our vision to be a globally-acknowledged centre of excellence for clinical care, education training, and res

1. OUR VISIONTo be a globally-acknowledged centre of excellence for clinical care, education & training, and research in diabetology and endocrinology.

3. TAKE HOME MESSAGES Read the fine print Familiarize yourself with side-effects, kinetics, doses Give ACEI if cardiac morbidity is a concern Give ARB if renal morbidity is a concern, in type 2DM [ACEI in type 1] Give both if both are a concern Make sure you control BP

4. WHY CONTROL B.P ? Decreased risk of stroke cardiovascular disease nephropathy Decreased mortality BOTH SYSTOLIC & DIASTOLIC BP ARE IMPORTANT (JNC 7, MONICA �94,BHRC �90)

5. Questions Unanswered A specific endpoint Blood pressure Cardiac morbidity Renal morbidity Cerebrovascular morbidity Mortality �class effect� Specific dose

6. Class effect All drugs of a particular class have a �common minimum structure� or �common effect� Extra elements may add other [unknown] effects or take away beneficial effects

7. Class effect Development of a molecule is expensive It is much easier [and economical] to market a �me-too� molecule, based on class effect Studies may not be available to show a particular effect

8. Dose effect 10 mg of ramipril is not equal to 5 mg of ramipril 10 mg of ramipril is certainly not equal to 10 mg of quinapril 4 mg perindopril [PROGRESS] shows different results from 8 mg [EUROPA]

9. PHYSIOLOGY RENIN-ANGIOTENSIN SYSTEM Vasoconstrictor system Activation leads to hypertension Blockade of angiotensin II or its receptors leads to normotension This also prevents cerebrovascular, cardiovascular and renal events

10. Actions of RAS Circulating RAS Vasoconstriction Aldosterone release AVP release Stimulate thirst and sodium appetite Renal sodium and water reabsorption Tissue-based RAS Hypertrophy Hyperplasia Remodelling Cytokine activation Collagen deposition/ fibrosis

12. Endothelium and Ang II Vasoconstriction Inflammation Remodelling Thrombosis Oxidative stress Stimulation of metalloproteinases which break down extracellular matrix

14. Rationale for ARBs/combinattion ACEI don�t suppress Ang II production over 24 h Partial recovery of Ang II occurs [ACE escape] Ang II is also produced by cathepsin G, elastase, tPA, chymase, chymostatin-sensitive Ang II generating enzyme [CAGE], tonin Cough and angioedema are less common with ARBs as they do not increase bradykinin levels 18% pts respond only to ACEI, 15% only to ARB [Stergiou , 2001]

15. ACE[I] Reduce morbidity and mortality in heart failure patients Meta-analysis of 7105 patients in 32 trials >= 8 weeks duration showed 0.77 OR for all-cause mortality, 0.65 OR for mortality + hospitalization due to CCF Meta-analysis of 12763 patients of LV dysfunction +/- MI in 5 trials showed 0.80 OR for all-cause mortality, 0.67 OR for hospitalization due to failure, 0.79 OR for reinfarction

16. ACE[I] Meta-analysis of 98496 patients in 4 trials treated within 0-36 hrs of MI with ACE[I] showed 7% reduction in 30-day mortality and significant decrease in nonfatal heart failure

17. ACE[I] IN DIABETIC HYPERTENSIVES FACET: 380 pts. Fosinopril vs. amlodipine. HR 0.49 for acute MI, stroke and hospitalization due to angina. B.P control was better with amlodipine [ -19 mm SBP vs. �13 mm SBP with fosinopril; -8 mm DBP with both ] ABCD: 470 pts. Enalpril vs. nisoldipine had lower risk for MI, though BP control was same. UKPDS: no difference b/w captopril and atenolol

18. ACE[I] IN HYPERTENSION STOP: 6614 patients 70 � 84 yrs old. ACE[I] better than CCB [RR 0.77] but not different from BB or diuretic w.r.t risk for MI CAPPP: 10985 pts. No difference b/w captopril and BB-diuretic groups w.r.t risk of MI

19. ACE INHIBITORS HOPE STUDY marked reduction in complications of diabetes RR 0.84 Reduction in new cases of diabetes RR 0.66 Improved insulin sensitivity decreased hepatic clearance of insulin antiinflammatory effect improved pancreatic blood flow

20. HOPE 9297 patients at high risk of CV events Risk of MI, stroke, death from cardiovascular causes lower for ramipril group [RR 0.68 to 0.84] 20% risk reduction in MI is more than the 5% RR expected with a 3 mm redction in SBP

21. Different ACE[I] 4 ACEIs have not been shown to reduce morbidity/mortality in any indication: benazepril, fosinopril, moexipril, quinapril A 5th � perindopril has shown benefit at 8 mg but not at 4 mg ramipril has the broadest approval

22. ARBs and blood pressure CCBs are taken to be potent anti-hypertensives 24 hour coverage is needed to protect against early morning activation of RAS Telmisartan is more potent than amlodipine for DBP control and control during 4 hours prior to dosing [Lacourciere et al, 1998]

23. ARBs and nephropathy IRMA2 trial: irbesartan reduced overt nephropathy by 71% in diabetics with microalbuminuria (Parving, 2001) Similar results by Brenner in RENAAL (losartan, 2001), Lewis in IDNT (irbesartan, 2001), Viberti in MARVAL (valsartan, 2002) in type 2 diabetics with overt nephropathy

24. ACE(I) or ARBs for the kidney ? Best results for type 2 renoprotection seen with ARBs IRMA2: 71% RR with 300 mg irbesartan Ravid �94: 30% with enalapril MICRO-HOPE: 25% with ramipril

25. ARBs and heart failure ELITE : losartan better tolerated, reduced mortality, with better compliance w.r.t captopril [1997] ELITE II: no difference in mortality [2000] ValHeFT: addition of valsartan reduced endpoint by 13.2% in all pts; by 45% in pts not on ACEI [2001] LIFE: losartan and atenolol equipotent for BP control; losartan RR 0.75 for stroke, 0.87 for combined endpoint [2002]

26. ARBs SCOPE: candesartan reduces risk of stroke by 28%; no change in cognitive function [2002] ACCESS: candesartan reduced mortality/ complications by 47.5% in stroke survivors

27. Different ARBs Losartan, eprosartan: b.d dose Rifampicin induces, fluconazole reduces metabolism of losartan Losaretan is uricosuric Avoid digoxin + telmisartan Can give valsartan, telmisartan with food** Avoid losartan in hepatic dysfunction Prefer telmisartan in severe renal failure Candesartan most potent; telmisartan longest t 1/2

28. Combination RESOLVD: candesartan = enalapril , but combination is better for 6MWD, ventricular function, NYHA-FC and QOL. Optimum dose = enalpril 20 mg + cande 8 mg [1999] OPTIMAAL: losartan 50 mg = captopril 150 mg/d [2002] Pfeffer et al, 2003: valsartan = captopril = combination. CHARM: candesartan reduced endpoint by 15%

29. ARBs: optimal dose Higher doses provide more benefit [various] Valsartan 160 mg Losartan 100 mg Candesartan 8 mg Valsartan 160 mg = lisinopril 20 mg = amlodipine 10 mg Valsartan 160 mg better than enalapril 20 mg, benazepril 20 mg

30. ACE[I] + ARBs (DUAL BLOCKADE) Rossing, 2000: candesartan 8 mg + enalapril/lisinopril 20 mg or captopril 100 mg CALM study, 2000: candesartan 16 mg + lisinopril 20 mg: greater decline in DBP, SBP but no significant reduction in urinary albumin: creatinine ratio

31. COMBINATION THERAPY >65% of diabetics require combination therapy to achieve B.P.< 130/80 (Nat Kid Fnd Ht & Diab Exec Com Work Gp, 2000 Sep) Diabetics require 2nd & 3rd drugs 40% & 100% more frequently than non-diabetics (Brown et al, 2000 May) Similar guidelines from JNC 7 & ESH, 2003

32. ACE[I] + BETA-BLOCKERS Both lower sympathetic drive Both act on high- renin hypertension Combination is not synergistic No such combination available in market

33. CONCLUSION Control B.P. aggressively CONVINCE YOURSELF BEFORE CONVINCING THE PATIENT Use appropriate monotherapy or combination therapy Increase compliance