Diabetes - Risk Management & New Drugs 15/06/12 National Prescribing Centre
Concomitant Use of Antihypertensive Drugs Antihypertensive drugs typically are very complimentary; however, there are some combinations which tend to be more favorable and are shown in this slide by the yellow lines. Although drug combinations shown by the pink line can be used, they tend to be less complimentary and frequently do not result in an additive reductions in BP. Reference: Chalmers J. The Place of Combination Therapy in the Treatment of Hypertension in 1993. Clin Exp Hypertens. 1993;15:1299-1313.
Diabetes - Risk Management & New Drugs 15/06/12 National Prescribing Centre
10/24/97 1 J:\\artem\\F151097\\Europa
ACE INHIBITORS : FROM VENOM TO DRUG Dr Syed Raza MD,MRCP(UK),CCT(UK),DIP.CARD(UK),FCCCP Consultant Cardiologist
Objectives• Overview of ACEI• Indications and Uses• Effectiveness and• The Evidence
Franklin D Roosevelt – 1940sHoward Bruenn lamented in the Annals of Internal Medicine, "I haveoften wondered what turn the subsequent course of history might havetaken if the modern methods for the control of hypertension had beenavailable’’
Originally synthesized fromcompounds found in pit vipervenom(Sir John Vane -1960s)
Angiotensinogen Renin Angiotensin I Bradykinin Non ACE ACE (-) ACEi (-) Angiotensin II Inactive Metabolites ARBAT1 Receptor AT2 Receptor
Clinical Indications for ACEI• Hypertension• CHF• Post MI• Diabetes Mellitus• Proteinuria• Vascular Disease• Post - transplant
Additional Benefits of ACEI• Prevention of diabetes• Prevention of stroke recurrence• Prevention of atrial fibrillation
How ACEI is useful in hypertension?• ACE inhibitors block the conversion of angiotensin I to angiotensin II• Lower arteriolar and renovascular resistance• Increase venous capacity,• Increase cardiac output, cardiac index and stroke volume.
Which antihypertensive? NICE Diabetes Clinical Guideline 66;May 2008. NICE Full Diabetes Guideline;2008• First-line BP lowering therapy should be a once-daily, generic ACE inhibitor• Exceptions to this are: – People of African-Caribbean descent – Women for whom there is a possibility of becoming pregnant – For a person with continuing intolerance to an ACE inhibitor
Choice of antihypertensive agents When implementing blockade of the renin– angiotensin system start treatment with an ACE inhibitor first then move to an ARB if the ACE inhibitor is not tolerated.
Pharmacotherapy –BP Control• In people without CKD aim to keep the systolic blood pressure below 140 mmHg (target range 120–139 mmHg) and the diastolic blood pressure below 90 mmHg.• In people with CKD and diabetes with urinary protein excretion 1 g/24 h or more) aim to keep the systolic blood pressure below 130 mmHg (target range 120–129 mmHg) and the diastolic blood pressure below 80 mmHg
Fixed Drug Combination► To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents. Is there a preferred combination?
Concomitant Use of Antihypertensive Drugs Diuretics Beta Blockers ACEIs Calcium ARBs Channel Blockers α1-Receptor Blockers Less effective Particularly effectiveAdapted from Chalmers J. Clin Exp Hypertens. 1993;15:1299–1313.
The Moral of the Tale As long as we reach the objective BP below 140/90 (130/80), it doesn’t matter how we get there
ALLHAT (JAMA 2002)“The key message from ALLHAT is that what matters most is getting blood pressure controlled’’
The Heart Matters – the effect of ACEI• Prevents cardiac hypertrophy• Limits infarct size• Improves cardiac function• Improves cardiac metabolism
ACEI in Heart Failure• ACE inhibitors are recommended to treat HF due to systolic dysfunction.• The benefit of ACE inhibitors has been demonstrated in all severities of symptomatic HF and in patients with asymptomatic left ventricular (LV) dysfunction.
ACE in Heart Failure: the evidence A meta-analysis evaluated five trials• Improvement in symptoms• A lower total mortality.• A lower rate of readmission for HF).
ACE Inhibitors for ‘Diastolic’ Heart Failure?• Guidelines for the management of heart failure focus on patients with left ventricular systolic dysfunction.• However, guidelines make no recommendation for their use in patients with heart failure and preserved left ventricular systolic function.
ACE inhibitors versus ARBs: comparison of practice guidelines and treatment selection• ACC/AHA Heart Failure guidelines 2005. ACE inhibitors should be prescribed to all patients with left ventricular systolic dysfunction HF (class IA recommendation).• They recommend ARBs as a "reasonable alternative" first-line therapy (class IIA recommendation).
ACE inhibitors versus ARBs: comparison of practice guidelines : Contd• ACEI more cost effective• ARB better tolerated than ACEI• Deciding factor may be largely patient- specific.
Landmark trials with ACE inhibitors in HFTrial n EF% Drug Death Hospitalisation Follow up NNT (death)CONSENSUS 253 <35% enalapril 36 vs 50 reduced 1 year 61987 (IV)SOLVD-P 4228 <35 enalapril trend to reduced 4 years 1041992 (I) reductionSOLVD – T 2500 < 40 enalapril 12.3 vs 15.5 reduced 3 years 311991 (II-III)ATLAS 3164 <35 lisinopril no difference reduced 4 years -1997 (II-IV)
• The ACE inhibitor Enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure• Cachexia is a poor prognostic sign in patients with chronic heart failure. ACE inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.
Type 2 diabetesManagement of cardiovascular risk factors Lending our patients a hand
Can ACEI prevent Diabetes ?• Several recent studies indicate that ACE inhibitor therapy reduces the development of type 2 diabetes in persons with essential hypertension.• HOPE, CAPPP, SOLVD, and ALLHAT• DREAM & ONTARGET = more recent
Path physiology• Exact mechanism is not known• ACEI reduces oxidative stress• Increases insulin sensitivity in the liver• Reduces Insulin resistance in muscles• Helps in the preservation of islet cells of pancreas
ACEI and the KidneysClinical studies have shown ACE inhibitorsreduce the progress of diabetic nephropathyindependently from their blood pressure-lowering effect.This action of ACE inhibitors is used in theprevention of diabetic renal failure.
ACEI and the Kidneys – Contd:• Decreases Proteinuria (DM and Non-DM)• Beneficial effect on permeability• Beneficial effect on size selectivity• Slow the Rate of GFR Decline
Intensive Multiple Risk Factor Management Patients with Type 2 Diabetes and Microalbuminuria 60 N=160; follow-up=7.8 yearsPrimary Composite Endpoint* (%) Conventional Therapy 40 20% Absolute Risk Reduction 20 Aggressive treatment of†: – Microalbuminuria with Intensive Therapy† ACEIs, ARBs, or combination – Hypertension – Hyperglycemia – Dyslipidemia 12 24 36 48 60 72 84 96 – Secondary prevention of CVD Months of Follow-Up Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%).* Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease.† Behavior modification and pharmacologic therapy. Adapted from Gaede P, et al. N Eng J Med. 2003;348:383-393. Med.
EUROPA Randomised 12,218 patients with stable coronary artery disease (CAD) and a broad range of risk for cardiovascular complications Showed the benefit of long-term (mean 4.2 years) ACE-inhibition (perindopril 8 mg/day)
Study end pointsPrimary endpoint Non Fatal MI, Cardiac arrest and CV mortalitySecondary endpoints Heart failure Revascularisation (PCI/CABG) Stroke
Primary endpoint % CV death, MI or cardiac arrest1412 RRR: 20% Placebo p = 0.000310 Perindopril86420 0 1 2 3 4 5 Years Placebo annual event rate: 2.4%
The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial A double-blind, placebo-controlled, randomized trial Sponsored by the National Heart, Lung, and Blood Institute
HypothesisTo test whether ACE inhibitor therapy, when added to modern conventional therapy, reduces CV mortality, MI, or coronary revascularization in low-risk, stable CAD patients with normal or mildly reduced LV function.
Inclusion Criteria• Age ≥ 50 years• Coronary artery disease – MI, or – CABG or PCI, or – Coronary angiogram with obstruction of ≥50% luminal diameter in at least one native vessel• LVEF > 40%• Tolerated 2 week run-in of 2 mg/day trandolapril
PEACE Trial: All Death All-Cause Death p = 0.13 • A slight reduction in all- cause death seen in the10 Trandolapril arm was not statistically significant 8.18 7.26420 Trandolapril Placebo Presented at AHA 2004
PEACE Trial: Primary Endpoint The individual components of the primary endpoint were also equivalent in the Trandolapril and placebo groups 16 p=0.65 12.4 12.0 12 p=0.24 p=1.00 8 p=0.67 7.1 6.5% 5.3 5.3 3.5 3.7 4 0 Cardio death Nonfatal MI CABG PCI Trandolapril Placebo Presented at AHA 2004
IMAGINETrial design: IMAGINE was a double-blinded, randomized, placebo-controlled trialdesigned to test the effects of early ACE inhibitor initiation (quinapril 10 or 20 mg/day within7 to 10 days) after CABG in patients with preserved LV function, and no clear indication forACE inhibitor therapy. CONCLUSION CV death or cardiac arrest •In patients at low risk of CV (p = 0.57) events after CABG, routine early initiation of ACE 0.6 0.6 0.5 0.4 inhibitor therapy does not 0.4 0.4 appear to improve clinical% 0.2 0.2 outcome up to 3 years after CABG Conclusions 00 Quinapril Placeb (n = 1,280) o (n = 1,273)