Ambulatory: Diabetes Mellitus

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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 - PowerPoint PPT Presentation

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  • Ambulatory:Diabetes MellitusApril 9, 2007

  • SubtypesInsulin dependent (Type 1 /IDDM)Abrupt onset, < 30 yrsAutoimmune insulin deficiency due to islet cell destructionProne to ketoacidosis Non-insulin dependent (Type 2/NIDDM)Gradual onset, > 30 yrsObesityInsulin resistanceImpaired insulin secretion (beta cell dysfunction)

  • Type I DMInsulin deficiency secondary to -cell destruction usually by autoimmune processInsulin and C-peptide levels lowMay have islet cell autoantibodies, Autoantibodies to insulin, or antibodies to glutamic acid decarboxylase or tyrosine phosphatases. 20% risk of other autoimmune diseasesTypically will present with DKA due to absolute lack of insulin

  • Type IIInsulin resistance and relative insulin deficiency - -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.

  • SubtypesGestational DiabetesDysfunction of glucose metabolism with presentation in pregnancyIncreased fetal morbidityUp to 63% will develop non-gestational DM in 5-16 yearsMODY (maturity-onset diabetes of the young)Subset of Type 2 DMFamily history, early age of onset (teens, 20s)At least 5 subtypesImpairment of -cell functionResistance to ketoacidosis

  • SubtypesSecondary DiabetesPancreatic disease with resultant insulinopeniaChronic pancreatitis, pancreatectomy, CF, hemachromatosisDrug inducedHCTZ, steroids, estrogen, psychoactive agents, catacholamines, pentamidine

  • Subtypes EndocrinopathiesAcromegaly, pheochromocytoma, Cushings, Conns, glucagonomaInsulin receptor abnormalitiesGenetic syndromesHyperlipidemia, muscular dystrophies, Huntingtons chorea

  • DiagnosisPer the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003

  • Symptoms of DiabetesClassicPolyuria, polydipsia, unexplained weight LOSSFatigueBlurry visionNausea, vomitingInfections

  • Screening for DiabetesEvery 3 years if age 45 or older (if results are normal)More frequent screening if:Pre-DiabeticFasting plasma glucose concentration > 110 mg/dL or < 126 mg dLa.k.a. impaired fasting glucose or impaired glucose toleranceObese (BMI27)1st degree relatives with DMHigh risk ethnic groupAfrican-American, Hispanic-American, Native-American, Asian-American, Pacific Islander-AmericanPregnancy History of Gestational diabetesDelivery of baby weighing 9 or more poundsHTN (>140/90)DyslipidemiaHDL35 mg/dL, TGL250 mg/dL

  • Treatment rationaleDCCTRG39% reduction in progression of retinopathy for 0.9% reduction in HbA1cUKPDSGHbA1c of 7% associated with significant incidence of micro and macrovascular disease

  • Treatment RationaleMeticulous glucose control decreases long-term microvascular complication ratesAggressive insulin therapy in patients with a recent MI was associated with reduced mortality

  • Treatment of Diabetes MellitusGoals set by American Diabetes AssociationPreprandial glucose values of 80 to 120 mg/dLBedtime glucose values of 100 to 140 mg/dLHemoglobin A1C < 7%2 hour post-prandial glucose values < 160 mg/dL

  • Treatment of Type 1 Diabetes MellitusNeed insulinHealthy people generally have insulin production of 24-36 units per dayType 1 DM0.5 to 1.0 units/kg of insulin dailyVaries according to diet, exercise, stressVarious insulin preparations with various regimensTailor to the patientAttempt to mimic the healthy persons insulin peaks and valleys

  • Treatment of Type 1 Diabetes MellitusRapid Acting InsulinsLispro, AspartShort Acting InsulinsRegularIntermediate ActingNPHLenteLong ActingUltralenteGlargine

  • Pharmacokinetics of current insulin preparations Insulin Onset Peak Effective duration

    Lispro (Humalog)

  • Basal/Bolus regimenBasal/Bolus regimenDaily insulin dose consists of a basal insulin to inhibit hepatic glucose production and pre-meal insulin to cover intakemimics natural insulin productionTypically 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 insulinRequires multiple insulin injections and accuchecks, but provides greater flexibility in matching insulin to meal.

  • Treatment of Type 1 Diabetes MellitusPancreas Transplant with or without Kidney transplantTo help protect the transplanted kidney from hyperglycemiaMeet certain criteria, in general, frequent, acute metabolic complications and failure with insulin therapySurvival, immunosuppressionPancreatic islet cell transplantSimilar criteriaImmunosuppression

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

  • Treatment of Type 2 DiabetesInsulin Secretagogues (Beta-beaters)SulfonylureaMeglitinidesBiguanides decrease hepatic gluconeogenesisMetforminThiazolidinediones insulin sensitizerThe glitizonesAlpha-glucosidase Inhibitors decreased GI absorptionAcarbose

  • SulfonylureaFirst line after diet and exercise20-25% primary failure rateCaution in hepatic/renal dysfunctionMechanism of actionPromote increased pancreatic secretionSide effectsHypoglycemia, usually within 1st 4 monthsIncreased in elderly, worsening renal function, irregular meal schedulesWeight gainMedicationsGlyburide (Micronase, Diabeta)Duration of action 18-24 hoursHypoglycemia still commonGlipizide (Glucotrol)Glimepiride (Amaryl)Indicated for use with insulinsafe in renal failure

  • Meglitinides (rapid acting secretogogues)Theoretically offers improved post prandial controlMay benefit patients with unpredictable meal schedules or large post prandial glucose levelsQ meal dosingMechanism of actionSimilar to sulfonylureas, quicker on-off actionSide effectsHypoglycemiaWeight gainMedicationsRepaglinide (Prandin)Nataglinide (Starlix)Ultra short actingMost effective agent for post-prandial controlHypoglycemic contraindication with insulin

  • BiguanidesWeight loss due to appetite reductionLess hypoglycemia than sulfonylurea therapyMajor effects:Increased hepatic insulin sensitivity Decreased gluconeogenesis and glycogenolysisSide effectsLACTIC ACIDOSISGI intoleranceMechanism of action is unclearMedicationMetformin (Glucophage)Optimal dose 2000mg/dBID dosing

  • BiguanidesContraindications to metformin Serum creatinine >= 1.5 mg/dL in men, >= 1.4 mg/dL in womenAge > 75yearsDiscontinue before any radiologic contrast studies (stop during or before) or upon hospitalizationHepatic dysfunctionDehydrationMetabolic acidosisCHF requiring treatment

  • Thiazolidinediones (TZD)Mechanism of actionNot fully understoodDecrease insulin resistance, increase insulin sensitivity, probably at the peripheral skeletal muscle? Smaller effect on liver gluconeogenesisAdditive effect with metforminFavorable lipid profile effects, ? atherosclerosisSide effectsWeight gainEdema caution with CHFHypoglycemia, especially if coupled with other diabetic medicationLiver dysfunction? monitor LFTsMedicationsRosiglitizone (Avandia) - increase HDL levels Pioglitizone (Actos) - increase HDL, decrease TG levelsContraindicated: Hepatic dysfunctionAge greater than 80Advanced CHF

  • Thiazolidinediones (TZD)Monotherapy or combo with metformin, sulfonylureas, and insulin

    Other effects:Slightly reduce BPEnhance fibrinolysisImprove endothelial function

  • Alpha-glucosidase InhibitorsDecreases digestion of complex carbohydrates in small bowelSlows monosaccharide absorptionEffective only with diets >40% carbohydratesLowers post-prandial>pre-prandial glucoseNot as efficacious as other agents (decreases A1C by 0.5% - 1%)Side effects major limitationGas, abdominal pain, diarrheaMinimized with slow titrationMedicationsAcarbose (Precose)Miglitol (Glyset)

  • Oral Agent Monotherapy and Glycemic Control

    Drug

    Baseline HbA1c

    Decrease in HbA1c (%)

    Sulfonylurea

    Glipizide XL

    8.7

    1.8

    Glimepiride

    8.1

    1.9

    Rapid acting secretogogue

    Repaglinide

    8.7

    1.8

    Nateglinide

    8.1

    0.9

    Biguanide

    Metformin

    8.4

    1.8

    Alpha-glucosidase

    Inhibitor

    Miglitol

    8.9

    0.74

    Thiazolidinediones

    Rosiglitazone

    8.8

    1.5

    Pioglitazone

    10.3

    1.6

    Miscellaeous

    Glucovance

    8.2

    1.5

  • Combination Oral TherapyLowers 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 anotherThus, patients with an HbA1C >9% who are receiving monotherapy are unlikely to reach a target of
  • 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 f