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

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

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

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

  2. 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

  3. Multifactorial Approach • Not a GLUCOSE-CENTRIC strategy • But tight METABOLIC CONTROL • The EARLIER the better ….Imprinting • Additional effect with BP & Cholesterol 

  4. ABCDE • A : A1c, Aspirin • B : BP ,BMI • C : Cholesterol ,Complications • D : Diet • E : Exercise

  5. DM shortens Lives • Diabetes (-)……………….Live forever ! • DM …………………………..Minus 6 years • DM & MI ………………….Minus 12 years

  6. 2/3 DM patients die from a CV event • Modifiable Risks • A ( A1c), B ( BP), C ( Chol) • Non Modifiable Risks • Age, gender, ethnic group

  7. 3 Pillars of CV risk

  8. 3 Pillars of DM Review

  9. In 3 Pillars of CV Risk & Multifactorial Intervention Are all things equal ? A = B = C ?

  10. 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,

  11. ADOPT 10

  12. 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

  13. 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 *

  14. What Next ? • Sulphonylurea • Incretin • GLP 1 analogue ( daily/ weekly) • DPP IV • SGLT2 • TZD • Insulin

  15. New Position Statement

  16. HbA1c targets • Individualized • < 7.0% : For all ? • < 6.5% : For Newly diagnosed ? • What about the newly diagnosed 75year old ?

  17. A1c Targets & Effect in DM2

  18. 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)

  19. Impact of Glucose RCT Lowering Trials in DM

  20. HbA1c & Glucose Early Intervention & Metabolic Memory is KEY

  21. DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREAS 1 Glyburide Glyburide Glimepiride SU Glyburide 0 Alvarsson (n=39) GLY SU Alvarsson (n=48) Gliclazide RECORD (n=272) Glyburide Change in HbA1c (%) Hanefeld (n=250) Charbonnel (n=313) -1 Gliclazide UKPDS (n=1,573) Chicago (n=230) ADOPT (n=1,441) PERISCOPE (n=181) Tan (n=297) -2 0 1 2 3 4 5 6 10 TIME (years)

  22. 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 *

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

  24. DURABILITY OF GLYCEMIC CONTROL WITH THIAZOLIDINEDIONES 1 Hanefeld (n=250) Chicago (n=232) ADOPT (n=1,456) Charbonnel (n=317) Rosenstock (n=115) PERISCOPE (n=178) Tan (n=249) RECORD (n=301) 0 PIO Rosiglitazone Change in HbA1c (%) PIO ROSI PIO -1 PIO PIO -2 0 1 2 3 4 5 6 TIME (years)

  25. 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*

  26. 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

  27. 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

  28. 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

  29. 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

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

  31. Comparability

  32. Potential Combinations • SGLT2 & DPPIV • SGLT2 & GLP 1 analogues

  33. Not one Size Fits All

  34. 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 ?

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

  36. What did I do ? • Stopped gliclazide / Increase gliclazide • Add pioglitazone Combination ( Competact ) • Add Incretin ( DPPIV or GLP1 analogue) • Add SGLT2

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

  38. 56 year old DM2 What is his ULTIMATE target BP ? • A. <140/90 • B. < 130/80 • C. < 120/80

  39. ESC Sept. 2009* / 2015 New Targets : < 140 /90 in patients with DM

  40. 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 ?

  41. INVEST Trial

  42. Results: Outcomes – Tight Control Group 16 (n=2,255) Reference

  43. 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 ?

  44. 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)

  45. 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 ?

  46. Diabetes HDL >1, > 1.3  LDL < 1.8 * Tg < 1.7* Cholesterol Values

  47. 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%

  48. The Cholesterol Question !

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