TreatmentofType2Diabetes:WhatToDoWhenTreatmentwithMetformin

isInadequate?CanWeAchieveTherapeuticGoalsMore

Safely?MartinJ.Abrahamson,MDFACP

AssociateProfessorofMedicine,HarvardMedicalSchoolCOPYRIG

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WhatIwillcover

• Magnitudeoftheproblem• Pathophysiologyoftype2diabetes• The”guidelines”• Factorstoconsiderwhenchoosingamedication/stoaddtometformin

• Cardiovascularoutcomesstudies• Whichcombinationsmightbeappropriate?COP

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• Morethan29millionpeople– justover9%ofthepopulation

• 25%undiagnosed• Thenumberisgrowingby>1millionperyear• Amajorcauseofmortalityandmorbidity• Cost(directandindirect)$245billionperyear

• 1in10UShealthcaredollarsspentondiabetes• Almost86millionpeopleatriskfordiabetes• Goodnews– therateofnewcasesisdeclining(only1.4millionnewcasesperyearvs1.8million)

DiabetesintheUSAToday:AnEpidemic

Diabetes Care 2010

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PathogenesisofType2DM:FromtheTriumvirate…

FromDeFronzoDiabetes2009;58:773-795

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ToTheOminousOctet

GI,gastrointestinal;HGP,hepaticglucoseproduction;SU,sulphonylurea;T2D,type2diabetesDeFronzoRA.Diabetes 2009;58:773–795

AdiposetissueIncreasedlipolysis

SkeletalmuscleDecreasedglucoseuptake

LiverInsulinresistanceIncreasedHGP

BrainNeurotransmitterdysfunction

PancreasImpairedinsulin

secretion(β-celldecline)

GItractDecreasedincretineffect

KidneysIncreasedglucose

reabsorption

Isletα-cellsIncreasedglucagonsecretion

HyperglycemiaEnergyhomeostasis

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AddressingtheOminousOctet

DPP-4,dipeptidylpeptidase4;GI,gastrointestinal;GLP-1,glucagon-likepeptide-1;HGP,hepaticglucoseproduction;SGLT-2,sodium-glucoseco-transporter-2;SU,sulphonylurea;T2D,type2diabetes;DeFronzoRA.Diabetes 2009;58:773–795

AdiposetissueIncreasedlipolysis

SkeletalmuscleDecreasedglucoseuptake

LiverInsulinresistanceIncreasedHGP

BrainNeurotransmitterdysfunction

PancreasImpairedinsulin

secretion(β-celldecline)

GItractDecreasedincretineffect

KidneysIncreasedglucose

reabsorption

Isletα-cellsIncreasedglucagonsecretion

HyperglycemiaEnergyhomeostasisSUs Metformin

GLP-1

DPP-4

Insulin

DPP-4

GLP-1

GLP-1

GLP-1

Insulin

GLP-1

DPP-4 Insulin

GLP-1

InsulinGLP-1

Insulin

Cycloset

SGLT-2

Colesevelam

AGI

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Type2DiabetesManagement2016• LoweringA1ctoaround7%especiallyearlyafterdiagnosiscanreducetheriskforthedevelopmentorprogressionofthelongtermcomplicationsofdiabetes

• Therearemanymedicationsavailabletodaytotreattype2diabetes– ifusedappropriatelythiscouldtranslatetoimprovedcontrolandlessriskforcomplications

• ThechallengeforthepracticingphysicianistoknowwhichmedicationstouseandwhenbesttousethemCOPYRIG

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Type2DiabetesManagement2016• ThereIS consenus thatmetforminshouldbefirstlinetherapy

• ThereisNO clearconsensuswhattoaddtometforminwhenA1cgoalsarenotmet

• Fewheadtoheadcomparatortrials• Evenfewerlongtermstudiesevaluatingdurabilityofmedicationsonglycemiccontrol,especiallywhenaddedtometforminCOP

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more stringent

less stringent

Patient attitude and expected treatment efforts highly motivated, adherent,

excellent self-care capacities less motivated, non-adherent,

poor self-care capacities

Risks potentially associated with hypoglycemia and other drug adverse effects

low high

Disease duration newly diagnosed long-standing

Life expectancy long short

Important comorbidities absent severe few / mild

Established vascular complications absent severe few / mild

Readily available limited

Usually not modifiable

Potentially modifiable

HbA1c'7%('

PATIENT / DISEASE FEATURES

Approach to the management of hyperglycemia

Resources and support system

Figure'1.'Modula$on'of'the'intensiveness'of'glucose'lowering'therapy'in'T2DM'

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

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ADA/EASDPositionStatementGuidelinesforType2Diabetes

ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes.Inzucchi SE, et al. Diabetes Care. 2016

ToAboveDualTherapyadd3rd DrugfromtheseCategoriesTripleTherapy

GLP-1RA

BasalInsulin

BasalInsulin+PrandialInsulinorGLP-1RA

CombinationInjectableRx

LifestyleModification,Education

Metformin

DualTherapy

SU

HbA1c>7.0%

DPP-4inhibitorTZD SGLT2

inhibitor

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Therapeutic and behavioural barriers to glycemiccontrol/treatment intensification

Improved glycemic control

Inflexible/rigid

Weight gain

“Weight worry”

Fear ofhypoglycemia

Reduced adherence toavoid hypoglycemia

and complextreatmentregimens

Depression?

Resistance to initiationand poor adherence

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Howshouldwechoosewhichdrug/stoaddtometformin?

• Safety• Efficacy• Tolerability/acceptability• Cost

• PhenotypicandgenotypicapproachestodeterminemosteffectivetherapyarelackingCOP

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Safety

• Hypoglycemia

• Cardiacsafety

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Hypoglycemia

• Insulin

• Sulfonylureas(SUs)• NOT (whenusedalone/without insulinorSUs)

• Metformin• DPP-IVInhibitors• GLP-1agonists• TZD• SGLT-2inhbitors• Dopaminereceptoragonist• Colesevalam• Alphaglucosidase inhibitorsCOPYRIG

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Glibenclamide isAssociatedwithConsiderablyMoreHypoglycemiaThanGlimepiride

• Prospective 4yearstudyinGermany

• Plasmaglucose <50mg/dL andERTreatmentwithIVglucoseorglucagon

• Peoplewithhypoglycemia- meanage79,MeanHbA1c5.4%,62%hadcreat clear<60ml/min

17

Glimepiride Glibenclamide

Incidents/1000person-years 0.86 5.6

Prescriptionfrequency/1000person-years 6976 6789

HolsteinAetal,DiabetesMetabResRev2001;17:467-473

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CardiovascularsafetyCOPYRIG

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CumulativeIncidence(95%CIs)ofCardiovascularDiseaseorDeathComparingSulfonylureastoMetformin

19

Roumie,C.L.etal,AnnInternMed.2012;157:601-610

21%increase

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DPP4InhibitorsvsSUasAdd-OntoMetformin:ComparisonofOutcomes

DPP4inhibitor* SU* Hazard ratio Pvalue

Allcausedeath 18.06 26.84 0.63 < 0.001

MACE 10.43 15.74 0.68 <0.001

MI 3.42 4.87 0.75 0.109

Ischemic stroke 7.17 11.28 0.64 <0.001

Hospitalizationforheartfailure

4.96 5.53 0.78 0.108

Hypoglycemia 4.42 9.43 0.43 <0.001

*Incidencerateper1000personyears

Ou S-Metal.AnnalsofInternalMedicine2015;published online10/13/15

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Manyrecenttrialsofnewerglucose-loweringagentshavebeenneutralontheprimaryCVoutcome

21

SAVOR-TIMI 53

EXAMINE

HR:1.0(95%CI:0.89,1.12)

HR:0.96(95%CI:UL≤1.16)

TECOSHR:0.98(95%CI:0.88,1.09)

EMPA-REGOUTCOME®

ELIXAHR:1.02(95%CI:0.89,1.17)

Empagliflozin

DPP-4inhibitors*

Lixisenatide

CV,cardiovascular;HR,hazardratio; DPP-4,dipeptidylpeptidase-4*Saxagliptin,alogliptin,sitagliptin

AdaptedfromJohansenOE.WorldJDiabetes2015;6:1092-96

2013 2014 2015

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NEngl JMed2015;373:2117-2128

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EMPA-REGOUTCOME®• Randomised, double-blind, placebo-controlled CVoutcomestrial

• ObjectiveToexamine the long-termeffectsofempagliflozin versusplacebo,inaddition tostandardofcare,onCVmorbidityandmortality inpatientswithtype2diabetes andhighriskofCVevents

CV,cardiovascular

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Pre-specifiedprimaryandkeysecondaryoutcomes

• Primaryoutcome• 3-pointMACE:Time tofirstoccurrenceofCVdeath,non-fatalMIornon-fatalstroke

• Keysecondaryoutcome• 4-pointMACE:Time tofirstoccurrenceofCVdeath,non-fatalMI,non-fatalstrokeorhospitalisation forunstableangina

24CV,cardiovascular;MI,myocardialinfarction;MACE,MajorAdverseCardiovascularEvent

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BaselineCharacteristics

Meanage 63years(72%maleparticipants)

MeanA1c 8%

CVdisease 100%(abouthalf hadpreviousMI;and10%hadCHF)

%oninsulin 48

%onstatin 77

%onACEIorARB 80

%onaspirin 82

Mean BP 135/77mmHg

MeanBMI 30

Mean LDL 85mg/dL

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HbA1c

6.0

6.5

7.0

7.5

8.0

8.5

9.0

Adjustedm

ean(SE)HbA

1c(%

)

Week

Placebo

Empagliflozin10mg

Empagliflozin25mg

229422962296

PlaceboEmpagliflozin10mgEmpagliflozin25mg

227222722280

218822182212

213321502152

211321552150

206321082115

200820722080

196720582044

174118051842

145615201540

124112971327

110911641190

96210061043

705749795

420488498

151170195

12 28 52 94 10880 12266 1360 150 164 178 192 20640

Allpatients(includingthosewhodiscontinuedstudydrugorinitiatednewtherapies)wereincludedinthismixedmodelrepeatedmeasuresanalysis(intent-to-treat)

X-axis:timepointswithreasonableamountofdataavailableforpre-scheduledmeasurements

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Systolicbloodpressure

27

125

127

129

131

133

135

137

139

141

143

145

Adjustedm

ean(SE)systolic

bloo

dpressure(m

mHg

)

Week

232223222323

PlaceboEmpagliflozin10mgEmpagliflozin25mg

223522502247

220322352221

216121932197

213321742169

207321252129

202420952102

197420722066

177118531878

149215561571

127413271351

112611891212

98110341070

735790842

450518528

171199216

Placebo

Empagliflozin10mgEmpagliflozin25mg

16 28 52 94 10880 12266 1360 150 164 178 192 20640

Allpatients(includingthosewhodiscontinuedstudydrugorinitiatednewtherapies)wereincludedinthismixedmodelrepeatedmeasuresanalysis(intent-to-treat)

X-axis:timepointswithreasonableamountofdataavailableforpre-scheduledmeasurements

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Primaryoutcome:3-pointMACEHR0.86

(95.02%CI0.74,0.99)p=0.0382*

Cumulativeincidencefunction.MACE,MajorAdverseCardiovascularEvent;HR,hazardratio.*Two-sidedtestsforsuperioritywereconducted(statisticalsignificancewasindicatedifp≤0.0498)

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CVdeath

HR0.62(95%CI0.49,0.77)

p<0.0001

Cumulativeincidencefunction.HR,hazardratio

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Hospitalisationforheartfailure

HR0.65(95%CI0.50,0.85)

p=0.0017

Cumulativeincidencefunction.HR,hazardratio

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All-causemortality

HR0.68(95%CI0.57,0.82)

p<0.0001

Kaplan-Meierestimate.HR,hazardratio

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Patients with event/analysedEmpagliflozin Placebo HR (95%CI) p-value

3-pointMACE 490/4687 282/2333 0.86 (0.74,0.99)* 0.0382

CVdeath 172/4687 137/2333 0.62 (0.49,0.77) <0.0001

Non-fatalMI 213/4687 121/2333 0.87 (0.70,1.09) 0.2189

Non-fatalstroke 150/4687 60/2333 1.24 (0.92,1.67) 0.1638

0.25 0.50 1.00 2.00

CVdeath,MIandstroke

Favoursempagliflozin Favoursplacebo

Coxregression analysis.MACE,MajorAdverse Cardiovascular Event;HR,hazardratio; CV,cardiovascular;MI,myocardialinfarction

*95.02%CI

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Numberneededtotreat(NNT)topreventonedeathacrosslandmarktrialsinpatientswithhighCVrisk

1.4Sinvestigator.Lancet1994;344:1383-89,http://www.trialresultscenter.org/study2590-4S.htm;2.HOPEinvestigatorNEnglJMed2000;342:145-53,http://www.trialresultscenter.org/study2606-HOPE.htm

Simvastatin1for5.4years

HighCVrisk5%diabetes,26%hypertension

1994 2000 2015

Pre-statinera

HighCVrisk38%diabetes,46%hypertension

Ramipril2for5years

Pre-ACEi/ARBera

<29%statin

Empagliflozinfor3years

T2DMwithhighCVrisk92%hypertension

>80%ACEi/ARB

>75%statinCOPYRIG

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LEADER– 13%reductioninMACE(primaryoutcome)

Numberneededtotreattoprevent1eventin3years=66

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LEADER– deathfromcardiovascularcauses

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LEADER– deathfromanycause

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LEADER– nodifferenceinnonfatalstroke

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NEngl JMed2016;375:323-334

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Empaglaflozin slowsprogressionofrenaldisease

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Empaglaflozin slowsrateofdeclineofGFR

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EfficacyofMonotherapy inType2Diabetes

Agent A1Creduction(%)Insulinsecretagogues 1.0- 2.0Metformin 1.5– 2.0TZDs 0.6– 1.9Alphaglucosidaseinhibitors

0.5– 1.0

Colesevelam 0.5– 0.7

Bromocriptine 0.5– 0.7DPP-IVInhibitors 0.6– 1.0

GLP-1receptoranalogues

1.0– 1.5

SGLT2Inhibitors 1.0

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AntihyperglycemicMedications:EffectonWeight

Weightgain Weightneutral WeightlossSulfonylureas Metformin GLP1RAInsulin DPP4inhibitors SGLT2I

AlphaglucosidaseinhibitorsBromocriptineColesevelamCOPYRIG

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SOLET’SLOOKATSOMETREATMENTOPTIONSTRYINGTOMINIMIZEWEIGHTGAINANDHYPOGLYCEMIA

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Week 24 (LOCF)* change from baseline,

adjusted mean (95% CI)

†P value < 0.0001; ‡ DAPA 10 mg non-inferior to MET.

- 2.5

- 2.0

- 1.5

- 1.0

- 0.5

0.0

0 4 8 12 16 20 24

DAPA5mg+MET(n=185)

DAPA5mg(n=196)

MET(n=195)

Study week

Adju

sted

mea

n ch

ange

from

ba

selin

e in

HbA

1c (%

)

- 2.5

- 2.0

- 1.5

- 1.0

- 0.5

0.0

0 4 8 12 16 20 24

DAPA10mg+MET(n=202)

DAPA10mg(n=216)

MET(n=203)

Study week

-1.19 (-1.36, -1.02)-1.35 (-1.53, -1.18)

-2.05 (-2.23, -1.88) † -1.98 (-2.13, -1.83) †

-1.44 (-1.59, -1.29)-1.45 (-1.59, -1.31) ‡

DapagliflozininCombinationwithMetformin:ChangeinHbA1cOver24Weeks

Henry R, et al. Int J Clin Pract. 2012;66(5):446–456.

LOCF,lastobservationcarriedforward.

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DapagliflozinVersusSulfonylureaasAdd-ontoMetformin:ChangeinHbA1cOver208Weeks

• HbA1cdurabilitywasbetterwithdapagliflozinthanglipizide• Therisefrom52–208weekswaslesscomparedwithglipizide,givingasignificant

differencebetweentreatmentsat208weeks

Del Prato S, et al. ADA 2013; poster 62-LB.*Dataareadjustedmeanchangefrombaseline±95%CIderivedfromalongitudinalrepeated-measuresmixedmodel.

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Canagliflozin vs Sitagliptin addontoMTFandSU:ChangeinA1c

GScherthaner etal.DiabetesCare2013;epubApril5

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Canagliflozin vs.Sitagliptin:ChangeinWeight

GScherthaner etal.DiabetesCare2013;epubApril5

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OnceWeeklyExenatide PlusDapaglaflozin DailyAloneorinCombinationasAddontoMetformin

FriasJPetal.LancetDiabetesEndocrinol publishedonlineSeptember162016

MeanHbA1catbaseline9.3%

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WeightChange– GLP1RAorSGLT2IorBoth

FriasJPetal.LancetDiabetesEndocrinol publishedonlineSeptember162016

Dapaglaflozin

Exenatideweekly

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BasalInsulinAnalogues– aretheyany“safer”?

• GlargineU-100• Biosimilarglargine• Levemir• GlargineU-300(Toujeo)• Degludec (Tresiba)

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U300Glargine(Toujeo)vsU100Glargine:EquallyeffectivebutwithhigherdoseofU300Glargine

Yki JarvinenHetal.Diabetes,ObesityandMetabolism17:1142–1149,2015.

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U300GlargineisassociatedwithlesshypoglycemiathanU100glargine

Yki JarvinenHetal.Diabetes,ObesityandMetabolism17:1142–1149,2015.

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SWITCH 2Reduced risk of hypoglycaemia with insulin degludec vs. insulin

glargine U100 in a T2D population on basal insulin: A randomised

double-blind crossover trial

Clinical trial.gov identifier: NCT02030600Wysham et al. Presented at the American Diabetes Association, 76th Annual Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA

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Objective

Primary objective:

• To confirm superiority of IDeg OD compared with IGlar U100 OD in the rates of severe or BG-confirmed symptomatic hypoglycaemia during the maintenance period (after 16 weeks of treatment)

Secondary objectives:

• To confirm superiority of IDeg OD compared with IGlar U100 OD in the rates of severe or BG-confirmed symptomatic nocturnal hypoglycaemiaand the proportion of patients with severe hypoglycaemia during the maintenance period

BG, blood glucose; IDeg, insulin degludec; IGlar U100, insulin glargine U100; OD, once dailyWysham et al. Presented at the American Diabetes Association, 76th Annual Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA

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Hypoglycaemia risk: inclusion criteria

ADA, American Diabetes Association; eGFR, estimated glomerular filtration rateWysham et al. Presented at the American Diabetes Association, 76th Annual Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA

Eligible patients had at least one of the following hypoglycaemia risk factors:

• ≥1 severe hypoglycaemic episodes within the last year

• Moderate chronic renal failure (eGFR 30–59 mL/min/1.73 m2)

• Hypoglycaemic symptoms unawareness

• Exposure to insulin >5 years

• Episode of hypoglycaemia episode within the last 12 weeks (according to ADA definition: ≤70 mg/dL [≤3.9 mmol/L])COP

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HbA1c over time

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

0 4 8 12 16 20 24 28 32

HbA

1c(%

)

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

0 4 8 12 16 20 24 28 32

HbA

1c(%

)

Titration period 1 Maintenance period 1 Titration period 2 Maintenance period 2

Treatment period 1 Treatment period 2

0.0 0.0

End of treatment period 1Non-inferiority is confirmed

End of treatment period 2Non-inferiority is confirmed

CROSSOVER

IDegIGlar U100

Mean�SEMSEM, standard error of the meanWysham et al. Presented at the American Diabetes Association, 76th Annual Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA

6.98%

7.06% 7.08%

7.11%

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Severe or BG-confirmed symptomatic hypoglycaemia: maintenance period

SASComparisons: Estimates adjusted for multiple covariatesPYE, patient-year of exposure; SAS, safety analysis setWysham et al. Presented at the American Diabetes Association, 76th Annual Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA

30% lower rate with IDeg(p<0.0001)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

16 18 20 22 24 26 28 30 32

Sev

ere

or B

G-c

onfir

med

sym

ptom

atic

hyp

ogly

caem

ia(c

umul

ativ

e ev

ents

per

pat

ient

)

Time since start of treatment period (weeks)

IDegIGlar U100

IDeg IGlar U100

Proportion(% patients)

Rate(episodes/100 PYE)

Proportion(% patients)

Rate(episodes/100 PYE)

22.5% 185.6 31.6% 265.4COPYRIG

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Severe or BG-confirmed symptomatic nocturnalhypoglycaemia: maintenance period

SASComparisons: Estimates adjusted for multiple covariatesWysham et al. Presented at the American Diabetes Association, 76th Annual Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA

42% lower rate with IDeg(p<0.0001)

0.00

0.04

0.08

0.12

0.16

0.20

0.24

0.28

0.32

16 18 20 22 24 26 28 30 32

Sev

ere

or B

G-c

onfir

med

sym

ptom

atic

no

ctu

rna

lhy

pogl

ycae

mia

(cum

ulat

ive

even

ts p

er p

atie

nt)

Time since start of treatment period (weeks)

IDeg IGlar U100

Proportion(% patients)

Rate(episodes/100 PYE)

Proportion(% patients)

Rate(episodes/100 PYE)

9.7% 55.2 14.7% 93.6

IDegIGlar U100

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Uptitrating basalinsulinvsbasalinsulinandGLP1RACOPYRIG

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DUAL VStudy design

BMI, body mass index; HbA1c, glycated haemoglobin; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; PG, plasma glucose; T2D, type 2 diabetes; U, unitsLingvay I et al. JAMA 2016;315:898–907

Inclusion criteria− T2D− Metformin + IGlarU100 (20–50 units)− HbA1c7–10%− Age ≥18 years− BMI ≤40 kg/m2

Subjects with T2D uncontrolled on

basal insulin(N=557)

IDegLiraStarting dose: 16 dose stepsMaximum dose: 50 dose stepsIGlar U100Starting dose: Pre-trial doseMaximum dose: None

ScreeningRandomisation 1:1

(open label) End of trial Follow-up

Titration algorithm: IDegLira and IGlar U100

mmol/L mg/dL

<4.0 <72

4.0–5.0 72–90

>5.0 >90

dose steps or U

−2

0

+2

Mean fasting PG Dose change

IGlar U100 + metformin(n=279)

IDegLira + metformin(n=278)

0 27–2 26Week

L

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DUAL VHbA1c over time

Mean observed values with error bars (standard error mean) based on FAS and LOCF imputed data. Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF. ADA/EASD HbA1c target <7.0%; AACE HbA1c target ≤6.5% AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; ANCOVA, analysis of covariance; EASD, European Association for the Study of Diabetes; EOT, end of trial; FAS, full analysis set; HbA1c, glycated haemoglobin; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; LOCF, last observation carried forwardLingvay I et al. JAMA 2016;315:898-907

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26

7.1%

6.6%HbA

1c(%

)

Time (weeks)

IDegLira (n=278)IGlar U100 (n=279)

EOTTreatment difference ∆HbA1c

–1.81%

–1.13%

0.0

–0.59%p<0.001

L

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DUAL VConfirmed hypoglycaemia

Mean cumulative function based on SASTreatment ratio is estimated from a negative binomial model based on FASFAS, full analysis set; HbA1c, glycated haemoglobin; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; SAS, safety analysis setLingvay I et al. JAMA 2016;315:898–907

0.0

0.5

1.0

1.5

2.0

2.5

0 2 4 6 8 10 12 14 16 18 20 22 24 26Num

ber o

f ep

isod

es p

er s

ubje

ct

Treatment ratio:0.43

p<0.001

IDegLira IGlar U100

HbA1c at week 26 6.6% 7.1%

Time (weeks)

IDegLira (n=278)IGlar U100 (n=279)

L

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DUAL VChange in body weight over time

Mean observed values with error bars (standard error mean) based on FAS and LOCF imputed dataTreatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCFANCOVA, analysis of covariance; FAS, full analysis set; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; LOCF, last observation carried forwardLingvay I et al. JAMA 2016;315:898–907

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26

Treatmentdifference:–3.2 kg;p<0.001

Chan

ge in

bod

y w

eigh

t (k

g) +1.8 kg

–1.4 kg

Time (weeks)

IDegLira (n=278)IGlar U100 (n=279)

L

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DUAL VDaily insulin dose

There was no maximum dose for IGlar U100Mean observed values with error bars (standard error mean) based on SAS and LOCF imputed dataTreatment difference is estimated from an ANCOVA analysisANCOVA, analysis of covariance; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; LOCF, last observation carried forward; SAS, safety analysis set; U, unitsLingvay I et al. JAMA 2016;315:898–907

0

10

20

30

40

50

60

70

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Dos

e (u

nits

)

41 U

66 UTreatment difference:–25.47 Up<0.001

Time (weeks)

IDegLira (n=278)IGlar U100 (n=279)

L

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DUAL VSubjects achieving treatment targets

Values are based on FAS and LOCF imputed dataOdds ratios (IDegLira/IGlar U100) are from a logistic regression modelFAS, full analysis set; HbA1c, glycated haemoglobin; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; LOCF, last observation carried forward; OR, odds ratioLingvay I et al. JAMA 2016;315:898–907

71.6

54.3

38.8

47.0

29.4

12.20

20

40

60

80

100 OR: 3.45[2.36;5.05];

p<0.001 OR: 3.24[2.24;4.70];

p<0.001 OR: 5.53[3.49;8.77];

p<0.001

Perc

enta

ge o

f sub

ject

sac

hiev

ing

targ

ets

(%)

HbA1c <7% HbA1c <7%without hypoglycaemia

HbA1c <7%without hypoglycaemia

and weight gain

IDegLira (n=278)IGlar U100 (n=279)

L

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AddingGLP1RAtobasalinsulin:impactonglucosecontrol,weightandhypoglycemiaCOPYRIG

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Adding exenatide to insulin glargine

-0.1

0.1

0.3

0.5

0.7

0.9

1.1

1.3

1.5

Hyp

ogly

caem

ia r

ate

(eve

nts/

patie

nt-y

ear)

Exenatide + insulin glarginePlacebo + insulin glargine

Minorhypoglycaemia†

p=0.49

There was one episode of major hypoglycaemia in

the placebo group‡

*p<0.001†Minor hypoglycaemic episodes (plasma glucose, 3.1 mmol/L) were self-treated ‡Major episodes required third-party assistance, irrespective of plasma glucose levelsComparisons: Estimates based on ANCOVA with multiple covariates Buse et al. Ann Intern Med 2011;154:103–12

Insulin glargine + placebo

Insulin glargine + exenatide

Week0 10 20 30

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Chan

ge in

HbA

1cle

vel (

%)

* *

HbA1c Weight

Chan

ge in

bod

y w

eigh

t (kg

) 2.0

1.5

1.0

0.5

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0 0 2 4 6 8 10 14 18 22 26 30

WeekCOPYRIG

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GLP1RAaseffectiveatLispro withmealswhenaddedtobasalinsulin

DiamantMetal.DiabetesCare2014;37:2763-2773

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GLP1RAvsPrandialInsulinaddedtoBasalInsulin–WeightlossvsWeightGain

DiamantMetal.DiabetesCare2014;37:2763-2773

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ComparisonofMedicationsthatCouldbeAddedtoMetformin

SU TZD DPP-IV GLP-1

Efficacy High High Moderate High

Tolerability High Moderate High Moderate

Sideeffects HypoglycemiaWeightgain

Edema/CHFFracturesWeightgain

Rarepancreatitis GIRarepancreatitis

Riskofhypoglycemia Moderate Low Low Low

CVSafety Neutral Neutral Neutral LowersMACE(Leader)

Cost Low Low - Mod High High

AdaptedfromAbrahamson,MJ.DiabetesCare2015;38:166-169

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ComparisonofMedicationsthatCouldbeAddedtoMetformin

SGLT 2Inhibitor Cycloset Colesevalam AGI Insulin

Efficacy High Moderate Moderate Moderate Highest

Tolerability High Moderate High Low- Mod High

Sideeffects UTIVag yeastinfnOrthostasisBonefractures?

NauseaVomiting

Nil GI:FlatulenceDiarrhea

HypoglycemiaWeightgain

Riskofhypoglycemia

Low Low Low Low High

CVSafety Empa – lowersMACE

LowerMACE Neutral LowerMACE Neutral

Cost High Mod Mod Low - Mod Variable

AdaptedfromAbrahamson,MJ.DiabetesCare2015;38:166-169

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Costnotwithstanding,isthereanalternateapproachtotreatingtype2diabetes?

Lifestyle+

Metformin+

GLP-1 analogue/DPP-IV inhibitor/SGLT2 inhibitor

+Insulin

LifestyleLifestyle

+Metformin

Lifestyle+

Metformin+

GLP-1 analogueor

DPP-IV inhibitoror

SGLT2 inhibitor

Bariatric surgery?

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Summary• Multiplepathophysiologicalabnormalitiesexistinthepersonwithtype2DM

• Therearemedicationsthatcanaddressmostofthesepathophysiologicderangements

• NewerdataisemergingontheCVsafetyofdrugsusedtotreattype2DM• Moredrugsarenowavailablethathaveweight“benefit”andarenotassociatedwithhypoglycemia

• Useofnewerbasalinsulinanalogues,andcombinationsofbasalanalogueswithGLP1receptoragonistsreducesratesofhypoglycemia

• GLP1RAcanbeusedaseffectivelyasprandialinsulinwithfeweradverseevents

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