Multifactorial Intervention in DM ! Beyond a Glucose-centric Approach The ABCDE of Diabetes

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Multifactorial Intervention in DM !Beyond a
Glucose-centric ApproachThe ABCDE of Diabetes

• Maeve C. Durkan MBBS, FACP, Mmed.Ed
• Consultant in Diabetes, Endocrinology
  Metabolism

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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

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Multifactorial Approach

• Not a GLUCOSE-CENTRIC strategy
• But tight METABOLIC CONTROL
• The EARLIER the better .Imprinting
• Additional effect with BP Cholesterol ?

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ABCDE

• A A1c, Aspirin
• B BP ,BMI
• C Cholesterol ,Complications
• D Diet
• E Exercise

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DM shortens Lives

• Diabetes (-).Live forever !
• DM ..Minus 6 years
• DM MI .Minus 12 years

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2/3 DM patients die from a CV event

• Modifiable Risks
• A ( A1c), B ( BP), C ( Chol)
• Non Modifiable Risks
• Age, gender, ethnic group

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3 Pillars of CV risk
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3 Pillars of DM Review
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In 3 Pillars of CV Risk Multifactorial
Intervention

• Are all things equal ?
• A B C ?

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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,

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ADOPT 10
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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

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What did we get ?What so we want ?

• Past

• Options Now

• Limited choice
• Weight gain
• Hypoglycemia
• ? risk approaching target
• ? cell fatigue
• Loss durability
• Complications

• More choice
• Weight loss / neutrality
• Less hypoglycemia
• ? risk approaching targets
• ? cell preservation !
• Durability
• Complications

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What Next ?

• Sulphonylurea
• Incretin
• GLP 1 analogue ( daily/ weekly)
• DPP IV
• SGLT2
• TZD
• Insulin

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New Position Statement
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HbA1c targets

• Individualized
• lt 7.0 For all ?
• lt 6.5 For Newly diagnosed ?
• What about the newly diagnosed 75year old ?

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A1c Targets Effect in DM2
ACCORD 3 10251 ADVANCE 4 11150 UKPDS 5 5102
A1c lt 6.0 A1c gt 7.0 A1c lt 6.5 A1c lt 7.0
Glucophage
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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)

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Impact of Glucose RCT Lowering Trials in DM
Study Microvasc Extension CVD Extension Mortality Extension
UKPDS 33 ? ? ? ? ? ?
DCCT/EDIC ? ? ? ? ? ?
ACCORD ? ? ? ? ? ?
ADVANCE ? ? ? ? ? ?
VADT ? ? ? ? ? ?
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HbA1c Glucose

• Early Intervention Metabolic Memory is KEY

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DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREAS
1
Glyburide
Glyburide
Glimepiride
SU
Glyburide
0
Alvarsson (n39)
GLY
SU
Alvarsson (n48)
Gliclazide
RECORD (n272)
Glyburide
Change in HbA1c ()
Hanefeld (n250)
Charbonnel (n313)
-1
Gliclazide
UKPDS (n1,573)
Chicago (n230)
ADOPT (n1,441)
PERISCOPE (n181)
Tan (n297)
-2
0
1
2
3
4
5
6
10
TIME (years)
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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

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Driving Guidelines

• New European, UK Irish Guidelines
• gt 2 hypos / year ( On sulphonylureas )
• Glucose records required on SUs Insulin

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DURABILITY OF GLYCEMIC CONTROL WITH
THIAZOLIDINEDIONES
1
Hanefeld (n250)
Chicago (n232)
ADOPT (n1,456)
Charbonnel (n317)
PERISCOPE (n178)
Rosenstock (n115)
RECORD (n301)
Tan (n249)
0
PIO
Rosiglitazone
Change in HbA1c ()
PIO
ROSI
PIO
-1
PIO
PIO
-2
0
1
2
3
4
5
6
TIME (years)
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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 111IV)
• Bone thinning/ Fractures
• C/I with Dapagliflozin

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DPP IV Inhibitors

• Cons

• Pros

• Heart Failure
• TECOS rr 1.0
• Pancreatitis ?
• Cancer ? NO EVIDENCE

• Easily added to all, and/or insulin in DM 2
• Safe effective in CKD
• Weight neutral
• HbA1c ?(0.6-1)
• No hypoglycemia

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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
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GLP1 Inhibitors

• Cons

• Pros

• 1/3 dont respond
• Nausea
• Pancreatitis ? NO EVIDENCE
• No CV signal yet
• Lixizenatide
• Cancer ? NO EVIDENCE
• Needle

• Easily added to anything, and/or insulin in DM1
  2
• Safe effective in CKD
• Concomitant weight loss
• SBP DBP reduction
• HbA1c reduction
• No hypoglycemia

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SGLT2 Inhibitors

• Cons

• Pros

• UTI Genital tract infections
• LDL ? (unclear mechanism)
• HDL ? (unclear mechanism)
• No CV signal yet
• Canvas
• Limited to CKD ( eGFRgt45)
• Reversible shift in GFR

• Easily added to anything, and/or insulin in DM1
  2
• Simple dose response
• Concomitant weight loss
• SBP DBP reduction
• HbA1c reduction
• No hypoglycemia

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EMPA REGEmpagliflozin ( NEJM Sept 16,2015)

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

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Comparability
Admin HbA1c Weight Tolerability
Exenatide LAR Inj BD Inj week Broadly comparable Approx. 1-2 ?? Nausea
Liraglutide Inj QD Broadly comparable Approx. 1-2 ?? Nausea
DPP IVs PO Broadly comparable Approx. 0.5 1 ?? - -
SGLT2s PO Broadly comparable Approx. 0.5 1 ? -
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Potential Combinations

• SGLT2 DPPIV
• SGLT2 GLP 1 analogues

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Not one Size Fits All
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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 ?

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Whats his priority in treatment?

• Safety Independence
• Free of hypoglycemia
• Can drive
• Can tend to his farm
• Personalized HbA1c targets
• ComorbiditieseGFR 45

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What did I do ?

• Stopped gliclazide / Increase gliclazide
• Add pioglitazone Combination ( Competact )
• Add Incretin ( DPPIV or GLP1 analogue)
• Add SGLT2

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BP

• 50 year old man
• DM2 Diet controlled x 4 years
• Obese, Hypertensive
• No other co-morbidities
• What is his target BP ?

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56 year old DM2

• What is his ULTIMATE target BP ?
• A. lt140/90
• B. lt 130/80
• C. lt 120/80

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ESC Sept. 2009 / 2015

• New Targets lt 140 /90 in patients with DM

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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 ?

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INVEST Trial
SBPlt120 SBP 130-140 SBP gt 140
Tight Usual Not controlled
HR 1.15 CI (1.1-1.36) Risk Major Events Highest

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Results Outcomes Tight Control Group 16
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56 year old DM2 () microalbuminuria

• What is his target BP ?
• A. lt 130/80
• B. lt 120/80
• C. The lower the better, as tolerated
• Is there a J curve ?

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ACCORD 4733 patients

• SBP lt 120
• Intensive Arm
• RR Stroke 41
• NTT 89
• A/c ?12.4
• Macro ?6.4
• eGFR ? 74.9
• Creat ?1.1mg/dl

• SBB lt 140 (133.9)
• Conventional Arm
• A/C 18.6 ( p lt 0.0001)
• Macro 7.0 (p lt 0.0001)
• eGFR 80.6 (plt0.0001)
• Creat 1.0 ( plt0.0001)

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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 ?

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Cholesterol Values

• Diabetes
• HDL gt1?, gt 1.3 ?
• LDL lt 1.8
• Tg lt 1.7

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Treatment Guidelines

• EASD / BHS
• Target driven
• LDL lt 2 ( 2.5)

• AHA / ACC
• Not target driven
• 50 reduction in LDL
• High intensity vs Low Intensity statins
• ASCVD risk calculator 7.5

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The Cholesterol Question !
NCEP 2004 ACCF 2008 AHA 2008 AACE 2008 ADA 2010
LDL High Risk lt 2.5 lt1.8 lt1.8 lt1.8
LDL Low Risk lt2.0 lt2.0 lt2.0
TG lt2.0 lt1.7 lt1.7
HDL gt1 /1.3 gt1/1.3 gt1/ 1.3
Apo B High Risk lt90
Apo B Low Risk lt90
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LDL
Atorvastatin Lipitor 80mg Simvastatin Zocor 40mg Rosuvastatin Crestor 40mg
LDL? _at_ max 60 41 63

Tgs ? 29 (40mg) 18 (40mg) 28 (40mg)
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Ezetamibe/ Ezetrol

• 20 synergistic reduction in LDL
• IMPROVE IT ( ACC 02/2015)

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Starting Off

• LFTs
• CK

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Patient returns c/o muscle aches

• Do you ?
• A. Stop medication
• B. Switch to another statin
• C. Change to fibrate
• D. Add ezetrol

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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 ?

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JUPITER 17
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PCSK9 Trials

• ODDYSSEY
• FOURIER
• OSLER 1 2
• RUTHERFORD 2
• LDL nadir lt 0.6

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Take Home Message

• Treat LDL 1st
• Treat to Target lt 2.0 / 1.8
• Statins are 1st choice

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Targets
Hb A1c BP Cholesterol
lt6.5 lt7.0 lt135/80 lt120/80 ? LDL lt2.0/1.8 Tg lt2.3 HDL gt1.0 / 1.3
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Current Recommendation

• All patients with DM aged gt 40 should be on a
  statin !
• AHA, ADA

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More bang for Buck!

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