11

Update on the Update on the Pharmacological Treatments Pharmacological Treatments

for Diabetes Mellitusfor Diabetes Mellitus

Scott K. Stolte, Pharm.D.Scott K. Stolte, Pharm.D.Chair, Department of Pharmacy PracticeChair, Department of Pharmacy Practice

Bernard J. Dunn School of PharmacyBernard J. Dunn School of PharmacyShenandoah UniversityShenandoah University

This program has been made possible by an education grant from Pfizer Labs.

22

ObjectivesObjectives

At the completion of this program, the At the completion of this program, the participant will be able to:participant will be able to:– Identify the mechanisms of action, Identify the mechanisms of action,

pharmacology and the other important pharmacology and the other important information for the medications used to information for the medications used to treat both types of diabetes.treat both types of diabetes.

– Apply information about diabetes that Apply information about diabetes that has application in the daily practice of has application in the daily practice of pharmacy.pharmacy.

– Enhance the understanding of new Enhance the understanding of new treatment approaches for diabetes.treatment approaches for diabetes.

33

BackgroundBackground

About 18.2 million people with DMAbout 18.2 million people with DM Approximately 33% undiagnosedApproximately 33% undiagnosed 6.3% of US adults have DM6.3% of US adults have DM Higher prevalence:Higher prevalence:

– Ethnic Groups – AA, NA, LatinoEthnic Groups – AA, NA, Latino– Increased age and weightIncreased age and weight

44

BackgroundBackground

IncidenceIncidence– 625,000 cases diagnosed each year625,000 cases diagnosed each year

ImpactImpact– Leading cause of adult blindness (25x), Leading cause of adult blindness (25x),

renal failure (17x), nontraumatic renal failure (17x), nontraumatic amputation (5x)amputation (5x)

– 55thth leading cause of death due to disease leading cause of death due to disease– Direct and indirect medical costs > 50 Direct and indirect medical costs > 50

billionbillion

55

PharmacotherapyPharmacotherapy

Oral HypoglycemicsOral Hypoglycemics– SulfonylureasSulfonylureas– MeglitinidesMeglitinides– Alpha-glucosidase inhibitorsAlpha-glucosidase inhibitors– BiguanidesBiguanides– ThiazolidinedionesThiazolidinediones

InsulinInsulin

66

SulfonylureasSulfonylureas

Pancreatic ActionsPancreatic Actions– Stimulates insulin release from pancreatic Stimulates insulin release from pancreatic ββ--

cells – Primary acute mechanismcells – Primary acute mechanism Down-regulation of this affect over timeDown-regulation of this affect over time

– No stimulation of insulin release in chronic No stimulation of insulin release in chronic therapy – How do they continue to work?therapy – How do they continue to work? Explanation not clearExplanation not clear Reduced plasma glucose may allow circulating insulin Reduced plasma glucose may allow circulating insulin

to have pronounced effects on target tissuesto have pronounced effects on target tissues Chronic hyperglycemia impairs insulin secretionChronic hyperglycemia impairs insulin secretion

77

SulfonylureasSulfonylureas

Other pancreatic actions:Other pancreatic actions:– Reduce hepatic clearance of insulinReduce hepatic clearance of insulin– Suppress glucagon release slightlySuppress glucagon release slightly– Stimulate somatostatin releaseStimulate somatostatin release

88

SulfonylureasSulfonylureas

Extrapancreatic effectsExtrapancreatic effects– Responsible for long-term efficacyResponsible for long-term efficacy– Reduce hepatic gluconeogenesisReduce hepatic gluconeogenesis– May increase insulin receptor sensitivity May increase insulin receptor sensitivity

and numberand number– Potentiation of post-receptor insulin Potentiation of post-receptor insulin

effects - Stimulate synthesis of glucose effects - Stimulate synthesis of glucose transporterstransporters

99

SulfonylureasSulfonylureas

Two categories based on potency, duration Two categories based on potency, duration of action, and drug interaction/side effect of action, and drug interaction/side effect profilesprofiles

First GenerationFirst Generation– Tolbutamide (ORINASE), Chlorpropamide Tolbutamide (ORINASE), Chlorpropamide

(DIABINESE) , Tolazamide (TOLINASE) , (DIABINESE) , Tolazamide (TOLINASE) , Acetohexamide (DYMELOR) Acetohexamide (DYMELOR)

Second GenerationSecond Generation– Glyburide (DIABETA, GLYNASE), Glipizide Glyburide (DIABETA, GLYNASE), Glipizide

(GLUCOTROL), Glimepiride (AMARYL) (GLUCOTROL), Glimepiride (AMARYL)

1010

SulfonylureasSulfonylureas

CharacteristicsCharacteristics– Administered orallyAdministered orally– Few therapeutic differences among Few therapeutic differences among

agentsagents– Should be administered 30 min. before Should be administered 30 min. before

breakfast for maximal absorptionbreakfast for maximal absorption– Dose can be increased every 1-2 weeksDose can be increased every 1-2 weeks– Metabolized in liver, mainly excreted in Metabolized in liver, mainly excreted in

urine (glyburide – 50% in feces)urine (glyburide – 50% in feces)

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SulfonylureasSulfonylureasDrugDrug OnseOnse

t (h)t (h)Half-life Half-life (h)(h)

Duration (h)Duration (h) Starting Starting DoseDose

Max. Max. dose/dadose/dayy

TolbutamideTolbutamide 11 5.65.6 6-126-12 1-2g/d in 2 1-2g/d in 2 or 3 dosesor 3 doses

2-3 g2-3 g

AcetohexamidAcetohexamidee

11 55 10-1410-14 250-1500 250-1500 mg/dmg/d

1.5 g1.5 g

TolazamideTolazamide 4-64-6 77 10-1410-14 100-250 100-250 mg/d in 1 mg/d in 1 or 2 dosesor 2 doses

750mg – 750mg – 1 g1 g

ChlorpropamiChlorpropamidede

11 3535 7272 250 mg/d250 mg/d 500 mg500 mg

GlyburideGlyburide 1.51.5 2-42-4 18-2418-24 2.5 mg/d2.5 mg/d 20 mg20 mg

Glyburide, Glyburide, micronizedmicronized

1.51.5 2-42-4 18-2418-24 1.5 mg/d1.5 mg/d 12 mg12 mg

GlipizideGlipizide 11 3-73-7 10-2410-24 5 mg/d5 mg/d 40 mg*40 mg*

GlimeperideGlimeperide 22 4-64-6 18-2818-28 1-2 1-2 mg/daymg/day

8 mg8 mg* - Doses above 15 mg/day should be divided and administered twice daily

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SulfonylureasSulfonylureas Adverse effectsAdverse effects

– Hypoglycemia – fairly commonHypoglycemia – fairly common– Skin reactions (3%) – rashes, pruritisSkin reactions (3%) – rashes, pruritis– GI GI – Rare hematologic reactionsRare hematologic reactions

Drug InteractionsDrug Interactions– Increase in concentration from liver metabolism Increase in concentration from liver metabolism

inhibition or protein binding displacement – inhibition or protein binding displacement – fluconazole, warfarinfluconazole, warfarin

– Decrease in effect by increasing liver Decrease in effect by increasing liver metabolism or inhibiting insulin release - metabolism or inhibiting insulin release - rifampin, beta-blockersrifampin, beta-blockers

1313

MeglitinidesMeglitinides

Repaglinide (PRANDIN) Repaglinide (PRANDIN) – Nonsulfonylurea moiety of glyburideNonsulfonylurea moiety of glyburide

Nateglinide (STARLIX) Nateglinide (STARLIX) – Amino acid derivativeAmino acid derivative

Pharmacologic effect is the same as Pharmacologic effect is the same as sulfonylureassulfonylureas

Shorter duration of actionShorter duration of action

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RepaglinideRepaglinide

Absorbed rapidly from the GI tractAbsorbed rapidly from the GI tract Peak serum concentrations obtained Peak serum concentrations obtained

within 1 hourwithin 1 hour Half-life is about 1 hourHalf-life is about 1 hour Metabolized mainly by the liver – Metabolized mainly by the liver –

metabolites are inactivemetabolites are inactive 10% metabolized by the kidney10% metabolized by the kidney

1515

RepaglinideRepaglinide

Starting Dose – 0.5 mg po tid taken Starting Dose – 0.5 mg po tid taken immediately before eating each mealimmediately before eating each meal

Can increase dose every weekCan increase dose every week Maximum dose = 4 mg po tidMaximum dose = 4 mg po tid Main adverse effect is hypoglycemiaMain adverse effect is hypoglycemia Drug InteractionsDrug Interactions

– Metabolized by CYP450 3A4Metabolized by CYP450 3A4– May interact with inhibitors or inducers of that May interact with inhibitors or inducers of that

enzymeenzyme– Erythromycin, Azole antifungals, cimetidine, Erythromycin, Azole antifungals, cimetidine,

etc.etc.

1616

NateglinideNateglinide

Starting and maintenance dose – 120 Starting and maintenance dose – 120 mg po tid 1-30 minutes before mealsmg po tid 1-30 minutes before meals

Dose should be skipped if meal is Dose should be skipped if meal is skippedskipped

Highly bound to plasma proteinsHighly bound to plasma proteins– Clinical significance unknownClinical significance unknown

Metabolized in the liver by CYP450 2C9 Metabolized in the liver by CYP450 2C9 and 3A4and 3A4– Clinically significant interactions unknownClinically significant interactions unknown

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Alpha-Glucosidase InhibitorsAlpha-Glucosidase Inhibitors Acarbose (PRECOSE) Acarbose (PRECOSE) Miglitol (GLYSET) Miglitol (GLYSET) Mechanism of ActionMechanism of Action

– Inhibition of membrane bound intestinal brush Inhibition of membrane bound intestinal brush border alpha glucosidase enzymeborder alpha glucosidase enzyme

– Membrane-bound intestinal alpha-glucosidases Membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides and disaccharides hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the to glucose and other monosaccharides in the brush border of the small intestinebrush border of the small intestine

– Enzyme inhibition results in delayed glucose Enzyme inhibition results in delayed glucose absorption and lowering of postprandial absorption and lowering of postprandial hyperglycemia hyperglycemia

1818

AcarboseAcarbose

Not absorbed from the GI tractNot absorbed from the GI tract Will not induce hypoglycemia with Will not induce hypoglycemia with

monotherapymonotherapy Onset – 0.5 hrs.Onset – 0.5 hrs. Half-life – 1 to 2 hrs.Half-life – 1 to 2 hrs. Duration – 4 hrs.Duration – 4 hrs. Recommended starting dose – 25 mg/d with Recommended starting dose – 25 mg/d with

first bite of main meal, possibly 25 mg po tidfirst bite of main meal, possibly 25 mg po tid Max. dose/day – 300 mgMax. dose/day – 300 mg

1919

MiglitolMiglitol

Dose-dependent absorption from the GI tractDose-dependent absorption from the GI tract Absorption not related to therapeutic efficacyAbsorption not related to therapeutic efficacy Excreted in urine as unchanged drug (95%)Excreted in urine as unchanged drug (95%) Initial dose – 25 mg po tid with first bite of Initial dose – 25 mg po tid with first bite of

each main meal, some may need lower dose each main meal, some may need lower dose to minimize GI adverse eventsto minimize GI adverse events

Max. daily dose – 100 mg po tidMax. daily dose – 100 mg po tid

2020

Adverse EventsAdverse Events

Mainly GI Mainly GI – Abdominal pain – 11%Abdominal pain – 11%– Diarrhea – 29%Diarrhea – 29%– Flatulence – 42%Flatulence – 42%– Abdominal pain and diarrhea diminish Abdominal pain and diarrhea diminish

with continued treatmentwith continued treatment– AE’s minimized by starting at low dose AE’s minimized by starting at low dose

and utilizing slow dosage titrationand utilizing slow dosage titration Skin rash – 4.3%Skin rash – 4.3%

2121

Other ConsiderationsOther Considerations

Not recommended for patients with Not recommended for patients with inflammatory bowel diseaseinflammatory bowel disease

May alter liver function at high dosesMay alter liver function at high doses Diet and activity may have to be Diet and activity may have to be

altered to limit production of gasaltered to limit production of gas Often used in combination with other Often used in combination with other

antidiabetic agentsantidiabetic agents

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BiguanidesBiguanides

Metformin (GLUCOPHAGE) Metformin (GLUCOPHAGE) Mechanism of actionMechanism of action

– Decreases hepatic glucose production – Decreases hepatic glucose production – reduces gluconeogenesisreduces gluconeogenesis

– Decreases intestinal absorption of glucoseDecreases intestinal absorption of glucose– Improves insulin sensitivity (increases Improves insulin sensitivity (increases

peripheral glucose uptake and utilization) peripheral glucose uptake and utilization) – Does not produce hypoglycemia as Does not produce hypoglycemia as

monotherapymonotherapy

2323

MetforminMetformin

Absolute bioavailability is 50-60% - Absolute bioavailability is 50-60% - fastingfasting

Not bound to plasma proteinsNot bound to plasma proteins Excreted unchanged in the urineExcreted unchanged in the urine Does not undergo hepatic metabolismDoes not undergo hepatic metabolism Starting dose – 500 mg bid with Starting dose – 500 mg bid with

morning and evening mealsmorning and evening meals– Can be increased at rate of 1 tab/weekCan be increased at rate of 1 tab/week

Maximum daily dose – 2550 mg/dayMaximum daily dose – 2550 mg/day

2424

MetforminMetformin

Adverse reactionsAdverse reactions– GIGI

N/V/D, bloating, flatulence, anorexiaN/V/D, bloating, flatulence, anorexia Resolve spontaneously with continued Resolve spontaneously with continued

treatmenttreatment Decreased with gradual dose escalation and Decreased with gradual dose escalation and

administration with foodadministration with food

– Asymptomatic subnormal Vit. B12 Asymptomatic subnormal Vit. B12 concentrations-reversed by calcium supp.concentrations-reversed by calcium supp.

– Unpleasant metallic taste (3%)Unpleasant metallic taste (3%)

2525

MetforminMetformin

Drug InteractionsDrug Interactions– Cationic drugs that are excreted by renal Cationic drugs that are excreted by renal

tubular secretiontubular secretion– Compete with metformin for excretionCompete with metformin for excretion– Could increase metformin concentrationsCould increase metformin concentrations– Cimetidine, amiloride, digoxin, morphine, Cimetidine, amiloride, digoxin, morphine,

procainamide, quinidine, quinine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and ranitidine, triamterene, trimethoprim, and vancomycinvancomycin

– Theoretical except for cimetidine Theoretical except for cimetidine

2626

Metformin PrecautionsMetformin Precautions

Lactic acidosisLactic acidosis– Rare, but very serious (50% mortality)Rare, but very serious (50% mortality)– Occurs due to metformin accumulationOccurs due to metformin accumulation– Plasma levels > 5 mcg/mLPlasma levels > 5 mcg/mL– 0.03 cases/1000 patient years0.03 cases/1000 patient years– Increased risk with significant renal insufficiency, Increased risk with significant renal insufficiency,

CHFCHF– Hepatic disease increases risk – not often usedHepatic disease increases risk – not often used– Excessive alcohol intakeExcessive alcohol intake– Metformin should be D/C’d prior to radiocontrast Metformin should be D/C’d prior to radiocontrast

dye and held for 24 hours after administrationdye and held for 24 hours after administration

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Metformin PrecautionsMetformin Precautions

Renal functionRenal function– Should be assessed prior to starting Should be assessed prior to starting

metformin and at least yearly thereaftermetformin and at least yearly thereafter– Not generally used in patients with SrCr Not generally used in patients with SrCr

above upper limits of normal for age (SrCr above upper limits of normal for age (SrCr > 1.5 for males, 1.4 for females)> 1.5 for males, 1.4 for females)

– Caution with elderly patientsCaution with elderly patients Contraindicated in CHF requiring drug Contraindicated in CHF requiring drug

therapytherapy

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ThiazolidinedionesThiazolidinediones Pioglitazone (ACTOS) Pioglitazone (ACTOS) Rosiglitazone (AVANDIA) Rosiglitazone (AVANDIA) Mechanism of ActionMechanism of Action

– Improve glycemic control by improving insulin sensitivity Improve glycemic control by improving insulin sensitivity – Highly selective and potent agonists for the peroxisome Highly selective and potent agonists for the peroxisome

proliferator-activated receptor-gamma (PPARg)proliferator-activated receptor-gamma (PPARg)– P.A. receptors are found in key target tissues for insulin P.A. receptors are found in key target tissues for insulin

action such as adipose tissue, skeletal muscle, and liveraction such as adipose tissue, skeletal muscle, and liver– Activation of PPARg nuclear receptors regulates Activation of PPARg nuclear receptors regulates

transcription of insulin responsive genes involved in the transcription of insulin responsive genes involved in the control of glucose production, transport, and utilizationcontrol of glucose production, transport, and utilization

– PPARg-responsive genes also participate in the PPARg-responsive genes also participate in the regulation of fatty acid metabolism. regulation of fatty acid metabolism.

– Require insulin to be present for actionRequire insulin to be present for action– May also lower liver glucose productionMay also lower liver glucose production

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RosiglitazoneRosiglitazone

Absolute bioavailability – 99%Absolute bioavailability – 99% Half-life – 3 to 4 hoursHalf-life – 3 to 4 hours Peak concentration – 1 hr.Peak concentration – 1 hr. Maximal clinical effect in 6-12 weeksMaximal clinical effect in 6-12 weeks Highly protein bound, mostly albuminHighly protein bound, mostly albumin Extensively metabolized, no unchanged Extensively metabolized, no unchanged

drug excreted (mostly CYP2C8, some drug excreted (mostly CYP2C8, some 2C9)2C9)

Excreted in urine (64%) and feces (23%)Excreted in urine (64%) and feces (23%)

3030

RosiglitazoneRosiglitazone

DoseDose– Monotherapy or in combo. with metformin- 4 Monotherapy or in combo. with metformin- 4

mg administered qd or divided bid, dose may mg administered qd or divided bid, dose may be increased to 8 mg/day with inadequate be increased to 8 mg/day with inadequate response after 12 weeksresponse after 12 weeks

– Taken without regard to mealsTaken without regard to meals Hepatic ImpairmentHepatic Impairment

– Therapy not initiated with evidence of active Therapy not initiated with evidence of active liver disease or increased ALT (>2.5x upper liver disease or increased ALT (>2.5x upper limit of normal) at baselinelimit of normal) at baseline

– No evidence of induced hepatotoxicityNo evidence of induced hepatotoxicity

3131

RosiglitazoneRosiglitazone

Adverse reactionsAdverse reactions– Edema and anemia – mild to moderate, Edema and anemia – mild to moderate,

did not require drug D/Cdid not require drug D/C Drug Interactions – no clinically Drug Interactions – no clinically

significantsignificant PrecautionsPrecautions

– Ovulation - In premenopausal anovulatory Ovulation - In premenopausal anovulatory patients, treatment may result in patients, treatment may result in resumption of ovulationresumption of ovulation

3232

PioglitazonePioglitazone Characteristics very similar to rosiglitazoneCharacteristics very similar to rosiglitazone Therapy should not be initiated if clinical Therapy should not be initiated if clinical

evidence of active liver disease or ALT evidence of active liver disease or ALT exceeds 2.5 times the upper limit of normalexceeds 2.5 times the upper limit of normal– No evidence of drug-induced hepatotoxicityNo evidence of drug-induced hepatotoxicity

Metabolized by CYP 2C8 and to some Metabolized by CYP 2C8 and to some degree by CYP3A4degree by CYP3A4

Dose – 15 or 30 mg po qd, maximum 45 mg Dose – 15 or 30 mg po qd, maximum 45 mg qdqd– Without regard to mealsWithout regard to meals– Used in combination with sulfonylureas, Used in combination with sulfonylureas,

metformin, insulin metformin, insulin

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PioglitazinePioglitazine

Drug InteractionsDrug Interactions– Oral Contraceptives – troglitazine Oral Contraceptives – troglitazine

reduced plasma concs. of ethinyl reduced plasma concs. of ethinyl estradiol and norethindrone by 30%estradiol and norethindrone by 30% Due to 3A4 metabolismDue to 3A4 metabolism May lead to loss of contraceptionMay lead to loss of contraception Pioglitazone not investigatedPioglitazone not investigated

– Ketoconazole – inhibits metabolism, Ketoconazole – inhibits metabolism, monitor closelymonitor closely

– Other potential 3A4 interactions – no Other potential 3A4 interactions – no studiesstudies

3434

InsulinInsulin

Composed of two Composed of two peptide chainspeptide chains– A chain – 21 AA’sA chain – 21 AA’s– B chain – 30 AA’sB chain – 30 AA’s

Molecular Mass – Molecular Mass – 5734 Daltons5734 Daltons

3535

InsulinInsulin

ActionsActions– Increases glucose uptake by tissues Increases glucose uptake by tissues

(brain does not require insulin)(brain does not require insulin)– Increases liver glycogen productionIncreases liver glycogen production– Decreases glycogen breakdownDecreases glycogen breakdown– Increases fatty acid synthesisIncreases fatty acid synthesis– Inhibits breakdown of fatty acids to Inhibits breakdown of fatty acids to

ketone bodiesketone bodies– Promotes incorporation of AA’s into Promotes incorporation of AA’s into

proteinsproteins

3636

InsulinInsulin

Traditionally categorized by:Traditionally categorized by:– StrengthStrength– Onset and duration of action (PK)Onset and duration of action (PK)– Species sourceSpecies source– PurityPurity

Most important consideration now is PKMost important consideration now is PK– Most US patients on U-100 insulinMost US patients on U-100 insulin– Most use biosynthetic “human” insulin, may Most use biosynthetic “human” insulin, may

see some porcine or bovine usedsee some porcine or bovine used– All US insulin is purified All US insulin is purified

3737

Onset, Peak and Duration of Human Insulin Onset, Peak and Duration of Human Insulin PrepsPreps

Insulin TypeInsulin Type Onset (h)Onset (h) Peak (h)Peak (h) Effective Duration (h)Effective Duration (h)

Rapid-actingRapid-acting

Lispro (Humalog)Lispro (Humalog)0.250.25 0.5-1.50.5-1.5 2-42-4

Rapid-actingRapid-acting

Aspart (Novolog)Aspart (Novolog)0.250.25 0.6-10.6-1 3-53-5

Rapid ActingRapid Acting

Glulisine (Apidra)Glulisine (Apidra)0.25 – 0.50.25 – 0.5 1-21-2 3-43-4

Short-acting RegularShort-acting Regular 0.5-10.5-1 2-32-3 4-64-6

Intermediate Acting NPHIntermediate Acting NPH 2-42-4 4-104-10 10-1610-16

Intermediate Acting LenteIntermediate Acting Lente 3-43-4 4-124-12 12-1812-18

Long ActingLong Acting

UltralenteUltralente6-106-10 MinimalMinimal 14-2414-24

Long Acting Long Acting

Detemir (Levemir)Detemir (Levemir)???? 6-86-8 12-2412-24

Long ActingLong Acting

Insulin Glargine(Lantus)Insulin Glargine(Lantus)1-2 hours1-2 hours NoneNone 24-2824-28

3838

Insulin FormulationsInsulin Formulations

Insulin lispro and aspart made by altering Insulin lispro and aspart made by altering insulin AA structureinsulin AA structure

NPH (neutral, protamine, Hagedorn) NPH (neutral, protamine, Hagedorn) insulin made by adding protamine and insulin made by adding protamine and zinc to neutral regular insulinzinc to neutral regular insulin

Lente and ultralente made by adding Lente and ultralente made by adding acetate buffers and zincacetate buffers and zinc

Regular, lispro, aspart, and glargine are Regular, lispro, aspart, and glargine are clear and colorless in vialclear and colorless in vial– Glargine precipitates at physiologic pHGlargine precipitates at physiologic pH

3939

Insulin ConsiderationsInsulin Considerations

Regardless of type, potency is the sameRegardless of type, potency is the same– 1 unit lowers BG by 30-45 mg/dL in normal, 1 unit lowers BG by 30-45 mg/dL in normal,

healthy subjectshealthy subjects Regular insulin, Velosulin (R insulin with Regular insulin, Velosulin (R insulin with

added buffers), Humalog, and probably added buffers), Humalog, and probably Novolog can be used in insulin pumpsNovolog can be used in insulin pumps

Insulin suspensions (intermediate and Insulin suspensions (intermediate and long-acting) must be administered long-acting) must be administered subQ, not IVsubQ, not IV

4040

Type 1 DiabetesType 1 DiabetesInsulinInsulin

Exubera - dosingExubera - dosing– Do not switch from SQ Do not switch from SQ

insulin insulin based on units-to-dosebased on units-to-dose

Based on weight – then Based on weight – then titratetitrate

– 1 mg capsule = ~ 3 u SQ 1 mg capsule = ~ 3 u SQ insulininsulin

– 3 mg capsule = ~8 u SQ 3 mg capsule = ~8 u SQ insulininsulin

1mg + 1mg + 1mg ≠ 3 mg1mg + 1mg + 1mg ≠ 3 mg

– Adjusting dose…Adjusting dose… Change dose in 1 mg Change dose in 1 mg

incrementsincrements

Weight Weight (pounds(pounds

))

Pre-prandial Pre-prandial dosedose

Total Total daily daily dosedose

66-8766-87 1 mg1 mg 3 mg3 mg

88-13288-132 1 mg + 1 1 mg + 1 mgmg

6 mg6 mg

133-133-176176

3 mg3 mg 9 mg9 mg

177-177-220220

3 mg + 1 3 mg + 1 mgmg

12 mg12 mg

221-221-264264

3 mg + 1 3 mg + 1 mg + 1 mgmg + 1 mg

15 mg15 mg

265-265-308308

3 mg + 3 3 mg + 3 mgmg

18 mg18 mg

309 +309 + 3 mg + 3 3 mg + 3 mg + 1 mgmg + 1 mg

21 mg21 mg

4141

Type 1 DiabetesType 1 DiabetesInsulinInsulin

Contraindications – Exubera Contraindications – Exubera – Smokers or smoked within 6 monthsSmokers or smoked within 6 months

Discontinue immediately if resume smokingDiscontinue immediately if resume smoking

– Lung disease – asthma, COPDLung disease – asthma, COPD– FEVFEV11 < 70% predicted < 70% predicted– ?? Bronchodilator use – can increase absorption ?? Bronchodilator use – can increase absorption

Monitoring – ExuberaMonitoring – Exubera– Spirometry – baseline, then at 6 months, then Spirometry – baseline, then at 6 months, then

yearlyyearly If If 20% decrease in FEV 20% decrease in FEV11, repeat; if still , repeat; if still 20% 20%

decrease in FEVdecrease in FEV1 1 discontinue discontinue

4242

Average Daily Insulin Average Daily Insulin RequirementsRequirements

Diabetes TypeDiabetes Type Dose (u/kg ABW)Dose (u/kg ABW)

Type 1Type 1

Initial DoseInitial Dose 0.5-0.60.5-0.6

Honeymoon Phase Honeymoon Phase 0.1-0.40.1-0.4

Split-dose therapySplit-dose therapy 0.5-1.20.5-1.2

With ketosis or acute With ketosis or acute illnessillness

0.5-1.00.5-1.0

Type 2Type 2

Initial DoseInitial Dose 0.2-0.60.2-0.6

Split-dose therapySplit-dose therapy 0.5-1.20.5-1.2

With insulin resistanceWith insulin resistance 0.7-2.50.7-2.5

4343

TermsTerms

Honeymoon PhaseHoneymoon Phase– Type 1 DM patientsType 1 DM patients– Occurs soon after initial diagnosisOccurs soon after initial diagnosis– Insulin requirements lowInsulin requirements low– Patient should still use insulin:Patient should still use insulin:

To minimize insulin antibody productionTo minimize insulin antibody production To lessen probability of insulin resistanceTo lessen probability of insulin resistance

4444

TermsTerms

Split-Dose TherapySplit-Dose Therapy– Single daily injections not routinely usedSingle daily injections not routinely used– Doses are divided based on:Doses are divided based on:

Intensiveness of therapyIntensiveness of therapy Type of insulin used for treatmentType of insulin used for treatment

– Regimens try to mimic activity of Regimens try to mimic activity of functioning pancreasfunctioning pancreas

4545

Insulin Adverse EventsInsulin Adverse Events

HypoglycemiaHypoglycemia Weight gainWeight gain Insulin ResistanceInsulin Resistance Injection site effectsInjection site effects

4646

ExenatideExenatide Incretin mimeticIncretin mimetic Byetta – biosynthetic form of an incretin, Byetta – biosynthetic form of an incretin,

GLP-1 (GLP = glucagon like peptide)GLP-1 (GLP = glucagon like peptide) Mechanism of actionMechanism of action

– Mimics glucose dependent insulin secretion – Mimics glucose dependent insulin secretion – first phase responsefirst phase response

– Enhances glucose dependent insulin secretion Enhances glucose dependent insulin secretion by pancreatic beta cellsby pancreatic beta cells

– Suppresses inappropriately elevated glucagon Suppresses inappropriately elevated glucagon secretion during postprandial period secretion during postprandial period

– Slows gastric emptyingSlows gastric emptying Administered via SC injectionAdministered via SC injection

4747

Pramlintide AcetatePramlintide Acetate

SymlinSymlin Amylin mimeticAmylin mimetic

– Co-located with insulin in secretory granulesCo-located with insulin in secretory granules– Secreted with insulin in response to food intakeSecreted with insulin in response to food intake

Slows gastric emptyingSlows gastric emptying Suppresses inappropriate glucagon Suppresses inappropriate glucagon

secretionsecretion Centrally-mediated appetite modulationCentrally-mediated appetite modulation Administered via SC injectionAdministered via SC injection

4848

SitagliptinSitagliptin

JanuviaJanuvia DPP-4 Inhibitor (dipeptidyl peptidase-DPP-4 Inhibitor (dipeptidyl peptidase-

4)4) Block the breakdown of incretin via Block the breakdown of incretin via

inhibition of DPP-4inhibition of DPP-4 Thus, produces similar effects to Thus, produces similar effects to

incretin mimeticsincretin mimetics

4949

Questions?Questions?