Prevalence and impact of diabetes and prediabetes on presentation and complications of primary hyperaldosteronism at diagnosis

Abstract

BACKGROUND

Primary hyperaldosteronism (PH) is considered to contribute to increased risk of developing type 2 diabetes mellitus (T2DM) and prediabetes. Both PH and DM are associated with increased risk for hypertension, cardiovascular diseases, and chronic kidney diseases. However, data on prevalence of T2DM and prediabetes in PH, and impact of T2DM and prediabetes on presentation and cardio renal complications in PH at presentation is sparse.

AIM

To determine the prevalence of T2DM and prediabetes in PH at diagnosis and impact on presentation and complications of PH.

METHODS

A retrospective cohort study was conducted in tertiary care settings in individuals with confirmed diagnosis of PH at presentation. Demographic variables, clinical presentations, duration and degree of hypertension, complications, laboratory parameters including sodium, potassium levels, plasma aldosterone concentration (PAC), plasma renin activity (PRA), and aldosterone to renin ratio (ARR) and cardio-renal parameters were collected. Comparison was done between three groups: PH with no DM (Group A) or with pre-diabetes (Group B) or with T2DM (Group C). P < 0.05 was statistically significant.

RESULTS

Among 78 individuals with confirmed PH, 62% had pre-diabetes or diabetes; with 37% having DM. Mean duration of T2DM was 5.97 ± 4.7 years. The mean levels of glycaemic parameters among the group A vs B vs C individuals were fasting plasma glucose (mg/dL): 87.9 ± 6.5, 105.4 ± 9.02, 130.6 ± 21.1; post prandial plasma glucose (mg/dL): 122.7 ± 9.8, 154.9 ± 14, 196.7 ± 38.0; glycated haemoglobin (%) (5.3 ± 0.2, 5.9 ± 0.2, 7.5 ± 0.6, P < 0.05), respectively. There was no significant difference in the biochemical parameters (PAC, PRA, ARR, sodium, potassium levels), presentation and complications between the groups. Cardio renal parameters or degree and duration of hypertension were comparable between the groups.

CONCLUSION

Significant prevalence of T2DM and prediabetes in PH at diagnosis does not impact its presentation or complications. Early screening for undetected PH in T2DM and prediabetes subjects with hypertension may prevent complications.

Key Words: Primary hyperaldosteronism, Diabetes, Prediabetes, Hypertension, Aldosterone, Aldosterone to renin ratio

Core Tip: Current investigation found a high prevalence of type 2 diabetes mellitus (T2DM) and prediabetes in primary hyperaldosteronism (PH) at diagnosis. However glycaemic status did not impact clinical or biochemical profiles, number of antihypertensive medications or complications. Long duration of hypertension, high antihypertensive requirement and hypokalemia with hypertension was the most common presentation, suggesting delayed PH diagnosis irrespective of glycaemic status. Underlying undetected PH can worsen hypertension, glycemia and cardiorenal risk in hypertensive patients with T2DM/prediabetes. Screening and early detection of PH in T2DM/prediabetes subjects with hypertension especially with hypokalemia or resistant hypertension, might help in effective management and preventing complications of hypertension and uncontrolled T2DM.

INTRODUCTION

Primary hyperaldosteronism (PH) is characterized by unregulated autonomous over-secretion of aldosterone from adrenal gland primarily due to adenoma or hyperplasia[1]. Classical clinical presentations of PH include resistant hypertension with hypokalaemia[1]. PH is a common disease which is currently grossly underdiagnosed and undertreated[2].

Epidemiological studies found co-occurrence of PH in 4.1% of diabetes patients with hypertension and conversely, diabetes was observed in 21.6%-36% of PH patients[3-6]. Aldosterone overproduction in PH leads to excessive activation of mineralocorticoid receptors (MR) increasing insulin resistance and decreasing insulin secretion thus worsening glycaemic control[7,8].

Underlying PH can worsen hypertension, glycemia and cardiorenal risk in hypertensive subjects with type 2 diabetes mellitus (T2DM) or prediabetes[8]. Thus, co-existence of PH and diabetes could hasten development and progression of cardiovascular and renal complications leading to significant morbidity and mortality[9,10]. PH is known to increase the risk of coronary artery disease (CAD) by more than two-fold in T2DM patients[11].

Prevalence of T2DM and prediabetes and their association with cardiorenal complications, in PH subjects at diagnosis is not very well studied. Hence, the current study investigated the prevalence of diabetes and prediabetes and their association with clinical presentation, biochemical profile, and complication of PH at diagnosis.

MATERIALS AND METHODS

Study design

A retrospective cohort study was conducted in tertiary care settings in individuals with confirmed diagnosis of PH (as mentioned below) at presentation.

Study duration

Evaluation of records from January 2014 to January 2023.

Inclusion criteria

Adult patients (> 18 years) with confirmed diagnosis of PH with availability of baseline clinical and biochemical records.

Exclusion criteria

Patients with secondary hyperaldosteronism, type 1 diabetes mellitus, secondary hypertension (renovascular hypertension, pheochromocytoma), patients on spironolactone, eplerenone, amiloride, triamterene, pregnant and lactation women, chronic kidney disease (CKD) stage 5 [estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m²] were excluded.

Diagnosis for PH

The institutional protocol for diagnosis of PH was as follows: Patients with aldosterone to renin ratio (ARR) of ≥ 20 ng/dL per ng/mL/h and plasma aldosterone concentration (PAC) of value ≥ 10 ng/dL and suppressed plasma renin activity (PRA) of < 1 ng/mL/h), was considered screen positive[12] ARR for our study was derived as PAC/PRA. Patients with positive screening test underwent confirmatory saline suppression test (SST) after changing antihypertensive medications to verapamil and/or prazosin for at least 2 wk, as per the Endocrine Society guidelines[12]. Two litres of 0.9% normal saline were infused over 4 h, PAC ≥ 6 ng/dL after SST confirmatory test was considered positive as per the Endocrine Society guidelines[12].

Diabetes mellitus, prediabetes and hypertension were defined according to American Diabetes Association and ACC/AHA guidelines, respectively[13,14].

Subjects were divided into three categories based on the glycaemic status: PH with no DM (Group A) or PH with pre-diabetes (Group B) or with T2DM (Group C) and analysis was performed by comparing the three groups.

Retrospective data on demographic variables, clinical presentation, systolic blood pressure (SBP), diastolic blood pressure (DBP), duration of hypertension, number of antihypertensive, complications at baseline. Prevalence of hypokalemia including diuretic induced hypokalemia, hypokalemia periodic paralysis (HPP) was noted. Presentation was divided and analysed in 4 different categories: Resistant hypertension, Spontaneous hypokalemia with hypertension, Resistant hypertension with diuretic induced hypokalemia and Adrenal Incidentaloma with hypertension.

Prevalence of complications with previous documented records were noted: CKD by eGFR < 60 mL/min/1.73 m², left ventricular hypertrophy (LVH) by ECG or ECHO, diagnosed/history of CAD, atrial fibrillation (AF), cerebrovascular accident (CVA), obstructive sleep apnea.

Laboratory records assessed included: Serum sodium, potassium, fasting plasma glucose (FPG) and postprandial plasma glucose, glycated haemoglobin (HbA1c), PAC, PRA, ARR, PAC post SST confirmatory test.

Statistical analysis

SPSS 26.0 was used for statistical analysis. Continuous variables with normal distribution, expressed as mean and standard deviation were analyzed using Student’s t test; continuous variables with a skewed distribution, expressed as median (interquartile range) were analyzed using Mann-Whitney U test. Categorical variables, expressed as percentages, were analyzed using the χ² test. One-way ANOVA or Kruskal Walli’s test was conducted to compare the variation among pre-diabetic, diabetic and non-diabetic groups of the population. P values < 0.05 (2-tailed) was considered to be statistically significant.

RESULTS

Among the 78 patients diagnosed with PH in the study population, 48 (61.6%) had pre-diabetes or diabetes with 19 (24.4%) subjects classified as pre-diabetes, and 29 (37.2%) patients having diabetes while 30 (38.5%) had no evidence of pre-diabetes or diabetes. Patients with diabetes had a mean duration of 6.0 ± 4.7 years of diabetes.

Table 1 compares the demographic and glycaemic variables between the study groups. FPG, post prandial plasma glucose, HbA1c and body mass index (BMI) was significantly higher in diabetes subjects. There was no significant difference in age, SBP, DBP or duration of hypertension between groups.

Table 1 Demographic variables, glycaemic and hypertensive parameters (mean ± SD).

	No diabetes (n = 30)	Prediabetes (n = 19)	T2DM (n = 29)	P value
Age (yr)	52.53 ± 13.71	55.89 ± 15.1	56 ± 10.13	NS
HbA1c (%)	5.277 ± 0.25	5.926 ± 0.24	7.463 ± 0.59	< 0.0001
FPG (mg/dL)	87.9 ± 6.46	105.4 ± 9.02	130.6 ± 21.12	< 0.0001
PPPG (mg/dL)	122.7 ± 9.75	154.9 ± 14	196.7 ± 38.03	< 0.0001
HTN duration (yr)	11.27 ± 7.18	14.05 ± 8.35	14.83 ± 7.44	NS
SBP (mmHg)	164.9 ± 10.93	165.6 ± 15.3	165 ± 15.01	NS
DBP (mmHg)	95.37 ± 14.88	94.95 ± 7.41	98 ± 17.36	NS
BMI	23.6 ± 1.3	24.4 ± 1.4	25.2 ± 3.6	0.0479

NS: Non-significant, P ≥ 0.05; P < 0.05: Statistically significant; T2DM: Type 2 diabetes mellitus; HbA1c: Glycated haemoglobin; FPG: Fasting plasma glucose; PPPG: Post prandial plasma glucose; HTN: Hypertension; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; BMI: Body mass index.

Table 2 compares biochemical parameters of the study population. There was no significant difference in the biochemical parameters between the groups.

Table 2 Comparison of biochemical parameters at presentation (mean ± SD).

	Non-diabetes (n = 30)	Prediabetes (n = 19)	T2DM (n = 29)	P value
Serum potassium (mEq/L)	3.1 ± 0.6	3.0 ± 0.7	3.1 ± 0.5	NS
Serum Sodium (mEq/L)	139.1 ± 2.6	139.1 ± 2.1	139.9 ± 2.2	NS
PAC (ng/dL)	28.2 ± 21.1	31.95 ± 26.2	39.8 ± 55.8	NS
PRA (ng/ml/h)	0.4 ± 0.2	0.32 ± 0.2	0.3 ± 0.2	NS
ARR (ng/dL per ng/mL/h)	148.1 ± 253	270.7 ± 393.9	266.2 ± 506.8	NS
Aldo:K	10.7 ± 12.2	12.5 ± 12.9	15.3 ± 29.7	NS
PAC post SST (ng/dL)	15.6 ± 11.8	16.5 ± 13.6	15.8 ± 12.1	NS
Venous Bicarbonate (mEq/L)	24.3 ± 7.1	26 ± 5.0	23.6 ± 4.5	NS
Creatinine (mg/dL)	1.2 ± 0.5	1.1 ± 0.2	1.2 ± 0.2	NS
eGFR (mL/min/1.73 m2)	70.6 ± 24.2	76.7 ± 19.8	71.2± 16.2	NS

NS: Non-significant, P ≥ 0.05; P < 0.05: Statistically significant; T2DM: Type 2 diabetes mellitus; PAC: Plasma aldosterone concentration; PRA: Plasma renin activity; ARR: Aldosterone to renin ratio, Aldo:K: Aldosterone to potassium ratio; PAC post SST: Plasma aldosterone concentration post saline suppression test; eGFR: Estimated glomerular filtration rate.

The clinical presentation of PH patients in different study groups are presented in Table 3.

Table 3 Comparison of the pattern of clinical presentation, n (%).

Presentation	Non-diabetes (n = 30)	Prediabetes (n = 19)	T2DM (n = 29)	P value
Resistant hypertension	7 (23.3)	1 (5.35)	3 (10.3)	NS
Spontaneous hypokalemia with hypertension	15 (50)	11 (57.9)	15 (51.7)	NS
Adrenal incidentaloma with hypertension	2 (6.7)	2 (10.5)	2 (6.9)	NS
Resistant hypertension with diuretic induced hypokalemia	6 (20)	5 (26.3)	9 (31)	NS
Mean number of antihypertensives (mean ± SD)	3.0 ± 0.6	2.9 ± 0.6	3.1 ± 0.7	NS
No. of antihypertensives
1	1 (3.3)	1 (5.3)	1 (3.4)	NS
2	3 (1.0)	1 (5.3)	2 (6.9)
3	22 (73.3)	16 (84.2)	19 (65.5)
4	4 (13.3)	1 (5.3)	6 (20.7)
5	0 (0)	0 (0)	1 (3.4)

NS: Non-significant, P ≥ 0.05; P < 0.05: Statistically significant; T2DM: Type 2 diabetes mellitus.

There were no significant differences in presentation or number of antihypertensives used, between the groups with or without T2DM and prediabetes (Table 3). The majority of patients in all groups were presented with spontaneous hypokalemia with hypertension. Overall hypokalemia (both spontaneous and diuretic induced) at presentation was numerically more common in pre-diabetes 16 (84.2%) and diabetes 24 (82.7%) compared to non-diabetes 21 (70%) subjects, there was no significant difference between groups. HPP was present in 5 (16.7%), 3 (15.8%), 5 (17.2%) in non-diabetes, pre-diabetes, and diabetes groups respectively, with no significant difference between groups.

All groups were on average 3 or more antihypertensive medications, with numerically more diabetes subjects requiring 4 antihypertensives.

The type and number of complications of PH patients in different group is presented in Table 4. The prevalence of CVA was highest among PH patients with pre-diabetes, while LVH and CAD were highest among PH with diabetes.

Table 4 Type and number Pattern of complications in the study population, n (%).

Comorbidities	Non-diabetes (n = 30)	Prediabetes (n = 19)	T2DM (n = 29)	P value
Mean number of complications (mean ± SD)	1.4 ± 0.97	1.5 ± 0.8	1.7 ± 0.8	NS
LVH	23 (76.7)	17 (89.5)	26 (89.7)	NS
CKD 3	17 (56.7)	12 (63.2)	17 (58.7)	NS
CAD	3 (10)	4 (21)	8 (27.6)	NS
CVA	1 (3.3)	3 (15.8)	1 (3.4)	NS
No. of complications
0	3 (10)	3 (15.8)	3 (10.3)	NS
1	2 (6.7)	2 (10.5)	4 (13.8)
2	7 (23.3)	8 (42.1)	12 (41.4)
3	18 (60)	6 (31.6)	9 (31)
4	0 (0)	0 (0)	1 (3.4)

NS: Non-significant, P ≥ 0.05; P < 0.05: Statistically significant; T2DM: Type 2 diabetes mellitus; LVH: Left ventricular hypertrophy; CKD: Chronic kidney disease; CAD: Coronary artery disease; CVA: Cerebrovascular accident; HTN: Hypertension; OSA: Obstructive sleep apnea.

DISCUSSION

In our study population of confirmed PH patients at diagnosis, we observed high prevalence of diabetes (37.2%) and prediabetes (24.3%). BMI, FPG, PPG and HbA1c was significantly higher in diabetes. There were no differences in clinical or biochemical features between normoglycaemia, prediabetes and T2DM study subjects. There was no significant difference in age, SBP, DBP or duration of hypertension between groups (Table 1). All groups had a similar long duration of hypertension with majority of study subjects requiring on average 3 or more antihypertensive medications, though numerically more diabetes subjects required 4 antihypertensives. Most of our PH patients in all groups presented with spontaneous hypokalemia with hypertension Majority of our PH study patients across groups had 2 or more complications with high prevalence of LVH and CKD 3 or more. There was no statistically significant differences of type and number of complications among PH patients with or without diabetes and prediabetes.

Studies conducted in several countries have reported prevalence of diabetes in patients with PH ranging between 15.2%-23%[3,5,11,15]. Two prior meta-analyses reported 1.54-1.55-fold higher risk of glycemic abnormalities with lower marker of insulin secretion and higher insulin resistance in PH compared to essential hypertension (EH)[15,16]. In our PH patients at presentation, we observed high prevalence of diabetes (37.2%) and prediabetes (24.3%), possibly due to higher risk of diabetes in Asian Indian population caused by altered lifestyle, increased visceral fat and insulin resistance with dyslipidaemia[17]. PH could masquerade as metabolic syndrome in diabetes and hypertensive subjects, delaying PH diagnosis[15].

Prevalence studies have reported, 50-55 years as the average age of PH patients at diagnosis[15,18]. The mean age of individuals at presentation was similar in the current study across three groups.

The diagnosis of hypertension predated the diagnosis of diabetes among PH patients in the current study (Table 1). Our PH subjects with T2DM had a mean diabetes duration of 6.0 ± 4.7 years compared to mean duration of hypertension of 14.8 ± 7.4 years. A recent study in diabetes subjects reported hypertension predates DM diagnosis in PH patients compared to EH, whereas diabetes diagnosis antedate hypertension detection[18]. A meta-analysis reported, 15.2% prevalence of new onset T2DM in PH patients, corroborating PH pathophysiology leading to dysglycemia and T2DM[15].

A linear correlation was observed between HbA1c and renin activity[19]. At presentation in our PH patients, we found no differences between glycaemic groups, in biochemical parameters, including sodium, potassium, PAC, PRA, ARR, and PAC post SST confirmatory test (Table 2).

Hypokalemia with hypertension is hallmark of PH, due to unregulated hypersecretion of aldosterone causing increased sodium retention and excessive potassium loss[20,21]. However recent epidemiological studies have reported 9%-37% prevalence of hypokalaemia in PH patients, probably because of screening and early detection[1,20,22]. A study, screening for PH in diabetes subjects with hypertension found no difference in hypokalemia prevalence between screen positive and negative, suggesting early detection of asymptomatic PH and probably mild bilateral disease[18]. Spontaneous hypokalaemia with hypertension was the most common presentation of PH in our study population across all glycaemic groups, indicating symptomatic referral and late detection of PH (Table 3). Severe hypokalemia leading to neuromuscular dysfunction like HPP, are rarely observed among PH patients[18]. In our PH patients, 15.8%-17.2% presented with HPP (Table 3) without any difference between groups, probably due to delayed diagnosis of PH.

In PH, aldosterone induced hypokalemia can worsen hyperglycaemia by affecting islet cell function and impairing insulin secretion as well as increasing insulin resistance[8,21,23,24]. In our PH study subjects, overall hypokalemia (both spontaneous and diuretic induced) at presentation was numerically more common in pre-diabetes (84.2%) and diabetes (82.7%) compared to non-diabetes (70%) (Table 3). High sodium diet in India might further worsen hypokalaemia in PH[20,21,25].

Sustained activation of MR in PH, causes inflammation, necrosis, and fibrosis, leading to increased cardio-renal risk, independent of blood pressure[1,7]. A meta-analysis reported increased risk of metabolic syndrome, T2DM, LVH, CAD, stroke, AF, and heart failure, in PH[26]. Undetected PH can worsen glycemia, hypertension and exacerbate cardio-renal risk[8]. PH, hypertension, and diabetes all contribute to cardiovascular and renal complications affecting quality of life of patients[25,27]. A German Conn’s registry found higher DM prevalence in PH patients compared to matched population, partially explaining excess cardio-renal risk in PH[11]. PH is observed in at least 4.1-13% of diabetes patients with different degrees of hypertension[18,28]. LVH and CAD are common co-morbidities associated with both diabetes and hypertension[18]. Previous research has associated increased incidence of LVH with PH and diabetes[29,30]. PH patients have higher risk of developing CAD (relative risk of 1.67) as compared to those with EH[26].

In the current study at diagnosis of PH, more than three-fourths of the study population had LVH and 10%-25% had CAD across different groups. However, no significant differences in the and number and prevalence of cardiovascular co-morbidities (LVH, CAD) were noted between PH patients with different glycaemic status (Table 4). Numerically higher proportion of PH patients with diabetes developed LVH and CAD, compared to PH patients with normal glycaemic profile.

PH and diabetes, significantly increase renal morbidity[12,25,28]. Hypertension prevalence being higher in diabetes compared to non-diabetes patients; underlying hyperaldosteronism can further aggravate chronic diabetic complications[31].

We found high prevalence of CKD 3 or more in majority of PH subjects across glycaemic groups without any significant difference in renal parameters (creatinine, mean eGFR and CKD stage) (Tables 2 and 3). Higher serum creatinine and lower eGFR, have been reported in screen positive PH with diabetes and hypertension[18]. Aldosterone mediated renal and cardiac complications appear earlier and are more severe in PH compared to EH patients[26].

PH treatment with MR antagonists (MRA) inhibit MR overactivation, decreasing inflammation, fibrosis and development and progression of CKD, diabetes, and cardiovascular disease[32]. MRA helps in better blood pressure and glycemic control, improving cardio-renal risk[33,34]. Adrenalectomy in PH subjects has reportedly decreased DM prevalence and FPG levels[34].

Limitations of this study were its relatively small number of subjects and retrospective cross-sectional design. Complications were assessed based on history and previous testing while CKD was assessed by eGFR (mL/min/1.73 m²) only. PAC was analysed by immunoassay rather than mass spectrometry, which may lead to false positives.

CONCLUSION

Our PH patients had high prevalence of dysglycemia at diagnosis, with hypokalemia and resistant hypertension being the commonest presentation, indicating late detection. There were no differences in presentation, complications, or co-morbidities among PH patients irrespective of their glycaemic status, suggesting PH as the primary driver and emphasizing need for screening and early detection of underlying PH, especially in patients with hypertension and diabetes.