Multifactorial Intervention in DM !Beyond a Glucose-centric Approach

The ABCDE of DiabetesMaeve C. Durkan MBBS, FACP, Mmed.Ed

Consultant in Diabetes, Endocrinology & Metabolism

Steno-2 Study:Composite End Point

Gaede P et al. N Engl J Med. 2003;348:383-393.

*In accordance with national guidelines†Multifactorial intervention

No. at RiskConventional tx* 80 72 70 63 59 50 44 41 13Intensive tx† 80 78 74 71 66 63 61 59 19

Months0 12 24 36 48 60 72 84 96

60

50

40

30

20

10

0

Conventional therapy

Intensive therapy

P=0.007

Primarycomposite end point

(% )

53%

© 2005 Thomson Professional Postgraduate Services®

A Multifactorial ApproachLessons from Steno 2 1,2

HR• Cardiovascular Death 0.43• Cardiovascular Events 0.41• Photocoagulation 0.48

• Not a GLUCOSE-CENTRIC strategy• But tight METABOLIC CONTROL

Multifactorial Approach

• Not a GLUCOSE-CENTRIC strategy• But tight METABOLIC CONTROL

• The EARLIER the better ….Imprinting

• Additional effect with BP & Cholesterol

ABCDE

• A : A1c, Aspirin

• B : BP ,BMI

• C : Cholesterol ,Complications

• D : Diet

• E : Exercise

DM shortens Lives

• Diabetes (-)……………….Live forever !

• DM …………………………..Minus 6 years

• DM & MI ………………….Minus 12 years

2/3 DM patients die from a CV event

• Modifiable Risks

– A ( A1c), B ( BP), C ( Chol)

• Non Modifiable Risks

– Age, gender, ethnic group

3 Pillars of CV risk

3 Pillars of DM Review

In 3 Pillars of CV Risk & Multifactorial Intervention

Are all things equal ?

A = B = C ?

50 year old • DM2 x 5 years• Coexistent hypertension ( on CoDiovan )• Stable Angina . No CHF .• O/e : BMI 31, BP 145/90• Cardiac & Respiratory exam normal• On Glucophage 1gm BD

• HbA1c 7.8% ( 62 mmolar) , LFTs ALT 75,AST 45 • GFR 60 , Urine A/c ratio 3.5,

ADOPT 10

HbA1c Over Time

0 1 2 3 4 5

Time (years)

%

0

6.0

8.0

7.0

6.5

7.5

Rosiglitazone

Glyburide

Metformin

Rosiglitazone vs Metformin

0.13 ( 0.22 to 0.05), P=0.002

Rosiglitazone vs Glyburide 0.42 ( 0.50 to 0.33), P<0.001

What Next after Metformin

GRADE study : Worldwide Trial

•Post metformin•Randomization to any one of each class•Except SGLT2•Not powered as a CV trial

What did we get ?What so we want ?

Past Options Now • Limited choice• Weight gain• Hypoglycemia• risk approaching

target• Β cell fatigue• Loss durability• Complications

• More choice • Weight loss / neutrality• Less hypoglycemia• risk approaching

targets• Β cell preservation !• Durability• Complications *

What Next ?

• Sulphonylurea • Incretin

– GLP 1 analogue ( daily/ weekly)– DPP IV

• SGLT2• TZD• Insulin

New Position Statement

HbA1c targets

• Individualized

• < 7.0% : For all ?

• < 6.5% : For Newly diagnosed ?

• What about the newly diagnosed 75year old ?

A1c Targets & Effect in DM2

ACCORD 3

10251

ADVANCE 4

11150

UKPDS 5

5102

A1c < 6.0%

A1c > 7.0%

A1c < 6.5% A1c < 7.0%

Glucophage*

Mortality & A1c Targets

• ACCORD 10250 , High risk, Diabetes Duration 8-10years

• VADT 1791, High risk, Diabetes Duration 11.5 years

• ADVANCE 11,140 Moderate risk*, Diabetes Duration 8 yrs.

• STENO 160, Low risk, Short Duration

• UKPDS 3867, Low risk*, Newly diagnosed

• DCCT 1441, Low risk, Diabetes Duration (1-15 years)

Impact of Glucose RCT Lowering Trials in DM

Study Microvasc Extension CVD Extension Mortality Extension

UKPDS 33 ↓ ↓ ↔ ↓ ↔ ↓

DCCT/EDIC ↓ ↓ ↔ ↓ ↔ ↓

ACCORD ↓ ↓ ↔ ↔ ↑

ADVANCE ↓ ↓ ↔ ↔ ↔ ↔

VADT ↓ ↓ ↔ ↓ ↔ ↔

HbA1c & Glucose

Early Intervention & Metabolic Memory is KEY

-2

-1

0

1

Ch

ang

e in

Hb

A1c

(%

)

TIME (years)0 1 2 3 4 5 6 10

Hanefeld (n=250)

Charbonnel (n=313)

Chicago (n=230)

ADOPT (n=1,441)

UKPDS (n=1,573)

GliclazideGliclazide

PERISCOPE (n=181)

GLY

GlimepirideGlyburide Glyburide

Glyburide

Glyburide

SU

SU

Alvarsson (n=39)

Alvarsson (n=48)RECORD (n=272)

Tan (n=297)

Gliclazide

DURABILITY OF GLYCEMIC CONTROL DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREASWITH SULFONYLUREAS

Sulphonylureas

• Pros

• Effective• Work & work quickly• Work well• 100% responders• HbA1c ↓ 1-2 %• Around for years

• Cons

• Hypoglycaemia• Weight gain• Beta cell fatigue• Durability • CV risk *

Driving Guidelines

New European, UK & Irish Guidelines > 2 hypos / year ( On sulphonylureas ) Glucose records required on SU’s Insulin

-2

-1

0

1

Ch

ang

e in

Hb

A1c

(%

)

TIME (years)0 1 2 3 4 5 6

PIOPIO

PIO

RosiglitazoneRosiglitazone

DURABILITY OF GLYCEMIC CONTROL DURABILITY OF GLYCEMIC CONTROL WITH THIAZOLIDINEDIONESWITH THIAZOLIDINEDIONES

Hanefeld (n=250)

Charbonnel (n=317)

Chicago (n=232) ADOPT (n=1,456)

PIO

PERISCOPE (n=178)

PIO

RECORD (n=301)

Rosenstock (n=115)

ROSI

Tan (n=249)

PIO

TZDs: Pioglitazone (Actos)

• Pros • Effective , more slowly• No hypoglycemia• HbA1c ↓ 1-2 %• Improved Lipids ( LDL*, Tg)• Target IR • Durability• CV benefit proven• NAFLD target ?

• Cons • Weight gain (fluid)• Heart failure (NYC 111&IV)• Bone thinning/ Fractures• C/I with Dapagliflozin*

DPP IV Inhibitors Pros Cons

• Easily added to all, and/or insulin in & DM 2

• Safe & effective in CKD

• Weight neutral

• HbA1c ↓(0.6-1%)

• No hypoglycemia

•Heart Failure•TECOS rr 1.0

•Pancreatitis ?

•Cancer ? NO EVIDENCE

1o Composite Cardiovascular Outcome*

PP Analysis for Non-inferiority

* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina

Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

GLP1 Inhibitors Pros Cons

• Easily added to anything, and/or insulin in DM1* & 2

• Safe & effective in CKD

• Concomitant weight loss

• SBP & DBP reduction

• HbA1c reduction

• No hypoglycemia

• 1/3 don’t respond

• Nausea

• Pancreatitis ? NO EVIDENCE

• No CV signal yet– Lixizenatide

• Cancer ? NO EVIDENCE

• Needle

SGLT2 Inhibitors Pros Cons

• Easily added to anything, and/or insulin in DM1 & 2

• Simple & dose response

• Concomitant weight loss

• SBP & DBP reduction

• HbA1c reduction

• No hypoglycemia

• UTI & Genital tract infections

• LDL (unclear mechanism)

• HDL (unclear mechanism)

• No CV signal yet– Canvas

• Limited to CKD ( eGFR>45)

• Reversible shift in GFR

EMPA – REGEmpagliflozin ( NEJM Sept 16,2015)

•Clear Findings•High risk Group•↓Hospitalization for Heart failure•↓Cardiac mortality

Comparability

Admin HbA1c Weight Tolerability

Exenatide

LAR

Inj BD

Inj week

Broadly comparable

Approx. 1-2%

↓↓ Nausea

Liraglutide* Inj QD ↓↓ Nausea

DPP IVs POBroadly comparable

Approx. 0.5 – 1%

←→ -

-

SGLT2s PO ↓ -

Potential Combinations

• SGLT2 & DPPIV

• SGLT2 & GLP 1 analogues

Not one Size Fits All

65 year old Man• DM2 BMI 27• Glucophage 850mg tds, diamicron 60• HbA1c 7.5%• Spends 4/7 working on farm 200 km away• Stable CKD, eGFR 45• Significant low one night ( requiring 3rd party help)• Driving license due for renewal• What next ?

What’s his priority in treatment?• Safety & Independence• Free of hypoglycemia• Can drive• Can tend to his farm• Personalized HbA1c targets• Comorbidities…eGFR 45

What did I do ?

•Stopped gliclazide / Increase gliclazide

•Add pioglitazone Combination ( Competact )

•Add Incretin ( DPPIV or GLP1 analogue)

•Add SGLT2

BP

• 50 year old man

• DM2 : Diet controlled x 4 years

• Obese, Hypertensive

• No other co-morbidities

• What is his target BP ?

56 year old DM2

What is his ULTIMATE target BP ?

• A. <140/90

• B. < 130/80

• C. < 120/80

ESC Sept. 2009* / 2015

New Targets : < 140 /90 in patients with DM

56 year old DM2

• What is his ULTIMATE best target BP ?

• A. Is it ‘ The lower the better, as tolerated ‘

• B. Is there a J curve ?

INVEST Trial

SBP<120 SBP 130-140 SBP > 140

Tight Usual* Not controlled

HR 1.15

CI (1.1-1.36)

Risk Major Events Highest

(n=2,255)

Reference

Results: Outcomes – Tight Control Group 16

56 year old DM2 (+) microalbuminuria

• What is his target BP ?

• A. < 130/80• B. < 120/80• C. The lower the better, as tolerated

• Is there a J curve ?

ACCORD : 4733 patients

• SBP < 120• Intensive Arm• RR Stroke :41%

– NTT 89

• A/c 12.4• Macro 6.4%• eGFR 74.9*• Creat 1.1mg/dl*

• SBB < 140* (133.9)• Conventional Arm

• A/C 18.6 ( p < 0.0001)• Macro 7.0% (p < 0.0001)• eGFR 80.6 (p<0.0001)• Creat 1.0 ( p<0.0001)

Cholesterol• 52 year old man ,DM2 x 5 years• HbA1c 6.5%• No co-morbidities / or CAD+

• LDL 4, Tg 1.5, HDL 1 ( Total Cholesterol 4.3 *)

• Will you treat?• What will you treat ?• What is target ?

Cholesterol Values

• Diabetes

• HDL >1, > 1.3

• LDL < 1.8 *

• Tg < 1.7*

Treatment Guidelines• EASD / BHS

• Target driven

• LDL < 2 ( 2.5)

• AHA / ACC

• Not target driven

• 50% reduction in LDL

• High intensity vs Low Intensity statins

• ASCVD risk calculator 7.5%

The Cholesterol Question !

LDL

Atorvastatin

Lipitor

80mg

Simvastatin

Zocor

40mg

Rosuvastatin

Crestor

40mg

LDL @ max

60% 41% 63%

Tg’s 29%

(40mg)

18% (40mg)

28%

(40mg)

Ezetamibe/ Ezetrol

20% synergistic reduction in LDL

IMPROVE IT ( ACC 02/2015)

Starting Off

LFT’s CK

Patient returns c/o muscle aches

Do you ?

A. Stop medicationB. Switch to another statinC. Change to fibrate

D. Add ezetrol

LDL 1.3, Tg 1.5, HDL 1

• 52 year old man

• DM2 x 5 years

• HbA1c 6.5%

• STEMI last year / Stent x 1

How Low to GO ?

JUPITER 17

PCSK9 Trials

• ODDYSSEY• FOURIER• OSLER 1 & 2• RUTHERFORD 2

• LDL nadir < 0.6

Take Home Message

• Treat LDL 1st

• Treat to Target < 2.0 / 1.8

• Statins are 1st choice

Targets

Hb A1c BP Cholesterol

<6.5%

<7.0%

<135/80*

<120/80 ?

LDL <2.0/1.8*

Tg <2.3*

HDL >1.0 / 1.3*

Current Recommendation

All patients with DM aged > 40 should be on a statin !– AHA, ADA

More bang for Buck!

• Early Intervention• ABCD ( Ali et al NEJM 2013)• ADVANCE – IT, STENO, UKPDS,VADT,• A1c < 7%• Bp < 130/80• LDL < 2.5• Diet : Obesity an independent predictor in CKD