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Diabetes Crash Diabetes Crash Course:Course:
The Outpatient The Outpatient SettingSetting
Dr. Andrew Schmelz, PharmDDr. Andrew Schmelz, PharmDPost-Doctoral Teaching FellowPost-Doctoral Teaching Fellow
Purdue UniversityPurdue UniversityOctober 7, 2008October 7, 2008
[email protected]@purdue.edu
ObjectivesObjectives
Upon completion of this crash course, Upon completion of this crash course, clerkship students will be able to:clerkship students will be able to:
Differentiate characteristics of Type 1 and Differentiate characteristics of Type 1 and Type 2 diabetes mellitusType 2 diabetes mellitus
Describe the literature supporting intensive Describe the literature supporting intensive therapy for treating hyperglycemiatherapy for treating hyperglycemia
State goals of therapy for patients with DMState goals of therapy for patients with DM Organize antidiabetic agents into groups Organize antidiabetic agents into groups
based on place in DM pharmacotherapybased on place in DM pharmacotherapy Recommend an appropriate medication Recommend an appropriate medication
regimen for DM based on patient-specific regimen for DM based on patient-specific parametersparameters
Major ClassificationsMajor Classifications
Type 1 DiabetesType 1 Diabetes – results from β-cell – results from β-cell destruction, usually leading to destruction, usually leading to absolute insulin deficiencyabsolute insulin deficiency
Type 2 DiabetesType 2 Diabetes – results from a – results from a progressive insulin secretory defect progressive insulin secretory defect on the background of insulin on the background of insulin resistanceresistance
Gestational DiabetesGestational Diabetes – diagnosed – diagnosed during pregnancyduring pregnancy
Clinical TrialsClinical Trials
DCCTDCCT: Type 1 patients: Type 1 patients– Improved glycemic control reduces the Improved glycemic control reduces the
risk and slow the progression of risk and slow the progression of microvascular diseasemicrovascular disease
EDICEDIC: Type 1 patients: Type 1 patients– Improved glycemic control protects Improved glycemic control protects
against the occurrence of macrovascular against the occurrence of macrovascular diseasedisease
UKPDSUKPDS: Type 2 patients: Type 2 patients– Strict glycemic control results in a Strict glycemic control results in a
reduction in risk of microvascular diseasereduction in risk of microvascular disease
Decrease in A1CDecrease in A1C
Secondary analysis revealed that Secondary analysis revealed that a 1% decrease in A1C was a 1% decrease in A1C was associated with:associated with:– 35% reduction in microvascular 35% reduction in microvascular
endpointsendpoints– 18% reduction in MI18% reduction in MI– 17% reduction in all-cause 17% reduction in all-cause
mortality mortality
Glycemic GoalsGlycemic Goals
A1C is primary target for glycemic controlA1C is primary target for glycemic control A1C goal for patients A1C goal for patients in generalin general is 7% is 7% A1C goal for the A1C goal for the individual patientindividual patient is as is as
close to < 6% as possible without close to < 6% as possible without significant hypoglycemiasignificant hypoglycemia
Antidiabetic Antidiabetic MedicationsMedications
Patient CasePatient Case
BiguanidesBiguanides
Example: Metformin (Glucophage)Example: Metformin (Glucophage)– 500 mg daily or BID, Max: 2550 mg/day500 mg daily or BID, Max: 2550 mg/day
Lowers A1c 1.5-2% Lowers A1c 1.5-2% FIRST LINE FIRST LINE AGENTAGENT
MOA: Decreases hepatic glucose MOA: Decreases hepatic glucose production, increase response to insulinproduction, increase response to insulin
ContraindicationsContraindications– SCr > 1.5 (males) or 1.4 (females)SCr > 1.5 (males) or 1.4 (females)– Acute/chronic metabolic acidosisAcute/chronic metabolic acidosis– HF requiring treatmentHF requiring treatment
Biguanides (cont)Biguanides (cont)
Adverse EffectsAdverse Effects– GI: Diarrhea, flatulence, nauseaGI: Diarrhea, flatulence, nausea– Metallic tasteMetallic taste– Lactic acidosisLactic acidosis
MonitoringMonitoring– Therapeutic: A1c, FPGTherapeutic: A1c, FPG– AE: SCr (therapy initiation and annually), AE: SCr (therapy initiation and annually),
BMP, intoleranceBMP, intolerance Bottom LineBottom Line: Usually first choice for : Usually first choice for
Type II patients unless contraindicatedType II patients unless contraindicated
SulfonylureasSulfonylureas
Examples:Examples:– Glipizide (Glucotrol) 5 mg daily before Glipizide (Glucotrol) 5 mg daily before
breakfast, Clinical max: 20 mg dailybreakfast, Clinical max: 20 mg daily– Glyburide (DiaBeta, Micronase)Glyburide (DiaBeta, Micronase)– Glimepiride (Amaryl)Glimepiride (Amaryl)
Lower A1c 1.5-2% Lower A1c 1.5-2% FIRST LINE AGENT FIRST LINE AGENT MOA: Increase insulin secretionMOA: Increase insulin secretion Contraindications: Hypersensitivity Contraindications: Hypersensitivity
(sulfa)(sulfa)
Sulfonylureas (cont)Sulfonylureas (cont)
Adverse EffectsAdverse Effects– HypoglycemiaHypoglycemia– Some weight gainSome weight gain– Allergic skin reactions / photosensitivityAllergic skin reactions / photosensitivity
MonitoringMonitoring– Therapeutic: A1c, FBGTherapeutic: A1c, FBG– AE: FBGAE: FBG
Bottom LineBottom Line: Also used near : Also used near initiation of therapyinitiation of therapy
ThiazolidinedionesThiazolidinediones
Examples:Examples:– Pioglitazone (Actos) 15 mg daily, Max 45 Pioglitazone (Actos) 15 mg daily, Max 45
mg dailymg daily– Rosiglitazone (Avandia)Rosiglitazone (Avandia)
Lower A1c 1.0% Lower A1c 1.0% Alternative agent Alternative agent MOA: inhibit PPAR-gamma (improves MOA: inhibit PPAR-gamma (improves
cellular response to insulin)cellular response to insulin) Contraindications: CHF (also macular Contraindications: CHF (also macular
edema, risk for MI)edema, risk for MI)
TZDs (cont)TZDs (cont)
Adverse EffectsAdverse Effects– Hepatotoxicity (troglitazone pulled from Hepatotoxicity (troglitazone pulled from
market)market)– Exacerbation of CHFExacerbation of CHF– Macular edemaMacular edema
MonitoringMonitoring– Therapeutic: A1c, FBGTherapeutic: A1c, FBG– AEs: LFTs (baseline, periodically, d/c if AEs: LFTs (baseline, periodically, d/c if
>3 X ULN), CHF sxs, visual disturbances>3 X ULN), CHF sxs, visual disturbances Bottom LineBottom Line: Use only if near A1c : Use only if near A1c
goalgoal
Alpha-Glucosidase Alpha-Glucosidase InhibitorsInhibitors
Examples:Examples:– Acarbose (Precose) 25 mg 15-30 mins AC, Acarbose (Precose) 25 mg 15-30 mins AC,
Max 300 mg dailyMax 300 mg daily– Miglitol (Glyset)Miglitol (Glyset)
Lower A1c < 1.0% Lower A1c < 1.0% Special niche only Special niche only MOA: inhibit intestinal alpha-glucosidaseMOA: inhibit intestinal alpha-glucosidase Contraindications: DKA, IBD, colonic Contraindications: DKA, IBD, colonic
ulceration, intestinal obstructionulceration, intestinal obstruction
AGIs (cont)AGIs (cont)
Adverse effectsAdverse effects– GI: flatulence, diarrhea, abdominal GI: flatulence, diarrhea, abdominal
pain/crampspain/cramps– RashRash– Increased LFTsIncreased LFTs
MonitoringMonitoring– Therapeutic: A1c, FBGs, post-prandial Therapeutic: A1c, FBGs, post-prandial
glucoseglucose– AE: LFTs, s/sxs rash, intoleranceAE: LFTs, s/sxs rash, intolerance
Bottom LineBottom Line: Only for lowering PPG: Only for lowering PPG
MeglitinidesMeglitinides
Examples:Examples:– Repaglinide (Prandin) 4 mg TID with Repaglinide (Prandin) 4 mg TID with
meals, Max 12 mg TIDmeals, Max 12 mg TID– Nateglinide (Starlix)Nateglinide (Starlix)
Lower A1c 0.8-1% Lower A1c 0.8-1% Special niche Special niche onlyonly
MOA: Stimulate insulin secretionMOA: Stimulate insulin secretion Contraindications: Really, noneContraindications: Really, none
Meglitinides (cont)Meglitinides (cont)
Adverse EffectsAdverse Effects– Hypoglycemia (less than SUs)Hypoglycemia (less than SUs)– Weight gainWeight gain
MonitoringMonitoring– Therapeutic: A1c, FBGsTherapeutic: A1c, FBGs– AE: FBGAE: FBG
Bottom LineBottom Line: Alternative for pts : Alternative for pts unable to take sulfonylureaunable to take sulfonylurea
GLP-1 System DrugsGLP-1 System Drugs
First example:First example:– Exenatide (Byetta) 5 mcg SQ BID, Max Exenatide (Byetta) 5 mcg SQ BID, Max
10 mcg BID10 mcg BID Lowers A1c 0.8-1% Lowers A1c 0.8-1% Alternative Alternative
agentagent MOA: Synthetic GLP-1MOA: Synthetic GLP-1 Contraindications: Really, noneContraindications: Really, none
GLP-1 System Drugs GLP-1 System Drugs (cont)(cont)
Adverse EffectsAdverse Effects– Nausea (dose-dependant)Nausea (dose-dependant)– HypoglycemiaHypoglycemia– PancreatitisPancreatitis
MonitoringMonitoring– Therapeutic: A1c, FBGsTherapeutic: A1c, FBGs– AEs: FBGsAEs: FBGs
Bottom LineBottom Line: New drug, place in : New drug, place in therapy TBDtherapy TBD
GLP-1 System Drugs GLP-1 System Drugs (cont)(cont)
Second example:Second example:– Sitagliptin (Januvia) 100 mg daily (lower Sitagliptin (Januvia) 100 mg daily (lower
doses per renal function)doses per renal function) Lowers A1c 0.7-0.8 Lowers A1c 0.7-0.8 Alternative Alternative
agentagent MOA: inhibits DDP-IVMOA: inhibits DDP-IV Contraindications: Really, noneContraindications: Really, none
GLP-1 System Drugs GLP-1 System Drugs (cont)(cont)
Adverse EffectsAdverse Effects– Very little HAVery little HA
MonitoringMonitoring– Therapeutic: A1c, FBGsTherapeutic: A1c, FBGs
Bottom LineBottom Line: New drug, place in : New drug, place in therapy TBDtherapy TBD
Amylin AnalogsAmylin Analogs
Example:Example:– Pramlintide (Symlin) 60 mcg before Pramlintide (Symlin) 60 mcg before
meals, Max 120 mcgmeals, Max 120 mcg Lowers A1c 0.5-0.6 Lowers A1c 0.5-0.6 Not very good, Not very good,
used in combination with insulinused in combination with insulin MOA: Synthetic analog of amylinMOA: Synthetic analog of amylin Contraindications: Really, noneContraindications: Really, none
Amylin Analogs (cont)Amylin Analogs (cont)
Adverse effectsAdverse effects– NV, anorexia (decrease over time, delay NV, anorexia (decrease over time, delay
dose increase until nausea resolves)dose increase until nausea resolves)– HypoglycemiaHypoglycemia
MonitoringMonitoring– Therapeutic: A1c, FBGsTherapeutic: A1c, FBGs– AEs: FBGs, sxs NVAEs: FBGs, sxs NV
Bottom LineBottom Line: Utility? Only agent : Utility? Only agent besides insulin for Type 1 patientsbesides insulin for Type 1 patients
ComparisonComparison
AgentAgent FBG ↓ FBG ↓ (mg/dL(mg/dL
))
A1C A1C ↓↓
HypoglyceHypoglycemiamia
Weight Weight EffectsEffects
SulfonylureasSulfonylureas 50-6050-60 1.5-21.5-2 YesYes GainGain
MetforminMetformin 50-7850-78 1.5-21.5-2 NoNo --
αα-glucosidase -glucosidase inhibitorsinhibitors
10-2510-25 <1.0<1.0 NoNo --
ThiazolidinedioThiazolidinedionesnes
45-6545-65 1.01.0 NoNo GainGain
MeglitinidesMeglitinides 30-5030-50 0.8-10.8-1 YesYes GainGain
ExenatideExenatide 10-2510-25 0.8-10.8-1 NoNo LossLoss
SitagliptinSitagliptin 15-2015-20 0.7-0.7-0.0.88
NoNo --
PramlintidePramlintide 10-2010-20 0.5-0.5-0.0.66
YesYes LossLoss
InsulinInsulin ↓↓↓↓ >2.0>2.0 YesYes GainGain
InsulinsInsulins
Rapid-actingRapid-acting Peak ~ 1 hour Peak ~ 1 hour– Lispro (Humalog), Aspart (Novolog), Apidra Lispro (Humalog), Aspart (Novolog), Apidra
(Glulysine)(Glulysine) Fast-actingFast-acting Peak ~ 3 hours Peak ~ 3 hours
– Regular (Humulin R, Novolin R)Regular (Humulin R, Novolin R) Intermediate-actingIntermediate-acting Peak ~ 8 hours Peak ~ 8 hours
– NPH (Humulin N, Novolin N)NPH (Humulin N, Novolin N) Long-actingLong-acting
– Glargine (Lantus), Detemir (Levimir)Glargine (Lantus), Detemir (Levimir)
AS Case (cont)AS Case (cont)
DateDate BreakfastBreakfast LunchLunch DinnerDinner BedtimBedtimee
2/032/03 197197 298298
2/042/04 7070 178178
2/052/05 220220 276276
2/062/06 6767 145145
2/072/07 260260 259259
2/082/08 5858 121121
2/092/09 234234 267267
2/102/10 7272 132132
Lantus 34 units QHS and Humalog 6 units before meals