NavigatingtheMazeofTherapiesforDiabetes

Key to optimal control is early diagnosis and treatment to goal with agents that address the

underlying pathophysiologic abnormalities

EarlyDiagnosisisKey

Normal Blood Glucose

Normal Insulin

Years

IGT Diabetes

Avg Dx: 6.5 yrs

Postprandial BG

Insulin Resistance

Endogenous Insulin

Lifestyle

Match therapy to progressionPramlintide

InsulinOral Meds

Incretins

ß---Diabetes Self-Management Education and Suppot--à

TreatmentOptions

• Cornerstones of Therapy• Nutrition-Importance of moderation

– Follow food pyramid– Reduce carbs– Smaller meals– Lower glycemic index – Avoid saturated and trans fats– Add soluble fiber

• Physical activity– Incorporate “appropriate” physical activity into

daily routine– Start with low-impact

PharmacologicTreatmentOptions:Non-Insulin

Orals– a-glucosidase inhibitors(AGI)– Biguanides (metformin)– Dipeptidyl peptidase-4(DPP-4)

inhibitors(gliptins)– Dopamineagonists– Meglitinides– Sulfonylureas– SGLT-2Inhibitors– Thiazolidinediones (TZDsor

glitazones)– Bileacidsequestrants

Injectables– Glucagon-likepeptide-1(GLP-1)

analog– Amylinomimetic

PharmacologicTreatmentOptions:InsulinBasal

– IntermediateActing• NPHU-100

– Novolin-N– Humulin-N

– Long-acting• U-100 Detemir (Levemir)• U-100 Glargine (Lantus)• U-200 Degludec (Tresiba)

Bolus

• RapidU-100insulin– Lispro (Humalog)– Aspart (Novolog)– Glulisine (Apidra)

• RapidU-200Lispro• Short-acting :RegularU-100

– Humulin-R– Novolin-R

– RegularU-500

Pre-MixedInsulins :NPH/Regluar:Humulin orNovolin 70:30*NPH/Rapid;Novolog 70/30,Humalog75/25

It’s all about balance….

Key Points to Consider when Selecting Pharmacotherapy for T2DM

• How long the patient has had diabetes (duration of disease).• Cost and/or insurance coverage• Which blood glucose level is not at target

(e.g., fasting, postprandial, or both).• Patient preference for route of administration

(e.g., oral, inhaled, injectable).• The degree of A1C-lowering effect required to achieve goal. • The side effect profile and the patient’s tolerability.• Coexisting conditions (e.g., CVD, depression, osteoporosis).

Burke S et al. Clinician Reviews. 2008; 18:28-34.

7

6

9

8

10

Mean A1C of patients

Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

A1C,%

Duration of Diabetes

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD + multiple daily

insulininjections

OAD + basal insulin

Published Conceptual Approach

Earlier and More Prompt Intervention May Improve Treating to Target Compared With Conventional Therapy

EVERY 1% reduction in HBA1C

REDUCED RISK*

1%

Deaths from diabetes

Heart attacks

Microvascularcomplications

Peripheral vascular disorders

UKPDS 35. BMJ 2000; 321: 405-12

LessonsfromUKPDS:Bettercontrolmeansfewercomplications

*p<0.0001

Pharmacologic Therapy for Type 2 Diabetes Management

Choice of pharmacologic therapy based on patient-centered approachConsider Efficacy • Cost • Potential side effects • Effects on weight •

Comorbidities • Hypoglycemia risk • Patient preferences Insulin eventually needed for many patients due to progressive nature of type 2 diabetes; insulin therapy should not be delayed

Metformin*:preferredinitialtherapywhenlifestylechangesalonehavenotachievedormaintainedglycemicgoals

Considerinsulintherapywithorwithoutotheragents

Add2ndoralagent,GLP-1receptoragonist,orbasalinsulin

If noninsulin monotherapy at maximal tolerated dose does not achieve or maintain A1C target

over 3 mos

At outset in newly diagnosed patients with markedly

symptomatic and/or elevated blood glucose levels or A1C

Mostpatientsshouldbeginwithlifestylechanges

*If tolerated and not contraindicated

ADA2016Guidelines

American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S1-S106.

The Pyramid of ControlA1C

FPG PPGControl

Postprandial Glucose Contribution to A1C

% C

ontr

ibut

ion

A1C Range (%)

0

20

40

60

80

100

FPG (Fasting Plasma Glucose)PPG (Postprandial Plasma Glucose)

>10.2

70%

30%

9.3-10.2

60%

40%

8.5-9.2

55%

45%

7.3-8.4

50%

50%

<7.3

30%

70%

Data from Monnier L, et al. Diabetes Care 2003; 26:881-885

99% of patients with A1C > 7 have 2 hr. PPG levels > 200 mg/dl

At A1C of 7.3-9.2 overall glycemia is impacted similarly by FBG and PPG

Medication: Target Fasting or Postprandial?

Fasting•Metformin+•TZDs+•Sulfonylureas•Basal Insulin•SGLT-2 Inhibitors

Postprandial Control•GLP-1 Mimetics+•DPP-IV Inhibitors+•Meglitinides•Alphaglucosidase Inhibitors +•Prandial Insulins

– Rapid, Regular, possibly NPH• SGLT-2 inhibitors

+Effects not exclusive; drugs acting on FPG passively reducePPG, and drugs acting on PPG passively reduce FPG.

Putting it all together….

TZD or SU?

CVDPVD

Metformin

LDLCRFA1C

Who is our patient?

Metformin

• Approved1995USA• CurrentguidelinesfromADA/EASD andAACE/ACE

recommendearlyinitiationofmetforminasafirstlinedrugformonotherapy andcombinationtherapyforpatientswithT2DM.

• LowersFPGupto70mg/dL(monitorovernightBG)• LowersA1C1-2%• Target:InsulinResistanceinLiver/Muscle

– Reduceshepaticglucoseoverproduction– Increaseglucoseuptake inmuscleandfat

Metformin– Dosing

• Startwith500mgQD-BIDor750mgQD• Adjustdose:over1-2mos.(orq7-10days)• Maxdose:2550mg/dadults/2000mgchildren.Maxeffectivedoseis2Gmdaily.

• Aliquiddoseisavailableapprovedforchildren10yrs+• TakewithfoodtoreduceGISE

– XRDosing• StartXR500mg– XR750mgQD• Adjustdose:q14daysto2000mg/dmax

– Dosetitrationbasedonresponse/tolerability– MonitorA1cevery3mos.until<7%;thenq6mos.– MonitorovernightBGrise

Metformin• Advantages

– Goodfirstresponse rateandA1Creduction– Weightloss(2-5kg)– Positivelipideffects– Combinationtherapy– Generic /XR/Liquid– PossibleQDdosing– Lowriskofhypoglycemiaasmonotherapy– UKPDSLegacyStudy– LowerCVriskasmonotherapy(UKPDS)

• Otherindications– Children,PCOS(polycysticovariansyndrome),NASH(non-alcoholic

steatohepatitis),Prediabetes (At-Risk)

Metformin• Adverseeffects

– GI:N/V/diarrhea(takewithfoodorXR)– Metallictaste,HA,sweating,mayreduceB-12levels– Rare:Lacticacidosis

• Cautions– Holdforiodinatedcontrastdye(~48hr)– SevereCHF(classIII-IV)/blackboxwarning– Renaldosingguidelines(new:seeresourcesection)– LiverDisease,ETOHabuse,SevereGIdisorders– MayreduceB-12(esp.>3yrsonmetformin=2xrisk)

NextStepsIf not at goal afte~3 months consider additional therapy

Sulfonylureas• Action:

– Stimulate insulin secretion from pancreas via SUR (sulfonylurea receptor)

• Need functioning beta-cells to work

Efficacy: highHypoglycemia: moderate riskWeight: gainMajor side effects: hypoglycemiaCosts: low

Sulfonylureas

Second & Third Generation Sulfonylureas

Drug EquivalentDaily dose Frequency Dose

Range

Glimepiride (Amaryl®) 2 mg QD 1-8 mg

Glipizide (Glucotrol®) (30min AC) 5-10 mg QD-BID 2.5-40 mg

Glipizide extended release (Glucotrol XL®) 5 mg QD 5-20 mg

Glyburide (Diabeta®, Micronase®) 2.5-5 mg QD-BID 1.25-20 mg

Micronized glyburide (Glynase PresTab®) 3 mg QD 1.0-12 mg

DosingQD-BIDdosingTitrateevery4-6weeks

ClinicalEffectsDecreaseA1C1-2%(FBG&PPG)Monitor:PrimaryandSecondaryFailure

Sulfonylureas• Advantages

– Generally inexpensive– Longtrackrecord:1st generation introduced1955

• AdverseEffects– Hypoglycemia– WeightGain– AvoidGlyburideinCrCL<50– Caution:Sulfaallergy/Sunexposure– DrugInteractions

• OtherIndications– MODY– Pregnancy:notFDAapproved/CategoryB

TZDs (Thiazolidindiones)

Action:– Decreaseperipheral insulinresistance

– Improveinsulinsensitivityandglucoseuptakeinmuscleandadipocytes

– Decreasehepaticglucoseoutput

– Requirespresenceofinsulintowork

Efficacy: highHypoglycemia: low riskWeight: gainMajor side effects: edema, HF, Fx’sCost: high

TZDs• Dosing

– Delayedonset~3weeks• Fulleffect8-12+weeks• ReducedoseofinsulinorSUasefficacyincreases

– Withoutregardtomeals

• ClinicalEffects– DecreaseA1C1-1.5%

PioglitazoneQD

RosiglitazoneQD or BID

15 mg 2 mg30 mg 4 mg45 mg 8 mg

TZDs• Advantages

– PositiveLipideffects(Pioglitazone/?Rosiglitazone)– Minimalriskofhypoglycemia

• WatchBGpostexercise– Norenaladjustments

• AdverseEffects/Disadvantages– URI,HA,macularedema,wt.gain,anemia,fractures– Bladdercancerassociation

• Other“indications”– NASH(non-alcoholicsteatohepatitis),PCOS(polycisticovarysyndrome)

– ReducesIMT(intimamediathickness),stentfailure

TZDs

• Cautions– Liverdisease– monitorperiodically– Warnings

• ClassIIIorIVHeartDisease• BladderCancerrisk(actos)

– Fractures– Weightgainà5-12lbs./yr– Edema(4-30%)unresponsivetodiuretics– Increasedfertility(PCOS)– Notapprovedpregnantwomenorchildren

Incretin Actions

GLP-1 Receptor Agonists GLP-1 RA’s or Mimetics

Enough“like”endogenousGLP-1tocouplewithreceptorButnotenoughlikeGLP-1tobe“recognized” anddeactivatedbyDPP-IVenzyme

GLP-1 RA’s

• Actions:– Restoreglucose-stimulatedinsulinsecretion

• Firstphaseinsulin– Inhibitgastricemptying– Increasesatiety– ResistanttoDPP-4enzyme

• Clinicaleffects– ReducesA1C0.5-1%

• LongeractingagentsaffectFBGandresultingreaterA1Cdrop• ShorteractingagentsmorePPGeffectsandlessA1Cfall

Efficacy: highHypoglycemia: low riskWeight: lossSide effects: GICosts: high

PatientEducation• Mostcommonsideeffectsinclude:

– Nausea(usuallymildtomoderate– Diarrhea

• Tipstominimizenausea– Longeractingpreparations: lessGIsideeffects– Eatsmallermeals/eatslowly– Avoidovereating/recognizewhenfull– Cutdownonfattyfood– Takeshort-actingclosetomealtostart

• Startwithlowdose:titrateiftolerated

• Mayslowabsorptionofothermeds

DPP-4 Inhibitors• Inhibits DPP-4 enzyme

– Prolongs “life” of endogenous GLP-1

– Increases circulating incretins 2-3 fold

– Rapid absorption: 87% bioavailable

• Clinicaleffects– primarilypostprandial

• ReduceA1C0.5-0.8%

Efficacy: intermediateHypoglycemia: low riskWeight: NeutralSide effects: rareCosts: high

DPP-IV inhibitor

DPP-4Actions:• IncreaseendogenousGLP-1concentration• Enhanceinsulinsecretioninaglucose-dependentmanner• Suppresselevatedglucagonsecretioninaglucosedependent

manner

DPP-4 Inhibitors• Advantages

– Weightneutral– Welltolerated– Oral:Oncedaily“anytime” dosing– Hypoglycemiarisklowasmono/withmetformin

• AdverseEffects/Precautions– Upperrespiratory– Stuffynose– Possibleacutepancreatitis

• Cautions– Renaldoseadjustments (exceptlinagliptin)– CautionwithconcurrentCYP3A4/5meds– Notapprovedinpregnancy,children,type1

DPP-4Inhibitors

Clinicaleffects:primarilypostprandialReduceA1C0.5-0.8%

Additional Therapeutic Options• Included inADAalgorithmand/orAACEguidelines

– Glinides/Non-sulfonylureas– α-GLucosidaseInhibitors– Pramlintide

• Newindications foroldmeds….– BileAcidSequesterants– Bromocriptine

• Newesttomarket– SGLT2inhibitors

Non-sulfonylurea Secretagogues

• Repaglinide - Prandin® • Nateglinide - Starlix®• Stimulate short-term insulin secretion

– Require functioning beta-cells – Do not bind to SU receptor

• Rapid onset and short duration– Peaks in ~1 hour; effects ~ 4 hours

• May see prolonged effects in renal insufficiency/elderly

– Insulin secretion “glucose dependent”

Non-sulfonylureas• Dosing

– Take0-30minutesbeforemealsandlargesnacks– Weeklytitrationbasedonresponse– Repaglinide

• 0.5-4mgTIDMax16mg/d– Nateglinide

• 60-120mgTIDStart60mgifclosetoBGtargetgoal)• Clinicaleffects

– ReducespeakPPG~60mg/dl– ReduceA1C:Repaglinide1-2%Nateglinide0.5-1.5%

Non-sulfonylureas• Advantages

– Maybeusefulinrenalimpairment– Considerforpatientswitherraticschedules– ?Maybeelderly:alternativetoSU’s?

• Adverseeffects/Disadvantages– Hypoglycemia(lesslikelythanwithSU)– Moderateweightgain– Cautioninliverfailureanddialysispatients– Dosedwitheach meal:adherence issues?– Lesslongtermoutcomesdata

α-Glucosidase Inhibitors

• Acarbose;Precose®andMiglitol;Glyset®

• Action:Delay(notreduce)carbohydrate absorption• inhibitintestinalenzymes- slowbreakdownofcomplexcarbs

• Effectsinsulindemand -notsecretion• Dose

– 25mgTID/adjustevery2-8weeks• Max:50mgTIDforpts.<60kg• Max:100mgTIDforpts.>60kg

– Takewithfirstbiteofmealorlargesnack– Maxresponse~6months

• Clinicaleffects: PrimarilyPPG• ReduceA1C0.5-1%

a-Glucosidase Inhibitors (AGIs)• Advantages

– Notabsorbed-lowpotential forsystemiceffects– PreventweightgainseenwithSU’s– STOP-NIDDM=CHDreduction

• SideEffects/Cautions– GIsideeffects(~77%)**

• AggravateconcurrentGIdisorders– Use“glucose” totreathypoglycemiawhenusedincombinationtherapy

– RareelevatedLFT’s

Amylin Analog: Pramlintide

• Pramlintide (Symlin®)Injection• Action

– Increasesatiety/reducefoodintake– Slowsgastricemptying– Suppressesglucagonsecretion

• decreasedhepaticglucoseoutput• Adjunct toInsulintherapy inType1and2• Clinicaleffects

– ReducePPG50-100mg/dl– ReduceA1C~0.4-0.8%

Pramlintide• Dosing

– Type1DM:15mcgà60mcg4steptitration– Type2DM:60mcgà1202steptitration– Doseescalatedevery3-7daysbasedontolerance– Decreasedoseofpreprandial insulinby50%– Administerimmediatelypriortomajormeals

• Guidelinesforadministration– SQinabdomenorthigh(notarm)– Injectatdistinctsite;atleast2inchesfrominsulin– Administerprior toeachmealof>250cal.or30gmCOH– Skip“missed” doses– Stable28daysatroomtemp.after1st use

Pramlintide

• Adverseeffects– Nausea,HA,lossofappetite(maybetransient)– Maypotentiateinsulinmediatedhypoglycemia

• blackboxwarning– Maydelayonsetofconcomitantmeds(pain/seizure)

• Avoid inpatients…– PoorcompliancewithinsulinregimenorA1C>9%– Recurrenthypoglycemiaorhypoglycemiaunawareness– Gastroparesis– Pediatricpatients

Bile Acid Sequestrants

• ColesevelamHCl:Welchol®• Target:Gut Blockglucoseabsorption/GLP-1?• Dose:3x625mgtabsBIDwithmeals&liquid

– Or6x625mgoncedaily• AdjuncttoMetformin, InsulinorSU’s• ClinicalEffects:LowersA1C0.5%• AdverseEffects:Constipation, indigestion,muscleaches,

nausea,hypoglycemia,mayincreaseTG• Cautions: Patientsw/GIdisorders,TG>500,historyof

pancreatitisorhypertriglyceridemia• Mayaffectconcurrentmeds.

– esp.Verapamil&fat-solublevitaminsàtake4hrs.apart.

Bromocriptine Mesylate (Dopamine Agonist)

• Cycloset®0.8mgtab:• Target:Reset“biologicalclock”

– ReduceshypothalamicdrivetoincreaseAMglucosereleasefromliver

– Enhanceinsulin-mediated glucosedisposal(reduceinsulin-resistance)

– Noincreaseininsulinsecretion• Dose:1.6mg– 4.8mgQAM

– Increaseby0.8mgweekly totolerabilityormaxdose– Takewithfood– Takewithin2hoursofwaking

• ClinicalEffects;LowersA1Cby0.5-1%(15-35mg/dl)• AdverseEffects:

– Nausea,vomiting,HA,Fatigue,Hypotension, lowerTG– Caution:druginteractions(sumatriptan)

• MonoorcombinationwithSUand/ormetformin• NotapprovedinPG,Nursing,Children

SGLT2Inhibitors

SGLT2Inhibitors

• Action– Blockreabsorptionoffilteredglucoseinthekidneys

• Clinicaleffects– A1Creduction0.6– 1%– AffectsFBGandPPG

• Dosing– Canagliflozin:100-300mgdaily– Dapagliflozin:5-10mgdaily– Empagliflozin:10-25mgdaily– Renaldosingperindividualproductrecommendations

AvailableProducts

SGLT2Inhibitors

• Effectivenessnotinsulindependent

• Effectsfastingandpostprandialbloodglucose

• Lowriskhypoglycemia• Couldresultinmodest

weightloss(~2-3kg)

SideEffects• Urinarytractinfections• Genitalmycoticinfections• Osmoticdiuresis

– Hypotension:mildreductioninbloodpressure (~3-5mm/HgSBP)

– Smallincrease inhematocritandLDL-C

• EuglycemicDKA

Benefits

Choice of Oral Agent• Factors determining choice:

– Level of hyperglycemia: “glucose toxicity” requires quick action with secretagogue or insulin

– Presence/absence of obesity: UKPDS showed metformin preferred

– Abnormal FBG vs. abnormal PPBG– What is the A1C ?

• What is the glucose lowering effect of the medication• Use therapies that confer benefit beyond glycemic control

– Effects on weight, lipids, BP, heart, vascular, microalbumin…– Consider end-organ function– Ability to preserve B-cell function: ?sensitizers– Patient acceptance: convenience, cost, unique toxicity concerns

Combination Therapy• Considerations…..

– T2DM is a progressive disease• Beta-cell loss ~10% per year• UKPDS: beta-cell fxn = 60% at diagnosis & 25% at

6 yrs.– Primary objective of combination therapy is to

address the core defects. – Combine medications that work at different

tissue sites for synergy– Select therapies that support patient goals – Avoid therapies that could be “problematic”

InsulinTherapy

• When isittimeforInsulin??– Type1Diabetes– Gestational– Type2Diabetes

• Unmetglycemicgoalsonoralmeds• Unabletotolerateoralmeds• Glucosetoxicity• Stressofillness/surgery• HyperosmolarHyperglycemicState(HHS)

• Valuabletoolforthepractitioner– Preparationthrougheducation– Plantthe“seeds” ofthoughtearly

Goals of Therapy

• Achieve tight glycemic control to reduce symptoms of hyperglycemia

• Minimize adverse events of treatment– Hypoglycemia, side effects

• Prevent or delay onset of complications of DM– Macrovascular/Microvascular

• “Patient friendly” therapy– AcceptàAdhereàAchieve

• AADE7 – Taking Medications• Maintain quality of life!!

Medication Adherence Evidence-Based Conclusions

Multicomponentinterventionsbestforadherenceandhealthoutcomes

– Seek regimenswithfewestsideeffects

– Simplify regimens,provideremindersandinformation

– Encourage self-monitoringofpill-takingbehavior

– Attention fromproviders,problem-solving

Haynes RB et al. Cochrane Database Syst Rev. 2002;3:1-66

What should you ask….• Some questions to ask at each visit to assess adherence

include:– Are you having any problems or side effects with your

medication?– Are you having trouble paying for any of your

medications?– About how often do you miss taking a dose?

• If doses are being missed—are you having difficulty taking your doses and why?

– How happy are you with your current treatment plan?– How can I help you the most?

ThankYou

AnyQuestions?

MedicationManagementAdditionalResources

Diabetes Medication Mechanism of Action/ Advantages/Disadvantages

Intervention/

MedicationMainMechanism MainSide

Effect Advantages Disadvantages

Lifestyleto w̄eightand­activity

Improveinsulinsensitivityandweight NONE Manybenefits Failsformostinfirstyear

Metformin Suppresshepaticglucoseproduction GI Weightneutral,CV

protective? GI,rarelacticacidosis

Thiazolidinediones

PioglitazoneRosiglitazone

PPAR-greceptorredistributingfattoimproveinsulinsensitivity

WeightgainIncreasesHDLExcellent insulin

sensitizer

Fluidretention,weightgainCHF

Sulfonylureas(SU) InsulinsecretionHypo-

glycemiaInexpensive Weightgain,

hypoglycemia

Glitinides

NateglinideRepaglinide

InsulinsecretionHypo-

glycemia

Canuseinchronicrenal

disease3x/daydosing,glucosecontrolsimilartoSU

α-glucosidase inhibitors

AcarboseMiglitol

Delayabsorptionofcomplexcarbohydrates GI Weightneutral FrequentGIsideeffects,

3x/daydosing

Diabetes MedicationMechanism of Action/ Advantages/Disadvantages

Medication MainMechanism MainSideEffect Advantages Disadvantages

Incretinagonist

Exenatide

Insulinsecretion/glucagonsuppression/gastricemptyingdelay/satiety

GI WeightlossInjections,frequentGIsideeffects,sideeffects

managementDPP-4inhibitors

SitagliptinSaxagliptin

Glucagonsuppression,insulinsecretion Rash(rare)

Well-tolerated, oralonce-daily

dosingLong-termsafetydata

needed

Bileacidsequestrant

Colesevelam

Unknown:

maydelaycarbohydrateabsorption?

GI Non-systemicdrug? 6tabs/day,constipation,smallA1C↓

Dopamineagonist

Bromocriptine

Unknown:

Improveinsulinsensitivity?Nausea Once-dailydosing

Notavailableyet.SmallA1C↓,GIsideeffects,DailyTimingofAMdose

Insulin InsulinaugmentationHypo-

glycemia

Nodoselimit,improvedtriglycerides

Injections,hypoglycemia,weightgain

Amylinomimetic

PramlintideGlucagonsuppression,Gastricemptyingdelay GI Weightloss

GIsideeffectsInjections

Selected Medications and Potential Target Populations

Medication Potential populations that may benefit

Insulin symptomatic, High A1Cs, pregnancy, type 1DM, long duration of DM

DPP-4 inhibitors (gliptins) elderly, GI side effectα-glucosidase inhibitors elderly, patients with constipation

Metformin overweight, unable to tolerate many other CV reduction interventions

Thiazolidinediones insulin resistant, overweight…

Nateglinide/ Repaglinide (glitinides)

erratic meals, hypoglycemia from low-dose SU, renal insufficiency

Exenatide (incretin agonist) overweight patients

Colesevelam (bile acid sequestrant)

unable to meet LDL goal despite optimal statin, additional lowering of glucose may be needed

Pramlintide (amylinomimetic) poor postprandial control despite insulin therapy, prone to weight gain on insulin therapy