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

anschmel@purdue.eduanschmel@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