medication management in diabeteswadepage.org/files/2019conf/wade_dm...

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Medication Management in Diabetes

Emerging Level

CheyenneNewsome,PharmD,PhC,BCACPCollegeofPharmacyandPharmaceuticalSciences

WashingtonStateUniversityWADEConferenceApril26,2019

Disclosures to Participants

•  NoticeofRequirementsforSuccessfulCompletion:•  Forsuccessfulcompletion,participantsarerequiredtobeinattendanceinthefullactivityandcompletetheprogramevaluationattheconclusionoftheeducationalevent.

•  PresenterConflictsofInterest/FinancialRelationshipsDisclosures•  Noconflictsexist.•  DisclosureofRelevantFinancialRelationshipsandMechanismtoIdentifyandResolveConflictsofInterest:Noconflictsofinterest.

•  Non-EndorsementofProducts:AccreditedstatusdoesnotimplyendorsementbyAADE,ANCC,ACPEorCDRofanycommercialproductsdisplayedinconjunctionwiththiseducationalactivity.

•  Off-labelUse:ParticipantswillbenotifiedbyspeakerstoanyproductusedforapurposeotherthanthatforwhichitwasapprovedbytheFoodandDrugAdministration.

Learning Objectives

• Discussmechanismofaction,commonsideeffects,contraindications,andclinicalpearlsforantidiabeticmedications

• Describepatientspecificconsiderationsforappropriatemedicationtherapyforpatientswithtype2diabetes

• Givenapatientcase,recommendoptimalanti-diabeticmedicationsbasedonbenefitsandpossiblesideeffects.

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Pathophysiologic Defects in T2DM Decreased Incretin Effect

Neurotransmitter Dysfunction

Islet β-cell Impaired Insulin

Secretion

Decreased Glucose Uptake

Islet α-cell Increased Glucagon Secretion

Increased Lipolysis

Increased Glucose Reabsorption

Increased HGP

DeFronzo RA. Diabetes. 2009;58(4):773-795.

Hyperglycemia

Common Antihyperglycemic Medications Class Available Agents Biguanide Metformin

Sulfonylureas Glyburide, Glimeperide, Glipizide

Thiazolidinediones Pioglitazone, Rosiglitazone

SGLT-2 Inhibitors Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin

DPP-4 Inhibitors Sitagliptin, Saxagliptin, Linagliptin, Alogliptin

GLP-1 Receptor Agonists

Exenatide, Liraglutide, Dulaglutide, Lixisenatide, Semaglutide

Insulin Many

Metformin: Mechanism of Action

•  Decreaseshepaticglucoseproduction•  Increasesskeletalmuscleglucoseuptake•  Decreasesintestinalabsorptionofglucose

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Metformin: Pros & Cons

Pros:• Highefficacy• Weightneutral•  Indirectloweringofinsulinlevels• Usuallydoesnotcontributetohypoglycemia

• Oraladministration

Cons:• GIintoleranceiscommon• PotentialforB12deficiency• ContraindicatedwitheGFR<30mL/min/1.73m2

Metformin: Dosage & Use

• Takewithmeals• Startwithsmalldose(500mg)forlessGIproblems

•  GIissues(diarrhea,stomachupset,etc.)isthebiggestbarriertouse•  XRcanhelpwithtolerability

• Increasedoseatweeklyintervals(orlessfrequently)• Maximumdose:

• 2000mg(effective)• 2550mg/day(FDA-approved)

• Given1,2or3timesaday(dependingondosageform)

Common Antihyperglycemic Medications Class AvailableAgentsBiguanide Metformin

Sulfonylureas Glyburide,Glimeperide,Glipizide

Thiazolidinediones Pioglitazone,Rosiglitazone

SGLT-2Inhibitors Canagliflozin,Dapagliflozin,Empagliflozin,Ertugliflozin

DPP-4Inhibitors Sitagliptin,Saxagliptin,Linagliptin,Alogliptin

GLP-1ReceptorAgonists Exenatide,Liraglutide,Dulaglutide,Lixisenatide,Semaglutide

Insulin Many

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Sulfonylureas: Mechanism of Action

• Insulinsecretagogues•  Stimulatebetacellsofthepancreastoreleaseinsulin

Sulfonylureas: Pros & Cons

Pros:• Highefficacy• Oraladministration•  Lowcost

Cons:• Highhypoglycemiarisk• Weightgain

Sulfonylureas: Dosage and Use

Agent Dosing DosinginCKDstages3,4and5(non-dialysis)

Glipizide 2.5to20mg/day,candivideBIDNodoseadjustmentnecessary

Glimepiride 1to8mgQday Startconservativelyat1mgdaily

Glyburide 2.5-20mg/day,candivideBID

Micronized:1.5mgto12mg/day,candivideBID

Avoiduse

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Insulin Many

Thiazolidinediones: Mechanism of Action

•  DirectlyreduceinsulinresistancebyactivatingPPAR-gammanuclearreceptors

•  Increaseglucoseuptakeinskeletalmuscleandfatcells

•  Lowerhepaticglucoseoutput

StumvollMetal.AnnMed2002;34:217-24.

Thiazolidinediones: Dosage and Use

• Norenaldoseadjustment,liverfunctionmonitoringrecommended

• Pioglitazone• 15to45mgPOQday

• Rosiglitazone

• 4to8mgPO/day,onceorindivideddoses

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Thiazolidinediones: Pros & Cons

Pros:• Highefficacy•  Lowhypoglycemiarisk•  Lowcost• BenefitinNASH(Nonalcoholicsteatohepatitis)

Cons:• Weightgain•  Fluidretention/edema(HFrisk)•  Fractures• BladderCancer(pioglitazone)•  Longonsetofaction







Insulin Many

SGLT-2 Inhibitors: Mechanism of Action

• Inhibition of SGLT2 transporters in the proximal kidney tubule blocks the reabsorption of filtered glucose

• Leads to increased glucose excretion via urine

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SGLT-2 Inhibitors: Pros & Cons

Pros:•  Intermediateefficacy• Weightloss•  Cardiovascular&renalbenefits(empagliflozin&canagliflozin)

•  Oraladministration• ModestdecreaseinBP•  Lowhypoglycemiarisk

Cons:•  Highcost•  Renaldoseadjustmentrequired•  Genitourinaryinfections•  Volumedepletion/hypotension•  Rare/SeriousSafetyConcerns:

•  Increasedamputationrisk(canagliflozin)

•  eDKA,bonefractures(canagliflozin)•  Fournier’sgangrene

SGLT-2 Inhibitors: Dosage and Use

• Allrequirerenaldoseadjustment,•  Ifthekidneysdon’tseetheglucose,theydon’tpeetheglucose

Canagliflozin(Invokana)

Dapagliflozin(Farxiga)

Empagliflozin(Jardiance)

Ertugliflozin(Steglatro)

100mgdailybeforebreakfast,Increaseto300mgdailyifneeded

5mgdailyintheAM;Increaseto10mgdaily

ifneeded

10mgdailyintheAM;Increaseto25mgif

needed

5mgdailyintheAM;Increaseto15mgif

needed







Insulin Many

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Nauck et al. Diabetologia 1986;29:46-52.

Oral glucose load Intravenous glucose infusion

Time (min)

Insu

lin (m

U/L

)

80

60

40

20

0 180 60 120 0

Time (min)

Insu

lin (m

U/L

)

80

60

40

20

0 180 60 120 0

Incretin effect

Control subjects (n=8) People with Type 2 diabetes (n=14)

Incretin Effect

GLP-1issecretedfromL-cellsofthejejunum

andileum

Thatinturn…

Stimulatesglucose-dependentinsulinsecretionSuppressesglucagonsecretion

Slowsgastricemptying

Leadstoareductionoffoodintake

After food ingestion…

Drucker.CurrPharmDes2001;7:1399-1412.Drucker.MolEndocrinol2003;17:161-171.DruckerDJ.CellMetab.2006;3:153-165.

Islet β-cell

Islet α-cell

GLP-1 Effect in Humans

Degradation of GLP-1

123 30GLP-1

EnzymaticcleavageofGLP-1byDPP-4inactivatesGLP-1

Des-HA-GLP-1(inactive)

12 330

DPP-4

Mentlein et al. Eur J Biochem 1993;214:829-835. Gallwitz et al. Eur J Biochem 1993;214:829-835.

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GLP-1 enhancement GLP-1 secretion is impaired in Type 2 diabetes

Natural GLP-1 has extremely short half-life

Add GLP-1 analogues with longer half-life: Exenatide (Byetta) – Twice daily Liraglutide (Victoza) – Once daily Lixisenatide (Adlyxin) – Once daily Exenatide Once Weekly (Bydureon) – Once

weekly Dulaglutide (Trulicity) – Once weekly Semaglutide (Ozempic) – Once weekly

Block DPP-4 to slow the enzymatic degradation of GLP-1: Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Tradjenta) Alogliptin (Nesina)

Incretin-based therapies: differences and similarities

GLP-1 RAs DPP-4 inhibitors Hypoglycemia No No Inhibition of gastric emptying Yes Marginal Effect on body weight Weight loss Weight neutral Side effects Nausea, Vomiting,

Diarrhea HA, Sinusitis, Rhinorrhea

Administration Subcutaneous Oral

Gallwitz B. Eur Endocr Dis 2006:43-46.

DPP-4 Inhibitors: Dosing and Usage

Characteristic Sitagliptin Saxagliptin Linagliptin Alogliptin

Hypoglycemia Risk

Low Low Low Low

Dose 100 mg daily 5 mg daily 5 mg daily 25 mg daily

Weight Neutral Neutral Neutral Neutral

Renal Dose Adjustment

• CrCl <50 mL/min: 50 mg daily

• CrCl <30 mL/min: 25 mg daily

• CrCl < 50 mL/min: 2.5 mg daily

No adjustment recommended based on renal function

• CrCl <60 mL/min: 12.5 mg daily

• CrCl <30 mL/min: 6.25 mg daily

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DPP-4 Inhibitors: Pros & Cons

Pros:•  Intermediateefficacy(preferentiallytargetPPG)

•  Lowhypoglycemiarisk(monotherapyorcombinationwithmetformin)

• Weightneutral• Oraladministration

Cons:• Highcost• Needforrenaldoseadjustment(canstillbeusedinESRD)

• Potentialriskforexacerbationofheartfailure(saxagliptin,alogliptin)

• Rare/SeriousSafetyConcerns:Acutepancreatitis,jointpain

•  Exenatide (Byetta) – Twice daily •  Liraglutide (Victoza) – Once daily •  Lixisenatide (Adlyxin) – Once daily •  Exenatide XR (Bydureon) – Once weekly •  Dulaglutide (Trulicity) – Once weekly •  Semaglutide (Ozempic) – Once weekly

GLP-1 Receptor Agonists MechanismsofAction:1.  Increaseglucose-dependentinsulin

secretion;2.  Decreaseglucagonsecretion3.  Slowgastricemptying4.  Increasesatiety(brain)

Islet β-cell Islet α-cell

GLP-1 Receptor Agonists: Pros & Cons

Pros:• Highefficacy•  Lowhypoglycemiarisk(monotherapyorcombinationwithmetformin)

• Cardiovascular&renalbenefits(liraglutide)

• Weightloss

Cons:• Highcost• Needforrenaldoseadjustment•  Injectable• GIintolerance• Rare/SeriousSafetyConcerns:ThyroidC-celltumors(long-actingagents),Acutepancreatitis

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Considerations for T2DM

Glucose-Lowering

Medication in T2D: Overall

Approach

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019; 42 (Suppl. 1): S90-S102

Glucose-Lowering


Approach


KeyConcepts:•  Atdiagnosis,first-linetherapyincludesmetformin+intensivelifestyleintervention

•  IfA1Cisabovetargetdespiterecommendedfirst-linetreatment,chooseasecond-lineagent

•  FirstrecommendedconsiderationisbasedonthepresenceofestablishedASCVD(atheroscleroticcardiovasculardisease)orCKD(chronickidneydisease)

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Glucose-Lowering


Approach


KeyConcepts:•  IfA1Cisabovetargetdespiterecommendedfirst-linetreatmentandthepatienthasASCVDorCKD:

•  ASCVDPredominates:•  AddGLP-1RAwithprovenCVDbenefit,OR

•  AddSGLT-2inhibitorwithprovenCVDbenefit(ifeGFRisadequate)

•  IfHForCKDPredominates:•  AddSGLT-2inhibitorwithevidenceofbenefit

•  Ifcan’ttakeanSGLT-2inhibitor,useaGLP-1RAwithprovenCVDbenefit

Glucose-Lowering


Approach


Case Practice - JS

•  JSisa66yearoldmalewithT2DM,hypertension,BPH,MIin2017

• Medications:•  T2DM:metformin1gramBID•  HTN:lisinopril10mgQday•  BPH:tamsulosin0.4mgQday•  MI:metoprololsuccinate50mgQday

•  Labs/vitals(today):•  A1c8.5% BMI:32kg/m2 BP:128/70mmHg

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Glucose-Lowering


Approach


Case Practice - JS

•  JSisa66yearoldmalewithT2DM,hypertension,BPH,MIin2017

• Medications:•  T2DM:metformin1gramBID•  HTN:lisinopril10mgQday•  BPH:tamsulosin0.4mgQday•  MI:metoprololsuccinate50mgQday

•  Labs/vitals(today):•  A1c8.5% BMI:32kg/m2 BP:128/70mmHg

Glucose-Lowering


Approach


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Summary

• Patientspecificfactorsshouldbeconsideredwhenrecommendingtherapy

• Comorbidities(obesity,CKD,ASCVD)• Cost• Hypoglycemiaconcerns

• Multimodalapproachoforalmedicationswithbenefitscanbeconsidered

Acknowledgments

•  ThankyoutoDr.JoshuaNeumillerforguidanceandassistance

medication management in diabeteswadepage.org/files/2019conf/wade_dm...

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