Primary Aldosteronism in Diabetic Subjects with Resistant Hypertension Umpierrez GE et al. Diabetes Care. July 2007; 3

1. Primary Aldosteronism in Diabetic Subjects with Resistant HypertensionUmpierrez GE et al. Diabetes Care. July 2007; 30(7): 1699-1703. Kerry Kay, MD Department of Family and Community Medicine Journal Club October 3, 2007

2. Diabetes and Hypertension 20 million people in US have diabetes. 50 million have hypertension. Hypertension markedly increases the risk for CVD and mortality in patients with DMII. Randomized prospective clinical trials have shown that rigorous blood pressure control in patients with DMII reduces macrovascular as well as microvascular complications. It is estimated that for each 10mmHg reduction in systolic blood pressure, there is a 13% reduction in microvascular complications, a 12% decreased risk of fatal and nonfatal myocardial infarction, and a 17% decreased risk of death. Despite this strong evidence, nearly 75% of diabetic patients do not achieve good blood pressure control.

3. Primary Aldosteronism 10-32% of patients with essential hypertension and hypokalemia, 5-32% of resistant hypertension. Aldosterone leads to sodium resorption and potassium secretion. Hypertension, hypokalemia, metabolic alkalosis, mild hypernatremia, mild hypomagnesemia.

4. Primary Aldosteronism Most common causes are adrenal hyperplasia, adrenal adenoma. Other causes unilateral hyperplasia, familial hyperaldosteronism, carcinoma, ectopic aldosterone-producing tumor Goal of study to determine prevalence of primary aldosteronism in diabetic subjects with poorly controlled hypertension despite treatment with multiple antihypertensive agents

5. Research Design 100 consecutive adult subjects with DMII and resistant hypertension were enrolled and screened for primary aldosteronism 93 blacks, 5 Caucasians, 1 Hispanic, 1 Native American Subjects continued their usual blood pressure medications: 98% ACEI or ARB, 92% diuretic, 73% beta-blocker, 62% CCB, 31% alpha-blocker or other

6. Research Design Screening test used: Plasma Aldosterone Concentration/Plasma Renin Activity Ratio (PAC/PRA) If PAC/PRA ratio > 30 ng/ml/hr, then further studies to confirm diagnosis of primary aldosteronism N=11 underwent Oral Salt Load: 3-day salt load of 2 grams of sodium TID on top of patient�s usual salt intake. 24 hr urine collection for aldosterone concentration. Primary Aldosteronism if urinary Aldosterone > 12 mcg. N=23 underwent IV Salt Load: 2 liters of NS infused over 4 hr at 500ml/hr. Primary Aldosteronism if PAC >= 5.0 ng/dl. Patients with a confirmed diagnosis of primary aldosteronism referred to Endocrine Service.

7. Exclusion Criteria Aldosterone antagonists Hemoglobin A1C > 9% Severe uncontrolled hypertension of 180/110mmHg History of heart failure Angina pectoris Serum creatinine > 1.8 mg/dl Pregnancy Breastfeeding Use of oral contraceptives Clinical relevant hepatic disease Drug or alcohol abuse Known primary aldosteronism History of pheochromocytoma, Cushing�s syndrome or hyperthyroidism

8. Results 34 subjects (34%) had an increased PAC/PRA ratio, 14 subjects (14%) had a confirmed diagnosis of primary aldosteronism. No statistically significant differences between subjects with or without primary aldosteronism for: Ethnicity, age, years of hypertension, years of diabetes, BMI, BP, A1C, number of antihypertensive agents. Subjects with primary aldosteronism had a lower serum potassium, lower serum creatinine, higher PAC, lower PRA, higher PAC/PRA ratio.

9. Author Conclusions Prevalence of primary aldosteronism in patients with DMII is about 14%, similar to that reported in non-diabetic subjects with resistant hypertension. All diabetic subjects who have not met their blood pressure goals despite treatment with = 3 drugs should be screened for primary aldosteronism.

10. Limitations 2 different confirmatory tests Lack of non-diabetic control group Small number of subjects Most subjects were African American (93%) Many exclusion criteria Patients screened while on antihypertensive meds ACEI, ARB, diuretics may increase PRA, CCB suppress aldosterone release, beta-blockers suppress PRA. Considered unethical and unsafe to take patients off antihypertensives Schwartz and Turner study showed that antihypertensives did not affect the sensitivity and specificity of PAC/PRA

11. Is PAC/PRA a good screening test for primary aldosteronism? Was there an independent, blind comparison with a reference standard? Did patient sample include an appropriate spectrum of patients? What are the results? Will the results help me in caring for my patients?

12. Evaluating a Study of Diagnostic Tests Was there an independent, blind comparison with a reference standard? No, not blinded and 2 different confirmatory tests Did patient sample include an appropriate spectrum of patients? No Lack of non-diabetic control group, small number of subjects, most subjects were African American (93%), long list of exclusion criteria Small number of subjects resulting in wide confidence intervals for prevalence (95% CI= 8% to 22%)

13. What are the results? No patients with a negative screening test were given the salt loading test to diagnosis primary aldosteronism. Therefore not possible to calculate sensitivity. Schwartz and Turner report PAC/PRA ratio has sensitivity of 73% and specificity of 74%, and a sensitivity of 87% and specificity 75% when on antihypertensive medication

14. Will the results help me in caring for my patients? Utility of screening for primary aldosteronism depends on outcomes from screening and subsequent treatment Patients with primary aldosteronism have been reported to have higher rates stroke (12.9 vs. 3.4% with essential hypertension), nonfatal myocardial infarction (4.0 vs. 0.6 percent) atrial fibrillation (7.3 vs. 0.6 percent). *

15. Will the results help me in caring for my patients? Treatment Options: Surgery in unilateral disease. Medical management with aldosterone antagonist or potassium-sparing diuretic (amiloride, triamterene) in bilateral disease. Sodium restriction, maintenance of ideal body weight, avoidance of alcohol, exercise contribute to success of medical management. Surgical treatment of primary aldosteronism can lead to decrease in BP and resolution of hypokalemia. * No data on morbidity and mortality with treatment of primary aldosteronism detected by screening.

16. Conclusions Higher prevalence of primary aldosteronism in patients with uncontrolled hypertension than generally recognized. Several important limitations to study. PAC/PRA a fair screening test for primary aldosteronism. To determine the utility of screening, will need further studies on whether treatment of primary aldosteronism in those with DMII decreases morbidity and mortality.

17. Bibliography Barratt, A et al. How to use guidelines and recommendations about screening. JAMA. June 2, 1999; 281(21): 2029. Hood SJ et al. The Spironolactone, Amiloride, Losartan and Thiazide (SALT) Double-Blind Crossover Trial in Patients with Low-Renin Hypertension and Elevated Aldosterone-Renin Ratio. Circulation. 2007; 116: 268-275. Jaeschke, R et al. How to use an article about a diagnostic test; what are the results and will they help me in caring for my patients? JAMA. March 2, 2004; 271(9): 703-8. Schwartz, GL and Turner ST. Screening for Primary Aldosteronism in Essential Hypertension: Diagnostic Accuracy of the Ratio of Plasma Aldosterone Concentration to Plasma Renin Activity. Clinical Chemistry. 2005; 51(2): 386-94. Umpierrez, GE et al. Primary Aldosteronism in Diabetic Subjects with Resistant Hypertension. Diabetes Care. July 2007; 30 (7): 1699-1703. Young, WF et al. Clinical Features of Primary Aldosteronism. Uptodate. 2007.