A 57-year-old man with a 10-year history of type 2 diabetes mellitus visits the physician's office because his home blood pressures have been in the 140-145/85-90 mm Hg range for the last month. He takes four subcutaneous injections of various insulins, along with aspirin, ramipril, metoprolol succinate, simvastatin and clopidogrel since discharge from the hospital for acute coronary syndrome 3 months ago, which resulted in coronary angioplasty and two new bare metal stents. His office blood pressure is 146/86 mm Hg, but his physical examination is otherwise unremarkable. His electrolytes and blood glucose are unremarkable except for a BUN of 30 mg/dL and serum creatinine of 1.6 mg/dL (eGFR = 48 mL/min/1.73 m2); his A1C is 6.9%. Urinalysis is unremarkable by dipstick and microscopy, but his first urine specimen this morning had an albumin/creatinine ratio of 960 mg/gm.
WARNING: The United States Food and Drug Administration has not specifically approved many antihypertensive agents or drug combinations for reducing cardiovascular or renal risk; the discussion of drug choices in the context of this patient therefore may be interpreted as "off-label" uses of such drugs.
The most appropriate addition to his antihypertensive drug regimen is which of the following?
The correct answer is: B. Amlodipine.
A. Although surrogate outcomes have been positive for the combination of aliskiren and another inhibitor of the renin-angiotensin system (ACE-inhibitor or angiotensin receptor blocker) in reducing albuminuria in type 2 diabetics,1 and improving left ventricular remodeling in survivors of myocardial infarction with diminished left ventricular function,2 long-term outcomes-based studies with the combination have not shown any specific benefit, and have instead demonstrated an increased risk of hyperkalemia and/or renal endpoints.3,4 As a result, the single-pill combination of aliskiren + valsartan was removed from the worldwide market, and marketing of aliskiren with an ACE-inhibitor has been curtailed. Of most importance for the patient in this case was the significant increase in the incidence of hyperkalemia (39.1% vs. 29.0%, P < 0.001) or hypotension (12.1% vs. 8.3%, P < 0.001) associated with aliskiren (vs. placebo) in the ALTITUDE trial, in which 8561 type 2 diabetics taking an ACE-inhibitor or angiotensin receptor blocker.3
B & C. The combination of amlodipine + benazepril was compared against hydrochlorothiazide + benazepril in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial.5 The study, which had 60.4% of its subjects with diabetes mellitus, was halted earlier than expected because of a significant 19.6% reduction in the time to the composite primary endpoint (nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, hospitalization for unstable angina, coronary revascularization or resuscitation after sudden cardiac arrest) in the amlodipine + benazepril group. A similar, and significant, 21% reduction in the composite primary endpoint, favoring amlodipine + benazepril, was seen in the diabetic subgroup.6 Some have argued that a major difference between the results of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) and ACCOMPLISH might be attributed to the fact that the former used chlorthalidone, and the latter used the shorter-acting and less powerful hydrochlorothiazide,7 but no randomized trials have directly compared these two diuretics regarding outcomes, although the experience in MRFIT favored chlorthalidone,8 as did a recent very selective meta-analysis.9
D. Although spironolactone reduced death and heart failure hospitalization in patients with NYHA Class III-IV heart failure due to impaired left ventricular function, when added to an ACE-inhibitor or angiotensin receptor blocker,10 and has been recommended as empirical fourth-line therapy in patients with resistant hypertension,11,12 this strategy carries an elevated risk of hyperkalemia or renal dysfunction,13,14 perhaps even greater in patients with longstanding diabetes,15 who are at higher risk of hyporeninemic hypoaldosteronism.
E. Although telmisartan was used alone successfully as the "positive control" in the Diabetics Exposed to Telmisartan or Enalapril trial (which provided an "evidence-base" for the use of ACE-inhibitors in type 2 diabetic nephropathy),16 when it was combined with ramipril in the Ongoing Telmisartan Alone or in combination with Ramipril Global Endpoints Trial (ONTARGET), there was only a small further reduction in blood pressure (compared to either drug alone), no significant benefit on cardiovascular events,17 and an increase in the risk of hyperkalemia or renal dysfunction.18
Parving H-H, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, et al., for the AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358:2433-2446.
Solomon SD, Shin SH, Shah A, et al. Effect of the direct renin inhibitor aliskiren on left ventricular remodeling following myocardial infarction with systolic dysfunction. Eur Heart J 2011;32:1227-1234.
Parving H-H, Brenner BM, McMurray JJV, et al., for the ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204-2213.
Gheorghiade M, Böhm M, Greene SJ, et al., for the ASTRONAUT Investigators and Coordinators. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: The ASTRONAUT randomized trial. JAMA 2013;309:1125-1135.
Jamerson K, Weber MA, Bakris GL, et al. for the ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-2428.
Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol 2010;56:77-85.
Parra D, Rosenstein R. Benazepril plus amlodipine or hydrochlorothiazide for hypertension [Letter]. N Engl J Med 2009;360:1147-1150.
Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: A retrospective cohort analysis. Hypertension 2011;57:689-694.
Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: Systematic review and network meta-analysis. Hypertension 2012;59:1110-1117.
Pitt B, Zannad F, Remme WJ, et al. , for the Randomized Aldactone Evaluation Study (RALES) Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-717.
Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: Diagnosis, evaluation, and treatment. A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008,51:1403-1419.
Chapman N, Dobson J, Wilson S, et al., for the Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007;49:839-845.
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone® Evaluation Study. N Engl J Med 2004;351:543-551.
Hernandez AF, Mi X, Hammill BG, et al. Associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction. JAMA 2012;308:2097-2107.
Oxlund CS, Henriksen JE, Tarnow L, Schousboe K, Gram J, Jacobsen IA. Low-dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabete mellitus: A double-blind randomized clinical trial. J Hypertens 2013;31;2095-2102.
Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004;351:1952-1961.
Yusuf S, Teo KK, Pogue J, et al., for the ONTARGET Investigators. Telmisartan, ramipril or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559.
Mann JFE, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both in people at high vascular risk (the ONTARGET study): A multicentre, randomized, double-blind controlled trial. Lancet 2008;372:547-553.