Managing Hypertension in Diabetes Sean Stewart, PharmD, BCPS, BCACP, CLS Internal Medicine Park Nicollet Clinic St Louis Park.

Transcription

1 Managing Hypertension in Diabetes 2015 Sean Stewart, PharmD, BCPS, BCACP, CLS Internal Medicine Park Nicollet Clinic St Louis Park Case Scenario Mike M is a 59 year old man with type 2 diabetes managed with metformin and diet. Hypertension has been managed with lisinopril 10 mg daily. His BP today averages 146/84

2 Case Scenario Treatment should be changed as follows: A. Increase Lisinopril to 20 or 40 mg B. Add an Angiotensin Receptor Blocker because combined RAA blockade provides additional cardiorenal benefit C. Add a Beta blocker because diabetic patients are at increased risk for coronary artery disease D. Add a thiazide or calcium channel blocker as these along with ACE inhibitors are the most proven and effective agents What s New? New Drugs-None JNC 8 out but controversial BP goal in diabetes no different from other patients <140/90 Return to Stepped Care approach

3 JNC 8 Abandoned by NHLBI and ACC/AHA Released by group members with considerable dissent Recommend for Diabetic/ Non diabetic Pts: Goal <140/90 Age 60+ <150/90 ACE or ARB, thiazide or CCB New ADA HTN Management Recommendations Systolic BP treatment target of <140 mmhg Lower systolic BP target of <130 mmhg for certain individuals (e.g. younger patients without undue treatment burden) Diastolic BP target <80 mmhg Treatment recommendations: ACE inhibitor or ARB as first line therapy Multiple medications often needed to achieve BP target, administer one or more at bedtime ADA Clinical Practice Recommendations Diab Care 36:Suppl. 1.

4 Treatment Goals Why have lower BP goals been endorsed in Diabetes? A high risk population HOT study: Subgroup analysis 37% RRR in diabetic subgroup for goal DBP<80 vs <90 Is There Evidence to Support a Lower BP Target in Diabetes? Trial N Mean SBP less intense Mean SBP more intense CVD Risk Reduction Syst-Eur % HOT 1, ** 140** 30-67% UKPDS 1, % ABCD No CVD reduction ** BP in diabetes + non diabetes population

5 Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial NHLBI 10,251 Type 2 diabetics BP arm 4,773 randomized to SBP<120 or <140 March 14, 2010 Mean # Meds Intensive: Standard: Average after 1 st year: Standard vs Intensive, Delta = 14.2

6 Intensive Events (%/yr) Standard Events (%/yr) RR (95% CI) P Primary 208 (1.87) 237 (2.09) 0.88 ( ) 0.20 Total Mortality 150 (1.28) 144 (1.19) 1.07 ( ) 0.55 Cardiovascular Deaths 60 (0.52) 58 (0.49) 1.06 ( ) 0.74 Nonfatal MI 126 (1.13) 146 (1.28) 0.87 ( ) 0.25 Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 ( ) 0.03 Total Stroke 36 (0.32) 62 (0.53) 0.59 ( ) 0.01 Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revascularization and unstable angina (HR=0.95, p=0.40) Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death Total Stroke Patients with Events (%) HR = % CI ( ) Patients with Events (%) HR = % CI ( ) NNT for 5 years = Years Post-Randomization Years Post-Randomization

7 Intensive Standard N (%) N (%) P Serious AE 77 (3.3) 30 (1.3) < Hypotension 17 (0.7) 1 (0.04) < Syncope 12 (0.5) 5 (0.2) 0.10 Bradycardia or Arrhythmia 12 (0.5) 3 (0.1) 0.02 Hyperkalemia 9 (0.4) 1 (0.04) 0.01 Renal Failure 5 (0.2) 1 (0.04) 0.12 egfr ever <30 ml/min/1.73m 2 99 (4.2) 52 (2.2) <0.001 Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93 Dizziness on Standing 217 (44) 188 (40) 0.36 Symptom experienced over past 30 days from HRQL sample of N=969 participants assessed at 12, 36, and 48 months post-randomization ACCORD CONCLUSIONS The ACCORD BP trial evaluated the effect of targeting a SBP goal of 120 mm Hg, compared to a goal of 140 mm Hg, in patients with type 2 diabetes The results provide no conclusive evidence that the intensive BP control strategy reduces the rate of a composite of major CVD events in such patients.

8 INVEST Study International Verapamil Trandolapril Study Diabetic Subgroup 6400, all with CAD Achieved SBP <130, , 140+ OUTCOME % Death, MI, Stroke Mortality TIGHT CONTROL USUAL CONTROL * UNCONTROLLED CI JAMA July 7,2010;304(1)61-68 Hypertension in Diabetes Guidelines : Changed from <130/80 to <140/80 (ADA) <140/90 (ICSI, JNC8) Evidence says: No renal or cardiac benefit with lower BP,? Small reduction in stroke ACE/ARB therapy do improve renal outcomes in patients with proteinuria /microalbuminuria Isolated Systolic HT in older Patients (?>60?>80) ; consider systolic goal <150, especially if patient is on 3+ meds

9 Treatment for HTN Where is the evidence pointing us? Classes of Antihypertensive Drugs First Line Diuretics ACE Inhibitors Calcium Channel Blockers Add On/Substitute ARBs Beta Blockers Alpha adrenergic blockers Central adrenergic agents Direct vasodilators Direct Renin Inhibitors

10 Cochrane Review, Drugs for HTN 57 trials, n=58,040 Conclusion: Low dose thiazides reduce all morbidity and mortality outcomes. ACEI and Calcium blockers may be similarly effective but the evidence is less robust. Beta blockers and high dose thiazides are inferior to low dose thiazides Multi drug Therapy Needed to Control BP Systolic BP ALLHAT (135 mm Hg) 2 IDNT (140 mm Hg) 3 RENAAL (140 mm Hg) 3.5 UKPDS ABCD (144 mm Hg) (132 mm Hg) HOT (141 mm Hg) 3.3 AASK (134 mm Hg) Number of BP Meds Modified from G. L. Bakris, J Clin Hypertens. 1999; 1: The ALLHAT Officers and Coordinators, JAMA 2002; 288: E. J. Lewis et al., N Engl J Med. 2001; 345: G. L. Bakris et al., Archive Int. Med. 2003, in press. 5. L. Hansson et al., Lancet 1998; 351: JAMA 2002; 288: J. T. Wright et al., JAMA 2002; 288: UK Prospective Diabetes Study Group, BMJ 1998; 317: R. O. Estacio et al., N Engl J Med. 1998; 338:

11 Thiazides, ACEI and CCBs The Big 3 Concept All appear about equally effective Work well together ALLHAT Cumulative Combined CHD Event Rate Combined CHD in Participants with a History of Diabetes Mellitus or FG 126+ mg/dl at Baseline HR (95% CI) p value A/C 1.02 ( ) 0.64 L/C 1.03 ( ) 0.56 Chlorthalidone Amlodipine Lisinopril Years to Combined CHD Event 22

12 A Modest Proposal: 3 Drug Step Care Step Care example: Step I Start any of the big 3 (ex lisinopril, hydrochlorothiazide or amlodipine). If 20 poits above goal start 2 Step 2 If close to goal increase thiazide dose to 25mg or amlodipine dose to 10 mg Otherwise add second drug Step 3 Add 3 rd drug (CCB ACE diuretic) Diuretics in HTN Thiazides are most effective; optimal dose mg. Chlorthalidone may be somewhat more effective Metolazone can be used if Cr CL<30 Spironolactone works well for many who don t tolerate thiazide Loop diuretics (except torsemide) need to be given twice a day

13 Dihydropyridine CCBs: The Swiss Army Knife of BP meds No contraindicating medical conditions (CHF, diabetes, CKD, arrhythmias etc) Effective in all age and ethnicity groups Good dose response curve Can be used with any other drug class, including nondihydropyridine CCBs Dihydropyridine CCBs: The Swiss Army Knife of BP meds Amlodipine Felodipine Isradipine Nicardipine SR Nifedipine ER Nisoldipine mg qd mg qd 5 20 mg qd mg qd mg qd mg qd

14 ARBs: Current Status ONTARGET No benefit combined Ramipril, Telmisartan Combination therapy caused higher rate of adverse events Similar findings in CHF trials Antiproteinuric with proven renal benefit in Type 2 DM Recent meta analysis confirms possible harmful effects of combined RAA inhibition Main use as substitute (not addition) when ACEI therapy not tolerated NEJMVolume 358: , April 10, 2008 Am J Hypertens (2013) 26 (3): ARBs: Available Agents Losartan (Cozaar) generic available Candesartan (Atacand) Eprosartan (Tevetan) Irbesartan (Avapro) generic available Olmesartan (Benicar) Telmesartan (Micardis) Valsartan (Diovan) generic available

15 Aliskerin (Tekturna) Newer Drugs Direct Renin Inhibitor, ACEI like ALTITUDE : RCT Aliskerin added to ACE or ARB in high risk diabetics, increased incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension over 18 to 24 months of follow up Nebivolol (Bystolic) Vasodilating Beta Blocker Treating to Goal More Drugs to Consider Example additions Non DHP CCBs Doxazosin 2 10 mg qhs (only with diuretic) Guanfacine 1 4 mg qhs Minoxidil (only with loop diuretic and Beta Blocker) Reserpine mg qhs Diltiazem or Verapamil qd) Beta Blockers ex Metoprolol er mg qd

16 Novel Future approaches Catheter Renal Nerve Ablation Minimally invasive procedure Significant BP reductions out to >24 months But, Medtronic wi5hdre from market after disappointing SYMPLICITY HTN 3 trial Carotid Baroreceptor Stimulation Pacemaker like device (ex Rheos system) Substantial short/ intermediate term BP reductions US clinical trials underway Diabetes and Hypertension Master Decision Path At Presentation Systolic BP 160 mmhg (Start 2 meds if SBP 160 mmhg) # BP Meds Blood Pressure Goal BP <140/80 BP <130/80 with nephropathy or microalbuminuria Non-Drug Therapy DASH, Low sodium Other HYPERTENSION ONLY ACEI /ARB or Thiazide Add Thiazide or ACEI/ARB Add medication if not at target Titrate dose, add medication if not at target in 1-2 months Titrate dose, add medication if not at target in 1-2 months Add DHP CCB HYPERTENSION + NEPHROPATHY ACEI or ARB Add Thiazide 4 Titrate dose add medication if not at target in 1-2 months Annual screen for microalbuminuria and egfr ( 5+ Add additional BP medication as needed Consider: Aldosterone antagonists, blocker, -blocker, guanfacine, hydralazine, reserpine

17 Case Scenario Mike M is a 59 year old man with type 2 diabetes managed with metformin and diet. Until recently he did not have health insurance has been off of BP medications. His BP today averages 146/84 Case Scenario Treatment should start with: A. Thiazide diuretic, calcium channel blocker or ACE Inhibitor B. ACE Inhibitor if he has proteinuria or microalbuminuria

18 Selected References ACCORD March 14, 2010 Cochrane review BP Targets, Cochrane review Medications for Hypertension ALLHAT JAMA, Volume 288. December 18, 2002 ICSI 2011 Hypertension