • Impairment of β-cell function • Resistance to ketoacidosis

  6. Subtypes • Secondary Diabetes • Pancreatic disease with resultant insulinopenia • Chronic pancreatitis, pancreatectomy, CF, hemachromatosis • Drug induced • HCTZ, steroids, estrogen, psychoactive agents, catacholamines, pentamidine

  7. Subtypes • Endocrinopathies • Acromegaly, pheochromocytoma, Cushing’s, Conn’s, glucagonoma • Insulin receptor abnormalities • Genetic syndromes • Hyperlipidemia, muscular dystrophies, Huntington’s chorea

  8. Diagnosis • Per the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003

  9. Symptoms of Diabetes • Classic • Polyuria, polydipsia, unexplained weight LOSS • Fatigue • Blurry vision • Nausea, vomiting • Infections

  10. Screening for Diabetes • Every 3 years if age 45 or older (if results are normal) • More frequent screening if: • Pre-Diabetic • Fasting plasma glucose concentration > 110 mg/dL or < 126 mg dL • a.k.a. “impaired fasting glucose” or “impaired glucose tolerance” • Obese (BMI≥27) • 1st degree relatives with DM • High risk ethnic group • African-American, Hispanic-American, Native-American, Asian-American, Pacific Islander-American • Pregnancy • History of Gestational diabetes • Delivery of baby weighing 9 or more pounds • HTN (>140/90) • Dyslipidemia • HDL≤35 mg/dL, TGL≥250 mg/dL

  11. Treatment rationale • DCCTRG • 39% reduction in progression of retinopathy for 0.9% reduction in HbA1c • UKPDSG • HbA1c of 7% associated with significant incidence of micro and macrovascular disease

  12. Treatment Rationale • Meticulous glucose control decreases long-term microvascular complication rates • Aggressive insulin therapy in patients with a recent MI was associated with reduced mortality

  13. Treatment of Diabetes Mellitus • Goals set by American Diabetes Association • Preprandial glucose values of 80 to 120 mg/dL • Bedtime glucose values of 100 to 140 mg/dL • Hemoglobin A1C < 7% • 2 hour post-prandial glucose values < 160 mg/dL

  14. Treatment of Type 1 Diabetes Mellitus • Need insulin • Healthy people generally have insulin production of 24-36 units per day • Type 1 DM • 0.5 to 1.0 units/kg of insulin daily • Varies according to diet, exercise, stress • Various insulin preparations with various regimens • Tailor to the patient • Attempt to mimic the healthy person’s insulin peaks and valleys

  15. Treatment of Type 1 Diabetes Mellitus • Rapid Acting Insulins • Lispro, Aspart • Short Acting Insulins • Regular • Intermediate Acting • NPH • Lente • Long Acting • Ultralente • Glargine

  16. Basal/Bolus regimen • Basal/Bolus regimen • Daily insulin dose consists of a basal insulin to inhibit hepatic glucose production and pre-meal insulin to cover intake • mimics natural insulin production • Typically this is achieved with Lantus QHS and Novolog (aspart) QAC. • Patients on this regimen should either be given a Sliding scale instructing them how to cover their premeal accuchecks and how to “Carb count” OR they need a standard dose of premeal insulin which you review when you see them in clinic based on their readings. • 15g carbs = 1 unit of insulin • Requires multiple insulin injections and accuchecks, but provides greater flexibility in matching insulin to meal.

  17. Treatment of Type 1 Diabetes Mellitus • Pancreas Transplant with or without Kidney transplant • To help protect the transplanted kidney from hyperglycemia • Meet certain criteria, in general, frequent, acute metabolic complications and failure with insulin therapy • Survival, immunosuppression • Pancreatic islet cell transplant • Similar criteria • Immunosuppression

  18. Treatment of Type 2 Diabetes • Weight Loss, Diet, Exercise • Decrease in body weight as little as 4-7% can help increase insulin sensitivity • United Kingdom Prospective Diabetes Study (UKPDS) • < 25% treated with diet and exercise alone maintain Hgb A1C < 7% after 3 years and < 10% after 9 years • Attributed in part to progressive loss of β-cell secretion of insulin • Supporting evidence of dual therapy with oral agents, i.e. one agent augmenting insulin secretion, another improving insulin action

  19. Treatment of Type 2 Diabetes • Insulin Secretagogues (“Beta-beaters”) • Sulfonylurea • Meglitinides • Biguanides – decrease hepatic gluconeogenesis • Metformin • Thiazolidinediones – insulin sensitizer • The “glitizones” • Alpha-glucosidase Inhibitors – decreased GI absorption • Acarbose

  20. Sulfonylurea • First line after diet and exercise • 20-25% primary failure rate • Caution in hepatic/renal dysfunction • Mechanism of action • Promote increased pancreatic secretion • Side effects • Hypoglycemia, usually within 1st 4 months • Increased in elderly, worsening renal function, irregular meal schedules • Weight gain • Medications • Glyburide (Micronase, Diabeta) • Duration of action 18-24 hours • Hypoglycemia still common • Glipizide (Glucotrol) • Glimepiride (Amaryl) • Indicated for use with insulin • “safe” in renal failure

  21. Meglitinides (rapid acting secretogogues) • Theoretically offers improved post prandial control • May benefit patients with unpredictable meal schedules or large post prandial glucose levels • Q meal dosing • Mechanism of action • Similar to sulfonylureas, quicker “on-off” action • Side effects • Hypoglycemia • Weight gain • Medications • Repaglinide (Prandin) • Nataglinide (Starlix) • Ultra short acting • Most effective agent for post-prandial control • Hypoglycemic contraindication with insulin

  22. Biguanides • Weight loss due to appetite reduction • Less hypoglycemia than sulfonylurea therapy • Major effects: • Increased hepatic insulin sensitivity • Decreased gluconeogenesis and glycogenolysis • Side effects • LACTIC ACIDOSIS • GI intolerance • Mechanism of action is unclear • Medication • Metformin (Glucophage) • Optimal dose 2000mg/d • BID dosing

  23. Biguanides • Contraindications to metformin • Serum creatinine >= 1.5 mg/dL in men, >= 1.4 mg/dL in women • Age > 75years • Discontinue before any radiologic contrast studies (stop during or before) or upon hospitalization • Hepatic dysfunction • Dehydration • Metabolic acidosis • CHF requiring treatment

  24. Thiazolidinediones (TZD) • Mechanism of action • Not fully understood • Decrease insulin resistance, increase insulin sensitivity, probably at the peripheral skeletal muscle • ? Smaller effect on liver gluconeogenesis • Additive effect with metformin • Favorable lipid profile effects, ? atherosclerosis • Side effects • Weight gain • Edema – caution with CHF • Hypoglycemia, especially if coupled with other diabetic medication • Liver dysfunction? – monitor LFTs • Medications • Rosiglitizone (Avandia) - increase HDL levels • Pioglitizone (Actos) - increase HDL, decrease TG levels • Contraindicated: • Hepatic dysfunction • Age greater than 80 • Advanced CHF

  25. Thiazolidinediones (TZD) • Monotherapy or combo with metformin, sulfonylureas, and insulin • Other effects: • Slightly reduce BP • Enhance fibrinolysis • Improve endothelial function

  26. Alpha-glucosidase Inhibitors • Decreases digestion of complex carbohydrates in small bowel • Slows monosaccharide absorption • Effective only with diets >40% carbohydrates • Lowers post-prandial>pre-prandial glucose • Not as efficacious as other agents (decreases A1C by 0.5% - 1%) • Side effects major limitation • Gas, abdominal pain, diarrhea • Minimized with slow titration • Medications • Acarbose (Precose) • Miglitol (Glyset)

  27. Oral Agent Monotherapy and Glycemic Control

  28. Combination Oral Therapy • Lowers A1C levels by about 2% • No evidence that a specific combination is any more effective in lowering glucose levels or more effective in preventing complications than another • Thus, patients with an HbA1C >9% who are receiving monotherapy are unlikely to reach a target of <7%

  29. A 56-year-old woman who has had type 2 diabetes mellitus for 12 years is evaluated because of poorly controlled diabetes. She is obese (body mass index, 32 kg/m2). She takes glyburide, and over the past 6 months, her hemoglobin A1C level has increased from 6.8% to 8.5%, while measurements of her fasting plasma glucose have been greater than 200 mg/dL and postprandial measurements range from 250 to 350 mg/dL. She refuses to take insulin. • Which of following is the best therapy for this patient? • ( A ) Discontinue glyburide and initiate metformin( B ) Discontinue glyburide and initiate a thiazolidinedione( C ) Continue glyburide and add metformin( D ) Continue glyburide and repeat measurement of hemoglobin A1C( E ) Continue glyburide and add acarbose

  30. Critique (Correct Answer = C) • Type 2 diabetes mellitus is a progressive disorder, and studies have documented that response to monotherapy is limited. Four options are available to obese patients who have become unresponsive to sulfonylureas: 1) add metformin, 2) add a thiazolidinedione, 3) add an α-glucosidase inhibitor, and 4) add insulin. Arguably the best treatment could be to initiate insulin at bedtime and continue the sulfonylurea. There is no consensus about which option is most effective. Adding metformin to the regimen provides an effective agent that complements the action of sulfonylurea. Several studies document that fasting plasma glucose and hemoglobin A1C values decline with this combination of sulfonylurea and metformin in patients with body mass indexes in the range of 27 to 30 kg/m2. Maximum dosages (2000 mg) of metformin should be administered in divided doses. A trial of this combination for 6 to 8 weeks should determine its effectiveness. If hemoglobin A1C values do not fall to the 7.0% to 7.5% range, the patient should be encouraged to start insulin therapy. • A thiazolidinedione and acarbose (an α-glucosidase inhibitor) are less powerful as hypoglycemic agents than sulfonylureas and metformin, and probably would be less effective in this patient than combination therapy. The patient’s obesity indicates that insulin resistance is a likely factor in the progressive hyperglycemia, and a thiazolidinedione warrants consideration; however, if it is used, greater laboratory monitoring is required.

  31. Oral Agent Metabolic Effects

  32. A 52-year-old woman is found to have a fasting plasma glucose concentration of 168 mg/dL during her annual physical examination. Her lifestyle is sedentary. Obesity has been a problem since early adulthood, and her weight in recent years has ranged from 90 to 103 kg (196 to 226 lb). Her blood pressure has been elevated for the past 18 years, and while taking captopril, it is in the 160/90 to 180/100 range. The hemoglobin A1C level is 8.4%. • After meeting with a dietitian and nurse educator, she starts a calorie-restricted diet and an exercise program; 6 weeks later, she weighs 91.8 kg (202 lb) and her hemoglobin A1C is 8.6%. Other laboratory tests include a total cholesterol of 238 mgldL and a fasting triglyceride level of 278 mgldL. • What is the best hypoglycemic agent for this patient? • ( A ) Insulin( B ) A sulfonylurea( C ) Metformin( D ) Acarbose( E ) Rosiglitazone

  33. Critique (Correct Answer = C) • Persistent hyperglycemia and hypertriglyceridemia in an obese patient make metformin an ideal agent. The drug will facilitate weight loss and have beneficial effects on the hypertriglyceridemia. The United Kingdom Prospective Diabetes Study indicated that insulin and sulfonylureas equally lower plasma glucose but do not help weight loss or prevent weight gain. The thiazinolinediones as monotherapy also increase weight as well as possibly adversely affecting serum cholesterol levels. Although metformin as well as insulin and sulfonylureas reduce hyperglycemia and consequently lower the risk for the several microvascular complications, these agents do not significantly alter the risk for myocardial infarction. • Insulin is most effective as the first choice in symptomatic patients, especially those who are normal weight or only slightly overweight. In the setting of infection, a vascular accident, or other medical problem, the patient with recent-onset type 2 disease benefits from insulin as first treatment. • Sulfonylureas would also probably lower plasma glucose in this patient, but weight gain or inability to lower weight are possible complications. In 10% to 15% of recently diagnosed patients, sulfonylureas are ineffective as hypoglycemic agents. The exact cause of this primary failure is unclear, although beta cells exposed to hyperglycemia for prolonged periods will not respond to sulfonylureas. • Acarbose is reserved for patients with type 2 diabetes mellitus in whom postprandial hyperglycemia is the major problem. In patients with elevated fasting glucose levels, acarbose will have limited effect. • The thiazolidinediones effectively reduce fasting plasma glucose concentration. These agents increase serum LDL-and HDL cholesterol slightly and lower triglycerides by about 10-15%.

  34. Which one of the following describes the effect of the thiazolidinediones? • ( A ) Inducing weight loss effect( B ) Decreasing low-density lipoprotein cholesterol( C ) Increasing production of insulin from pancreatic beta cells( D ) Increasing glucose transporter expression

  35. Critique (Correct Answer = D) • Resistance to the action of insulin is a prime cause of the hyperglycemia in most patients with type 2 diabetes. The thiazolidinediones are a group of drugs that improve sensitivity to insulin in several tissues by binding to PPAR-γ receptors, leading to increased expression of glucose transporters. The agent causes weight gain when used as monotherapy and in combination with insulin. Serum triglyceride values fall, whereas both LDL and HDL cholesterol values increase; the rise in LDL cholesterol in several studies is about 10% to 15%. The currently available thiazolidinediones, rosiglitazone and proglitazone, are equally effective in lowering glucose in patients with type 2 diabetes mellitus. Hemoglobin A1C levels fall about 1.5% in studies of these agents. Several cases of severe liver toxicity have been reported after troglitazone therapy, so it was removed from the market in March of 2000. The U.S. Food and Drug Administration recommends baseline and every 2 month monitoring of liver function tests during the first year of therapy if this class of drugs is used. The incidence of elevated liver enzyme levels in patients treated with proglitazone and rosiglitazone are 0.25% and 0.2% respectively, values similar to those in patients receiving placebos.

  36. Insulin Therapy in Type II DM • Newly diagnosed patients with DM2 have < 50% of normal insulin secretion at diagnosis • < 25% of normal insulin secretion 6 years after diagnosis

  37. Indications for Insulin Therapy in Type II DM • Why • More than 30% of type 2 diabetics require insulin • Progressive β-cell deterioration • Addition of a qHS basal insulin can reduce the Hgb A1C level from 8.6% to 6.9 % (Yale, Annal Int Med, 2001) • When • Persistent Fasting plasma glucose ≥ 250 mg/dL • Hgb A1C > 8% on maximum oral therapy • Hepatic or renal dysfunction that prohibits oral agents • All pregnant type II diabetics • All oral agents are contraindicated • How • UKPDS showed combination therapy with insulin and oral agent had better control • No recommended combinations at this time • Metformin + sulfonylurea + insulin • Sulfonylurea + bedtime insulin • Lispro + glyburide • Not recommended: thiazolidinediones + insulin = HYPOGLYCEMIA

  38. A 56-year-old overweight woman has had urinary frequency, nocturia, and dysuria for 5 days. She also reports increasing thirst. • On physical examination, her temperature is normal, she appears dehydrated, and has no costovertebral angle tenderness. Her plasma glucose concentration is 620 mg/dL. Urinalysis reveals 4+ glucose, no ketones, strongly positive protein, and 8 to 10 leukocytes per high-power field. Antibiotic therapy is begun for the urinary tract infection. • Which one of the following therapies is the most appropriate at this time? • ( A ) Sulfonylurea( B ) Diet and exercise program( C ) Insulin( D ) Metformin( E ) α-Glucosidase inhibitor

  39. Critique (Correct Answer = C) • The therapeutic goals in this patient are to alleviate symptoms and control hyperglycemia. When a newly diagnosed patient has symptoms, evidence of a urinary tract infection and markedly elevated plasma glucose concentration, treatment with insulin is the best assurance that symptoms will resolve and that the infection will respond readily to appropriate therapy. Hospitalization is usually not warranted unless ketoacidosis or severe dehydration and hypotension are present. Some patients will respond to oral agents, such as metformin, but that response may be slow and insufficient to alleviate symptoms. After prolonged periods of markedly elevated glucose, the response to sulfonylureas is blunted as the beta cells of the pancreas produce little or no insulin because of the glucose toxicity. After 6 to 8 weeks of good glycemic control effected by insulin, therapy may be switched to an oral agent if the patient prefers. A benefit of tight glycemic control with intensive insulin therapy in such patients is the reversal of glucose toxicity, with the improvement of both insulin sensitivity and insulin secretion. α-Glucosidase inhibitors like acarbose, reduce postprandial hyperglycemia by delaying glucose absorption, but do no affect glucose utilization or insulin secretion. They are less potent agents and therefore would not be the correct agents to use to control her hyperglycemia. • Every patient with newly diagnosed diabetes mellitus should be offered an educational program that emphasizes the importance of diet and exercise. In symptomatic patients with this severe a degree of hyperglycemia, diet and exercise are inadequate to achieve the desired goals.

  40. Initial Visit • History • Physical – don’t forget eye exam and foot exam (monofilament) • Labs • Fasting Chem 7, Hgb A1C (not diagnostic!!!), fasting lipids, LFTs, UA with urine microalbumin, TSH • ECG

  41. Prevent, Monitor, Manage and Educate • Diet, exercise, weight control • Smoking cessation • Blood pressure (strict BP goals) • Lipids (remember DM = CAD equivalent) • Renal function • Annual eye exam • Podiatric/orthopedic exam • Pneumovax, influenza vaccine

  42. Prevent, Monitor, Manage and Educate • Weekly, monthly follow up • Diabetic education!!! • Medication administration • Blood glucose monitoring • Lifestyle changes • HgbA1C q 3-6 months along with any other labs • Support groups • Websites (www.diabetes.org) • Your encouragement, support

  43. Diabetic Complications • Coronary Artery Disease • Acute Complications • DKA, HONK • Hyperglycemia, Hypoglycemia • Long Term Complications • CAD • Peripheral Vascular Disease • Diabetic Retinopathy • Nonproliferative, proliferative • Diabetic Nephropathy • Diabetic Neuropathy • Peripheral Sensory • Cardiovascular Autonomic • Gastrointestinal Autonomic • Erectile dysfunction • Diabetic Foot • Dr. Attinger

  44. Cardiovascular Disease • BP goal < 130/80 • Lipids: LDL < 100, TG < 150, HDL > 40/50 • Statins for DM patients > 40 to achieve LDL reduction of 30% regardless of baseline (Heart Protection Study) • Aspirin for primary or secondary prevention • Smoking cessation • Cardiac stress testing • any symptoms – typical or atypical • abnormal EKG • h/o peripheral vascular disease • Sedentary lifestyle, age > 35 and plans to exercise • > 2 risk factors (dyslipidemia, HTN, smoking, FH, micro/macroalbuminuria)

  45. Peripheral vascular disease/Foot care • Examine feet at every visit • Check pedal pulses • Check skin and nails • Vibrations sense, monofilament exam • Recommend podiatry

  46. Retinopathy • Optimal glycemic and BP control can substantially reduce the risk and progression of DM retinopathy • Annual screening for most • Laser therapy can reduce the risk of vision loss in patients with high risk characteristics (disc neovascularization or vitreous hemorrhage with any retinal neovascularization)

  47. Retinopathy • Background retinopathy • Vision normal • Microaneurysms • Hemorrhages • Exudates • May see a macular star

  48. Pre-proliferativeRetinopathy • Cotton-wool spots • Venous dilatation • Large deep hemorrhages

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