The Prevalence of Primary Aldosteronism in Diabetic Patients

Abstract

Increased plasma aldosterone concentrations (PACs) are associated with higher cardiovascular risk and target organ damage (TOD). Hyperglycemia can potentiate the cellular effects of aldosterone, and the prevalence of diabetes in primary aldosteronism (PA) is 7%–59%. The prevalence of PA in hypertensive individuals is estimated to be 10%–14%. This study of 61 hypertensive diabetic patients not taking spironolactone and with serum creatinine values <2.5 mg/dL sought to establish the prevalence of PA in hypertensive diabetics and compare the prevalence of PA in patients with TOD with those patients without TOD. PA was suspected if PACs were >15 ng/dL and plasma renin activity was <1 ng/dL/h (ratio >30). Although 14 patients had suppressed renin with PACs >8 ng/ dL (including two with PACs >11 ng/dL), none met our criteria for PA. There was no correlation between PAC and TOD. This study indicates that routine screening for PA in hypertensive diabetic patients is not justified and that PAC does not correlate with TOD. Further study is needed.

Primary aldosteronism (PA) is often associated with glucose intolerance and diabetes mellitus. PA and diabetes mellitus are associated with increased risk of cardiovascular disease (myocardial infarction, heart failure, and coronary artery disease) as well as increased myocardial fibrosis. ¹ , ² It has also been postulated that hyperaldosteronism, which has been shown to be associated with microalbuminuria in humans, is a contributing factor for progression of renal disease.

PA is strongly associated with diabetes mellitus and glucose intolerance. ³ Conn ⁴ described impaired glucose tolerance in 14 of 27 patients with PA (52%). Reevaluation of this data using the diagnostic criteria of the American Diabetes Association in 1997 revealed three cases of diabetes mellitus (11%) and nine cases of glucose intolerance (33%). ⁵ The exact mechanism associating glucose intolerance with PA is unclear. It has been suggested that hypokalemia is at least in part responsible for this effect by inhibiting insulin secretion by the pancreas. ⁶ Sindelka and colleagues ⁷ postulate that aldosterone has a direct effect, causing insulin resistance at the postreceptor level with normal serum potassium concentration. In addition, hyperglycemia accelerates the cellular effects of aldosterone. ⁸ The concurrence of diabetes mellitus and hyperaldosteronism could accelerate aldosterone‐induced damage to the heart, kidneys, and brain.

Aldosterone also acts to promote hypertension through both sodium retention and enhanced vascular reactivity. The direct cellular effects of increased aldosterone induce collagen deposition, fibrosis, necrosis, and fibroblast proliferation in cardiac cells and vascular smooth muscle cells. ⁹ , ¹⁰ Diabetic patients have a high prevalence of hypertension, and this mechanism causes additional damage to the heart and vascular system.

Aldosterone acts primarily on the mineralocorticoid receptors in the epithelium of the distal nephron, colon, and rectum, but receptors have also been found in blood vessels, the brain, and the heart. ¹¹ , ¹² Moreover, there is aldosterone production in endothelial, vascular smooth muscle, and myocardial cells. ¹³ , ¹⁴ Thus, these cells are able to produce, as well as respond to, aldosterone.

PA is the syndrome resulting from the autonomous hypersecretion of aldosterone either from solitary adenoma or bilateral hyperplasia. PA has been estimated to affect between 10% and 14% of the general population with hypertension ¹⁵ and 20% of patients with resistant hypertension. ¹⁶ PA is associated with plasma aldosterone concentrations (PACs) >15 ng/dL and plasma renin activity (PRA) <1 ng/dL/h. A plasma aldosterone‐to‐renin ratio >70 is considered diagnostic. A ratio >30 is a positive screening test suggesting further confirmatory tests. The incidence of PA in diabetic patients with hypertension has not been previously studied. Sato and colleagues ¹⁷ found that the addition of spironolactone to angiotensin‐converting enzyme inhibitors in diabetic patients who showed aldosterone escape during treatment resulted in reduction of albuminuria and left ventricular mass. Hypertension in diabetic patients is frequently resistant, requiring multiple medications. ¹⁸ Therefore, it is reasonable to suggest that if the prevalence of PA in diabetic patients with hypertension is high, physicians should routinely screen all hypertensive diabetic patients for PA and consider the use of aldosterone antagonists to ameliorate the development of target organ damage (TOD) and cardiovascular disease. This study sought to determine: 1) the prevalence of PA in diabetic patients with hypertension; and 2) whether higher PAC levels are associated with increased TOD.

RESEARCH DESIGN AND METHODS

After this study was reviewed and approved by the institutional review board of St. John Hospital and Medical Center in Detroit, MI, patients were recruited from a diabetic clinic at the urban teaching hospital. In addition to diabetes mellitus, those selected for this study also had hypertension, as indicated by current use of antihypertensive medications. Patients who were pregnant, younger than 18, taking spironolactone, or who had serum creatinine values >2.5 mg/dL were excluded.

Sixty‐one patients provided informed consent and demographic data, medication information, and blood pressure readings; any evidence of TOD, such as coronary artery disease, retinopathy, cardiovascular accident, impaired renal function, and microalbuminuria was obtained from the patients' medical charts. All patients were obese, and 35% had uncontrolled BP (>130/80 mm Hg). This cohort was 51% male. Thirty‐three percent (20) were African American, 52% (32) were Caucasian, and 15% (9) were of other or unknown ethnicity. Participants took an average of 2.1±0.1 antihypertensive medications; 85% were using angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers and 39% were on diuretics. All participants had blood drawn in the sitting position in the morning of their clinic visit for PAC and PRA. The chemiluminescent immunoassay was used for both. When possible, this draw was combined with a 3‐month check for glycosylated hemoglobin (Hgb‐A_lc), lipid profile, electrolytes, blood urea nitrogen, creatinine, and urinary micro‐albumin. PAC/PRA ratios >70 were considered to be diagnostic for PA. ¹⁹

Researchers used analysis of variance to compare continuous variables (e.g., age, weight) and chi‐square or Fisher exact tests (as appropriate) to compare categoric data (e.g., gender, race) for those with and without TOD.

RESULTS

The Table shows the findings for the 61 participants. The results are presented as mean ± standard error (SE). The average age of those with TOD (n=44) was 60±2.2 years; the average age of those without TOD (n=17) was 48±3.3 years. The mean Hgb‐A_lc was 7.3±0.4 for the entire cohort. The serum creatinine range was 0.4–2.4 mg/dL; 81% of the patients had serum creatinine <1.5 mg/dL. The mean PAC for all participants was 6.2±0.7 ng/dL, and mean PRA was 3.4±0.4 ng/mL/h. Two patients had PAC >11 ng/dL with suppressed renin, and 14 patients had PAC <8 ng/dL with suppressed renin. None of the participants met the definition of PA used here. The Figure depicts PA and PAC/PRA for those with and without TOD indicators. There was no correlation between PAC and TOD in this population.

CONCLUSIONS

This is the first study of the incidence of PA in hypertensive diabetic patients. If hypertensive diabetic patients were found to have a high risk of PA, treatment with aldosterone receptor blockers could be started early to prevent further TOD.

No participants met our diagnostic criteria for PA. Furthermore, higher circulating PAC levels did not correlate with increased TOD in this small population. There could be several reasons for these negative results. First, use of ACE inhibitors or ARBs may have lowered aldosterone levels. Second, Sato and colleagues ²⁰ found a positive correlation between left ventricular hypertrophy and aldosterone levels in end‐stage renal disease patients without diabetes, but not in patients with diabetes. This could be because diabetes mellitus is associated with hyporenemic hypoaldosteronism. ²⁰ Finally, systemic levels of aldosterone might not correlate with increased local levels of aldosterone in tissue.

Since our study has been submitted, there is only one published abstract showing that 27% of diabetic patients with resistant hypertension had a positive aldosterone‐to‐renin ratio. ²¹ Our patient population was not resistant, using on average 2.1 antihypertensive medications with 65% of patients' blood pressure <130/80 mm Hg.

Based on data from our study, routine screening of hypertensive diabetic patients for PA cannot be recommended. Additional studies are needed.