Multifactorial Intervention in DM Beyond a Glucosecentric Approach

Multifactorial Intervention in DM ! Beyond a Glucose-centric Approach The ABCDE of Diabetes Maeve C. Durkan MBBS, FACP, Mmed. Ed Consultant in Diabetes, Endocrinology & Metabolism

A Multifactorial Approach Lessons from Steno 2 1, 2 HR • Cardiovascular Death • Cardiovascular Events • Photocoagulation 0. 43 0. 41 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 : A 1 c, 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 ( A 1 c), B ( BP), C ( Chol) • Non Modifiable Risks – Age, gender, ethnic group

3 Pillars of CV risk • A 1 c • Glucose Control • Blood Pressure • • Cholesterol •

3 Pillars of DM Review • A • Aspirin • B • C • BMI • • Complications • Retinopathy • Creat/ e. GFR • Neuropathy

In 3 Pillars of CV Risk & Multifactorial Intervention Are all things equal ? A = • A 1 c • Glucose Control B = • Blood Pressure • C? • Cholesterol •

50 year old • • • DM 2 x 5 years Coexistent hypertension ( on Co. Diovan ) Stable Angina. No CHF. O/e : BMI 31, BP 145/90 Cardiac & Respiratory exam normal On Glucophage 1 gm BD • Hb. A 1 c 7. 8% ( 62 mmolar) , LFTs ALT 75, AST 45 • GFR 60 , Urine A/c ratio 3. 5,

ADOPT 10

What Next after Metformin GRADE study : Worldwide Trial • • Post metformin Randomization to any one of each class Except SGLT 2 Not powered as a CV trial

What did we get ? What so we want ? Past Limited choice Weight gain Hypoglycemia risk approaching target • Β cell fatigue • Loss durability • Complications • • Options Now 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 • SGLT 2 • TZD • Insulin

New Position Statement

Hb. A 1 c targets • Individualized • < 7. 0% : For all ? • < 6. 5% : For Newly diagnosed ? • What about the newly diagnosed 75 year old ?

A 1 c Targets & Effect in DM 2 ACCORD 3 10251 ADVANCE 4 11150 UKPDS 5 5102 A 1 c < 6. 0% A 1 c > 7. 0% A 1 c < 6. 5% A 1 c < 7. 0% Glucophage*

Mortality & A 1 c Targets • ACCORD 10250 , High risk, Diabetes Duration 8 -10 years • 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 ↓ ↓ ↔ ↔

Hb. A 1 c & Glucose Early Intervention & Metabolic Memory is KEY

DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREAS Change in Hb. A 1 c (%) 1 Glyburide Glimepiride Glyburide GLY SU Gliclazide 0 Glyburide SU Alvarsson (n=39) Alvarsson (n=48) RECORD (n=272) Hanefeld (n=250) Glyburide Charbonnel (n=313) -1 Gliclazide UKPDS (n=1, 573) Chicago (n=230) -2 ADOPT (n=1, 441) PERISCOPE (n=181) Tan (n=297) 0 1 2 3 4 TIME (years) 5 6 10

Sulphonylureas • Pros • • • Effective Work & work quickly Work well 100% responders Hb. A 1 c ↓ 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

DURABILITY OF GLYCEMIC CONTROL WITH THIAZOLIDINEDIONES Change in Hb. A 1 c (%) 1 Hanefeld (n=250) Charbonnel (n=317) Chicago (n=232) ADOPT (n=1, 456) PERISCOPE (n=178) Rosenstock (n=115) Tan (n=249) RECORD (n=301) 0 PIO Rosiglitazone PIO ROSI PIO -1 PIO -2 0 1 2 3 4 TIME (years) 5 6

TZDs: Pioglitazone (Actos) • • • Pros Effective , more slowly No hypoglycemia Hb. A 1 c ↓ 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 • Heart Failure • TECOS rr 1. 0 • Safe & effective in CKD • Pancreatitis ? • Weight neutral • Hb. A 1 c ↓(0. 6 -1%) • No hypoglycemia • Cancer ? NO EVIDENCE

1 o 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/NEJMoa 1501352

GLP 1 Inhibitors Pros • Easily added to anything, and/or insulin in DM 1* & 2 • Safe & effective in CKD • Concomitant weight loss • SBP & DBP reduction Cons • 1/3 don’t respond • Nausea • Pancreatitis ? NO EVIDENCE • No CV signal yet – Lixizenatide • Hb. A 1 c reduction • Cancer ? NO EVIDENCE • No hypoglycemia • Needle

SGLT 2 Inhibitors Pros Cons • Easily added to anything, and/or insulin in DM 1 & 2 • UTI & Genital tract infections • Simple & dose response • LDL (unclear mechanism) • Concomitant weight loss • HDL (unclear mechanism) • SBP & DBP reduction • No CV signal yet • Hb. A 1 c reduction • Limited to CKD ( e. GFR>45) • No hypoglycemia • Reversible shift in GFR – Canvas

EMPA – REG Empagliflozin ( NEJM Sept 16, 2015) • • Clear Findings High risk Group ↓Hospitalization for Heart failure ↓Cardiac mortality

Comparability Admin Hb. A 1 c Weight Tolerability Exenatide LAR Liraglutide* Inj BD Inj week Inj QD Broadly comparable ↓↓ Nausea DPP IVs PO ←→ - ↓ - SGLT 2 s PO Approx. 1 -2% Broadly comparable Approx. 0. 5 – 1%

Potential Combinations • SGLT 2 & DPPIV • SGLT 2 & GLP 1 analogues

Not one Size Fits All

65 year old Man • • DM 2 BMI 27 Glucophage 850 mg tds, diamicron 60 Hb. A 1 c 7. 5% Spends 4/7 working on farm 200 km away Stable CKD, e. GFR 45 Significant low one night ( requiring 3 rd 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 Hb. A 1 c targets Comorbidities…e. GFR 45

What did I do ? • Stopped gliclazide / Increase gliclazide • Add pioglitazone Combination ( Competact ) • Add Incretin ( DPPIV or GLP 1 analogue) • Add SGLT 2

BP • • 50 year old man DM 2 : Diet controlled x 4 years Obese, Hypertensive No other co-morbidities • What is his target BP ?

56 year old DM 2 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 DM 2 • 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* HR 1. 15 CI (1. 1 -1. 36) Not controlled Risk Major Events Highest

Results: Outcomes – Tight Control Group 16 (n=2, 255) Reference Other significant variables in Cox regression model: age, race, PAD, MI, CHF, US residency, renal impairment, LVH, TIA/stroke

56 year old DM 2 (+) 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% • SBB < 140* (133. 9) • Conventional Arm – NTT 89 • • A/c 12. 4 Macro 6. 4% e. GFR 74. 9* Creat 1. 1 mg/dl* • • A/C 18. 6 ( p < 0. 0001) Macro 7. 0% (p < 0. 0001) e. GFR 80. 6 (p<0. 0001) Creat 1. 0 ( p<0. 0001)

Cholesterol • 52 year old man , DM 2 x 5 years • Hb. A 1 c 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 • AHA / ACC • Target driven • Not target driven • LDL < 2 ( 2. 5) • 50% reduction in LDL • High intensity vs Low Intensity statins • ASCVD risk calculator 7. 5%

The Cholesterol Question ! NCEP ACCF 2004 2008 AHA 2008 AACE 2008* ADA 2010 < 2. 5 <1. 8 <2. 0 TG* <2. 0 <1. 7 HDL* >1 /1. 3 >1/1. 3 LDL High Risk* LDL Low Risk* Apo B <90 High Risk Apo B <90 >1/ 1. 3

LDL Atorvastatin Simvastatin Rosuvastatin Lipitor Zocor Crestor 80 mg 40 mg LDL @ max 60% 41% 63% Tg’s 18% (40 mg) 29% (40 mg)

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 medication B. Switch to another statin C. Change to fibrate D. Add ezetrol

LDL 1. 3, Tg 1. 5, HDL 1 • • 52 year old man DM 2 x 5 years Hb. A 1 c 6. 5% STEMI last year / Stent x 1 How Low to GO ?

JUPITER 17

PCSK 9 Trials • • ODDYSSEY FOURIER OSLER 1 & 2 RUTHERFORD 2 • LDL nadir < 0. 6

Take Home Message • Treat LDL 1 st • Treat to Target < 2. 0 / 1. 8 • Statins are 1 st choice

Targets Hb A 1 c 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, A 1 c < 7% Bp < 130/80 LDL < 2. 5 Diet : Obesity an independent predictor in CKD