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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