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; p = .004) and diastolic (85.3 ± 11.1 vs. 81.7 ± 10.7 mmHg; p = .007) blood pressures. Patients with positive confirmatory test had longer duration of diabetes (108 [60–162] vs. 42 [24–87] months; p = .012), hypertension (84 [42–153] vs. 36 [15–81] months; p = .038) and higher creatinine (1.16 [1.02–1.42] vs. 0.95 [0.84–1.12] mg/dl; p = .021).

Conclusions: PA is prevalent (at least 4.1%) in Asian Indian patients with T2DM and hypertension. Further studies are needed to assess the cost-effectiveness of routine screening.

Introduction

Primary aldosteronism (PA) is characterized by excessive and autonomous aldosterone production, which classically manifests as hypertension and hypokalemia.^[1] Excess level of aldosterone with sodium excess is associated with worse cardiovascular outcomes than essential hypertension at comparable blood pressure levels.^[1] A recent meta-analysis suggests that PA is associated with an increased risk of coronary artery disease, stroke, atrial fibrillation, heart failure, diabetes mellitus, metabolic syndrome and left ventricular hypertrophy.^[2]

The prevalence rates of PA in the routine hypertensive population in the two large series are 7.2%–19.5% and 3.9%–11.8%, using aldosterone renin ratio (ARR) as the screening test followed by confirmatory testing.^[3,4] A recent study using oral sodium suppression test regardless of baseline aldosterone and renin levels showed the prevalence of 11.3%–22% across the spectrum from normotensives to resistant hypertension.^[5]

Type 2 diabetes mellitus (T2DM) frequently coexists with hypertension. Patients with type 1 diabetes mellitus usually develop hypertension after nephropathy sets in, whereas hypertension in T2DM is due to associated obesity, higher risk of atherosclerosis, nephropathy and higher sympathetic drive due to insulin resistance.^[6] The development of hypertension in T2DM increases cardiovascular risk, retinopathy, renal failure and other target organ damage. Underlying PA can lead to a worsening of hypertension and glycemia and may escalate cardiovascular risk.^[7]

While screening for PA in severe hypertension is advised by the Endocrine Society, there are no recommendations for screening patients with T2DM and hypertension. Studies in T2DM patients with resistant or difficult to control hypertension have shown a higher prevalence of PA (13%–14%). The studies on the prevalence of PA in T2DM patients without resistant hypertension are a few with conflicting results; studies from Japan (n = 124) and China (n = 256) reported the disease burden of 11.3% and 19%, respectively, while other studies (n = 61, n = 551) have reported a very low prevalence (0%–0.93%).^[8–13]

Thus, there are a few studies with varying evidence on PA in patients with T2DM and hypertension. A couple of studies from the Indian subcontinent show high PA prevalence in hypertensives, but none specifically investigated patients with T2DM and hypertension.^[14,15] In addition, Asian Indians have a different phenotype with higher abdominal fat, insulin resistance and dyslipidemia, which predisposes them to an increased risk of T2DM and coronary artery disease.^[16] Therefore, to elucidate the prevalence and contribution of possible underlying PA, we aimed to screen patients with T2DM and hypertension for PA.

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Next Section

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.