Prevalence of Primary Aldosteronism in Type 2 Diabetes Mellitus and Hypertension

A Prospective Study From Western India

Saba S. Memon; Anurag Lila; Rohit Barnabas; Manjunath Goroshi; Vijaya Sarathi; Vyankatesh Shivane; Virendra Patil; Nalini Shah; Tushar Bandgar

Disclosures

Clin Endocrinol. 2022;96(4):539-548.

Abstract and Introduction

Abstract

Objective: Type 2 diabetes mellitus (T2DM) and hypertension commonly coexist; however, underlying primary aldosteronism (PA) can lead to worsening of hypertension, glycemia and cardiovascular risk. We aim to screen patients with T2DM and hypertension for PA by conducting a prospective monocentric study from Western India, which included adults with T2DM and hypertension from the outpatient diabetes clinic.

Design: Prospective study.

Patients and Measurements: Patients with an aldosterone renin ratio of ≥1.6 ng/dl/μIU/ml with plasma aldosterone concentration (PAC) ≥ 10 ng/dl were considered to be positive on a screening test. A PAC ≥ 6 ng/dl on seated saline suppression test (SST) was used to confirm the diagnosis of PA.

Results: Four hundred and eighty-six patients were included in this study. Seventy-six (15.6%, 95% confidence interval [CI]: 12.7%–19.1%) patients had a positive screening test with positive confirmatory test in 20 of the 36 (55.5%, 95% CI: 39.3%–71.7%) screen-positive patients who underwent SST. Patients with positive screening test had a higher proportion of females (65.8% vs. 50%; p = .011), frequent history of hypertensive crises (21.1% vs. 8%; p = .001), uncontrolled blood pressure (51.3% vs. 34.6%; p = .006), diagnosis of hypertension before diabetes (32.9% vs. 21.7%; p= .035) and higher systolic (137.6 ± 6.9 vs. 131.2 ± 17.8 mmHg;

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Characteristics of patients with positive and negative screening tests
	Positive screening test (n = 76)	Negative screening test (n = 410)	p Value
Age (years)	59.5 ± 9.1	57.7 ± 9.5	.131
Female sex	50 (65.8%)	205 (50%)	.011*
Hypertension duration (months)	72 (36–144)	72 (24–120)	.193
Diabetes duration (months)	78 (36–144)	84 (36–132)	.888
Preceding history of DM before HT	25 (32.9%)	134 (32.7%)	.971
Preceding history of HT before DM	25 (32.9%)	89 (21.7%)	.035*
Diagnosis of HT and DM at same time	26 (34.2%)	187 (45.6%)	.066
Hypertensive crisis^a	16 (21.1%)	33 (8%)	.001*
Hypertension family history	16 (21.1%)	79 (19.3%)	.719
CVA family history	3 (3.9%)	28 (6.8%)	.450
Coronary artery disease	12 (15.8%)	63 (15.4%)	.925
CVA	6 (7.9%)	37 (9%)	.75
Systolic blood pressure (mmHg)	137.6 ± 16.9	131.2 ± 17.8	.004*
Diastolic blood pressure (mmHg)	85.3 ± 11.1	81.7 ± 10.7	.007*
Uncontrolled blood pressure^b	39 (51.3%)	142 (34.6%)	.006*
BMI (kg/m²)	26.3 ± 3.5; n = 76	27.4 ± 4.9; n = 408	.067
Fasting plasma glucose (mg/dl)	125.8 (107.3–142.6); n = 63	123 (103.5–153.3); n = 369	.603
Postmeal plasma glucose (mg/dl)	173 (145–228); n = 43	177 (136.3–235.5); n = 220	.695
HbA1c (%)	7.2 (6.4–8.5); n = 74	7.3 (6.7–8.5); n = 391	.246
Serum creatinine (mg/dl)	1.1 (0.99–1.44); n = 75	1.09 (0.92–1.26); n = 408	.121
eGFR > 90 ml/min/1.73 m²	3/75 (4%)	42/408 (10.3%)	.277
eGFR: 60–89 ml/min/1.73 m²	34/75 (45.3%)	199/408 (48.8%)
eGFR: 45–59 ml/min/1.73 m²	21/75 (28%)	108/408 (26.5%)
eGFR: 30–44 ml/min/1.73 m²	14/75 (18.6%)	48/408 (11.8%)
eGFR: 15–29 ml/min/1.73 m²	3/75 (4%)	11/408 (2.7%)
eGFR < 60 ml/min/1.73 m²	38 (50.7%); n = 75	167 (40.9%); n = 391	.117
Serum sodium (mEq/L)	137.7 (136–139.4); n = 54	137 (135.3–138.7); n = 300	.178
Serum potassium (mEq/L)	4 (3.6–4.4); n = 55	3.9 (3.6–4.3); n = 299	.471
Hypokalemia	4/55 (7.3%)	14/299 (4.7%)	.499
Spot urine albumin–creatinine ratio (mg/g)	25 (8.4–60.8); n = 74	23.8 (6.4–51.9); n = 388	.329
No albuminuria	42/74 (56.8%)	226/388 (58.2%)	.418
Moderately increased albuminuria	32/74 (43.2%)	154/388 (39.7%)
Severely increased albuminuria	0	8/388 (2.1%)
Number of antihypertensives
0	1/75 (1.3%)	13/409 (3.2%)	.149
1	43/75 (57.3%)	200/409 (48.9%)
2	20/75 (26.7%)	154/409 (37.7%)
3	7/5 (9.3%)	34/409 (8.3%)
4	4/75 (5.3%)	8/409 (2.0%)
Resistant hypertension	5/75 (6.7%)	19/409 (4.6%)	.398
ACEI	10/75 (13.3%)	98/409 (24%)	.042
ARB	23/75 (30.7%)	175/409 (42.8%)	.050
Beta blockers	20/75 (26.7%)	81/409 (19.8%)	.179
Calcium channel blockers	57/75 (76%)	243/409 (59.4%)	.007
Diuretics	7/75 (9.3%)	41/409 (10%)	.849
Plasma aldosterone (ng/dl)	17.4 (13.2–21.1)	11.5 (7.9–17.8)
Direct renin concentration (μIU/ml)	5.8 (3.3–9.9)	37 (17.4–96.2)
Aldosterone renin ratio (ng/dl/μIU/ml)	2.8 (1.9–4.9)	0.3 (0.1–0.7)

Note: Data are expressed as n (%), median (interquartile range) or mean ± SD.
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CVA, cerebrovascular accident, DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated haemoglobin; HT, hypertension.
^aHypertensive crises refer to past history of systolic blood pressure ≥ 180 and/or diastolic blood pressure ≥ 120 mmHg, requiring either visits to the emergency department or hospitalisation.
^bUncontrolled blood pressure refers to blood pressure > 140/90 on existing medications.
*p < .05.

Table 2. Characteristics of patients with a positive confirmatory test
	Positive confirmatory test (n = 20)	Negative confirmatory test (n = 16)	Primary aldosteronism ruled out^a (n = 426)	p Value for confirmatory pos vs. neg	p Value for confirmed vs. ruled out
Age (years)	57.6 ± 8.6	55.1 ± 10.4	57.6 ± 9.6	.45	.994
Female sex	13 (65%)	12 (75%)	217 (50.9%)	.517	.257
Hypertension duration (months)	84 (42–153)	36 (15–81)	66 (24–120)	.038*	.164
Diabetes duration (months)	108 (60–162)	42 (24–87)	78 (36–123)	.012*	.146
Preceding history of DM before HT	8 (40%)	6 (37.5%)	140 (32.9%)	.878	.628
Preceding history of HT before DM	5 (25%)	8 (50%)	97 (22.8%)	.169	.788
Diagnosis of HT and DM at same time	7 (35%)	2 (12.5%)	189 (44.4%)	.245	.493
Hypertensive crisis^b	5 (25%)	2 (12.5%)	35 (8.2%)	.426	.025*
Hypertension family history	6 (30%)	2 (12.5%)	81 (19%)	.257	.247
CVA family history	1 (5%)	0	28 (6.6%)	1.0	1.0
Coronary artery disease	1 (5%)	1 (6.3%)	64 (15%)	1.0	.334
CVA	1 (5%)	1 (6.3%)	38 (8.9%)	1.0	1.0
Systolic blood pressure (mmHg)	138.3 ± 14.5	129.1 ± 12.9	131.2 ± 17.7	.056	.075
Diastolic blood pressure (mmHg)	85.7 ± 12.7	86.1 ± 9.9	81.9 ± 10.7	.914	.123
Uncontrolled blood pressure^c	11 (55%)	5 (31.3%)	147 (34.5%)	.191	.091
BMI (kg/m²)	26.7 ± 3.5	26.5 ± 3.7	27.3 ± 4.8	.842	.572
Fasting plasma glucose (mg/dl)	134.9 ± 35.1; n = 17	120.4 ± 2.8; n = 13	137.9 ± 52.9; n = 382	.214	.692
Postmeal plasma glucose (mg/dl)	186.5 ± 54.8; n = 13	176.1 ± 54.6; n = 7	195.2 ± 83.1; n = 227	.691	.807
HbA1c (%)	7.25 (6.65–8.5)	6.85 (6.1–7.65)	7.3 (6.7–8.5)	.101	.993
Serum creatinine (mg/dl)	1.16 (1.02–1.42)	0.95 (0.84–1.12)	1.09 (0.92–1.26)	.021	.110
eGFR (ml/min/1.73 m²)	56.8 ± 14.27	68.81 ± 20.84	65.74 ± 18.66	.048	.026
eGFR > 90 ml/min/1.73 m²	0	2 (12.5%)	44 (10.4%)	.274	.252
eGFR: 60–89 ml/min/1.73 m²	9 (45%)	9 (56.3%)	208 (49.1%)
eGFR: 45–59 ml/min/1.73 m²	6 (30%)	3 (18.8%)	161 (38%)
eGFR: 30–44 ml/min/1.73 m²	5 (25%)	2 (12.5%	11 (2.6%)
eGFR < 60 ml/min/1.73 m²	11 (55%)	5 (31.3%)	172 (40.6%)	.191	.246
Serum sodium (mEq/L)	137.3 ± 3.3; n = 13	138.5 ± 2.8; n = 12	136.9 ± 2.9; n = 312	.337	.700
Serum potassium (mEq/L)	4.01 ± 0.66; n = 14	4.03 ± 0.58; n = 12	3.97 ± 0.54	.966	.793
Hypokalemia	2/14 (14.3%)	0/12 (0%)	14/311 (4.5%)	.483	.146
Spot urine albumin–creatinine ratio (mg/g)	45.85 (14.25–83.55); n = 19	16.53 (7.98–49.28); n = 16	23.21 (7.22–51.81); n = 404	.196	.182
No albuminuria	9/19 (47.4%)	11/16 (68.8%)	237/404 (58.7%)	.306	.455
Moderately increased albuminuria	10/19 (52.6%)	5/16 (31.3%)	159/404 (39.4%)
Severely increased albuminuria	0	0	8/404 (2%)
Number of antihypertensives	1 (1–2)	1 (1–1.75)	1 (1–2)	.125	.126
1	11 (55%)	11 (68.8%)	211 (49.6%)
2	5 (25%)	3 (18.8%)	157 (36.9%)
3	2 (10%)	1 (6.3%)	35 (8.2%)
4	2 (10%)	0	8 (1.9%)
Resistant hypertension	2 (10%)	0	19 (4.5%)	.492	.242
ACEI	3 (15%)	2 (12.5%)	100 (23.5%)	1.0	.587
ARB	8 (40%)	4 (25%)	179 (42.1%)	.481	1.0
Beta blockers	7 (35%)	4 (25%)	85 (20%)	.718	.152
Calcium channel blockers	13 (65%)	11 (68.8%)	254 (59.8%)	1.0	.816
Diuretics	3 (15%)	0	41 (9.7%)	.238	.435
Plasma aldosterone (ng/dl)	16.25 (13.3–19.85)	16.2 (12.28–18.6)	11.6 (8.05–18.03)	.622	.003
Direct renin concentration (μIU/ml)	5.3 (2.3–9.28)	5.3 (2.33–8.38)	35.2 (15.88–90.08)	.824	.000
ARR (ng/dl/μIU/ml)	2.99 (2.0–6.02)	3.23 (1.87–4.85)	0.34 (0.13–0.74)	.975	.000
Pre-SST plasma aldosterone (ng/dl)	14.25 (11.48–18.85)	9.18 (8.23–11.93)	–	.001	–
Pre-SST direct renin concentration (μIU/ml)	3.35 (0.6–8.6)	2.8 (1–5.3)	–	.911	–
Pre-SST ARR (ng/dl/μIU/ml)	4.94 (1.83–20.14)	4.1 (1.36–10.4)	–	.373	–
Post-SST plasma aldosterone (ng/dl)	9.44 (7.63–11.93)	4.15 (3.59–5.37)	–	.00	–

Note: Data are expressed as n (%), median (interquartile range) or mean ± SD.
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARR, aldosterone renin ratio; BMI, body mass index; CVA, cerebrovascular accident; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated haemoglobin; HT, hypertension; SST, seated saline suppression.
^aNegative screening test + positive screening but negative confirmatory test.
^bHypertensive crisis refer to past history of systolic blood pressure ≥ 180 and/or diastolic blood pressure ≥ 120 mmHg requiring either visits to the emergency department or hospitalisation.
^cUncontrolled blood pressure refers to blood pressure > 140/90 on existing medications.
*p < .05.

Table 3. Literature data on the prevalence of primary aldosteronism in type 2 diabetes
Author (year)	n Centre	• Age (years) • DM duration • HT duration (years)	• Mean SBP • Mean DBP (mmHg)	• Screening criteria • Confirmatory criteria	Screen positive	Yield of confirmatory test
Jefic et al. (2005)	n = 61 USA	– – –	– –	S: PAC > 15 ng/dl with PRA < 1 ng/dl/h	0	–
Tancredi et al. (2017)	n = 551 Sweden	65.8 ± 10.6 10 ± 7.7 –	137.1 ± 16.7 77.5 ± 9.9	S: ARR > 65 pmol/L/mIU/L C: SST	38 (6.9%)	5/22 (22.7%)
Li et al. (2012)	n = 178 China	50.72 ± 9.6 – –	– –	S: ARR > 20–35 ng/dl/ng/ml/h ± PAC > 15 ng/dl C: SST 5–10 ng/dl	15.7%–27%	25/48 (52%) 41/48 (85.4%)
Murase et al. (2013)	n = 124 Japan	63.01 ± 12.1 12.84 ± 11.3 11.55 ± 11.5	142.4 ± 22.5 79.84 ± 13.6	S: ARR > 200 pg/ml/ng/ml/h with PAC > 7 ng/dl C: CCT/frusemide loading/rapid ACTH	17 (13.7%)	14/17 (82.4%)
Hu et al. (2020)	n = 256 China	49.9 ± 11.8 3 (1–12) month 2 (0.17–6)	145.3 ± 18.9 93.2 ± 12	S: ARR ≥ 30 ng/dl/ng/ml/h with PAC > 15 ng/dl C: CCT	99 (39%)	49/99 (49.5%)
Our study	n = 486 India	57.9 ± 9.5 7 (3–11.3) 6 (2.4–10)	132.2 ± 17.8 82.3 ± 10.9	S: ARR ≥ 20 ng/dl/ng/ml/h with PAC ≥ 10 ng/dl C: SSST ≥ 6 ng/dl	76 (15.6%)	20/36 (55.5%)

Note: Data are expressed as mean ± SD or median (interquartile range) or n (%).
Abbreviations: ACTH, adrenocorticotrophic hormone; ARR, aldosterone renin ratio; C, confirmatory test; CCT, captopril challenge test; DBP, diastolic blood pressure; DM, diabetes mellitus; HT, hypertension; PAC, plasma aldosterone concentration; PRA, plasma renin activity; S, screening test; SBP, systolic blood pressure; SST, saline suppression test; SSST, seated saline suppression test.