Patient demographics and clinical characteristics

Overall, 210 patients (LINC 3, n = 137; LINC 4, n = 73) were included in the pooled analyses. At baseline, 82.9% (n = 174/210) of patients had hypertension and 40.0% (n = 84/210) had diabetes (Table 1). Mean baseline (standard deviation [SD]) mUFC levels (x ULN) were: 6.2 (10.0) in patients with hypertension and 4.4 (7.5) in those without; 6.4 (10.7) in patients with diabetes and 5.4 (8.9) in those without.

Table 1 Patient demographics and baseline characteristics

There were some differences between subgroups with and without hypertension or diabetes at baseline in the proportion of males, age, baseline mUFC, time to first dose since diagnosis, and number of comorbidities (Table 1). Baseline characteristics for patients with both, neither, or just one of hypertension and diabetes at baseline are summarized in Supplementary Table 1.

Osilodrostat dose and exposure

In patients with and without hypertension at baseline, median (min–max) osilodrostat exposure was 101.2 (1–245) and 87.1 (6–204) weeks, respectively. Median (min–max) average osilodrostat dose was 6.2 (1–47) and 6.9 (1–21) mg/day, and median (min–max) dose given for the longest duration was 6.0 (0–60) and 6.0 (1–20) mg/day. Corresponding values in patients with and without baseline diabetes were, respectively: exposure, 102.6 (1–228) and 96.3 (1–245) weeks; dose, 6.1 (1–47) and 6.8 (1–46) mg/day; dose given for the longest duration, 6.0 (1–60) and 6.0 (0–60) mg/day.

Change in blood pressure parameters over timeChange in SBP and DBP by presence/absence of hypertension at baseline

In patients with hypertension at baseline, SBP and DBP decreased from baseline (mean [SD]: 135.3 [14.9] and 86.5 [10.4] mmHg, respectively) to W12 (126.0 [13.7] and 80.5 [9.4] mmHg), and these reductions were maintained up to W72 (123.8 [13.4] and 79.9 [9.3] mmHg; Fig. 1a). In patients without hypertension at baseline, mean SBP and DBP remained normal during osilodrostat treatment (Fig. 1a).

Fig. 1

(a) Changes in mean SBP and DBP over time in patients with and without hypertension at baseline. Shift in (b) SBP and (c) DBP over time in patients with high blood pressure (SBP > 130 mmHg, DBP > 90 mmHg) at baseline. (d) Changes in mean SBP and DBP over time according to antihypertensive medication use during the studies in patients with hypertension at baseline. Dashed gray lines (panels a and d) represent upper limits beyond which hypertension is indicated: SBP 130 mmHg and DBP 90 mmHg

In patients with SBP > 130 mmHg at baseline, 56.4% (n = 57/101) and 49.1% (n = 54/110) had SBP ≤ 130 mmHg at W12 and W72, respectively (Fig. 1b). Among those with DBP > 90 mmHg at baseline, 73.3% (n = 44/60) and 58.5% (n = 38/65) had DBP ≤ 90 mmHg at W12 and W72, respectively (Fig. 1c). Overall, 21.4% (n = 18/84) of patients with SBP ≤ 130 mmHg at baseline had SBP > 130 mmHg at W12, and 7.2% (n = 9/125) of patients with DBP ≤ 90 mmHg at baseline had DBP > 90 mmHg at W12. At W72, these proportions were 14.0% (n = 14/100) for SBP and 4.1% (n = 6/145) for DBP.

The largest decreases in SBP/DBP occurred in patients with the highest baseline SBP/DBP (see Supplementary Fig. 1 for further details).

Additional analyses assessed levels of 11-deoxycorticosterone, 11-deoxycortisol, and potassium in patients with versus without hypertension and/or hypokalemia at baseline (see Supplementary Figs. 2–4 for further details).

Change in SBP and DBP in patients with hypertension at baseline, by antihypertensive medication use

Overall, 54.3% (n = 114/210) of patients received antihypertensive medication at baseline, most commonly (≥ 10% of patients) amlodipine (14.9% [n = 17/114]), spironolactone (14.0% [n = 16/114]; all female), ramipril, and hydrochlorothiazide (both 13.2% [n = 15/114]). Of the 96 patients not taking antihypertensive medication at baseline, eight, 13, and 15 patients received antihypertensive medication at W12, W48, and W72, respectively. Twenty-three female patients started spironolactone during the study.

The proportion of patients taking antihypertensive medication declined over time (56.1% [n = 97/173] at W12, 47.3% [n = 61/129] at W72). At W12, 52.6% (n = 50/95) of patients had stopped/reduced their dose, 41.1% (n = 39/95) had no change, and 6.3% (n = 6/95) had increased their dose/started a new antihypertensive medication. Corresponding values at W72 were 26.8% (n = 19/71), 47.9% (n = 34/71), and 25.4% (n = 18/71), respectively. Of the 39 women treated with spironolactone (at baseline or during treatment), 32 stopped taking it during the studies.

In patients with hypertension at baseline, mean SBP/DBP decreased from baseline to W72, regardless of whether patients received antihypertensive medication during the studies (Fig. 1d). Reductions in mean SBP/DBP were similar irrespective of any change in antihypertensive medication over time (Supplementary Fig. 5).

Change in SBP and DBP by baseline mUFC severity and mUFC control

Baseline mean (SD) SBP/DBP in patients with hypertension at baseline was higher in those with severe mUFC elevation (> 5 x ULN; 138.1 [13.7]/89.5 [8.1] mmHg) than in those with mild (< 2 x ULN; 134.1 [15.6]/85.4 [9.4] mmHg) or moderate elevation (2–5 x ULN; 134.4 [15.2]/85.4 [11.8] mmHg) at baseline. Decreases in mean SBP/DBP over time were similar across all three baseline mUFC severity groups (Supplementary Fig. 6).

Of patients with hypertension at baseline, the proportions with mUFC ≤ ULN were 73.2% (n = 115/157) at W12 and 74.1% (n = 106/174) at W72. Corresponding proportions for patients without hypertension were 71.4% (n = 20/28) and 71.4% (n = 20/28), respectively. Patients with hypertension at baseline who achieved mUFC ≤ ULN or partial mUFC control at W72 had decreased SBP/DBP (Supplementary Fig. 7). Overall, there was a weak correlation between change in SBP/DBP and change in mUFC from baseline to W72 (r = 0.20, P = 0.048/r = 0.22, P = 0.028). There was no correlation between SBP/DBP and mUFC at W72.

Changes in antihypertensive medication in patients with hypertension at baseline, including a separate analysis for those receiving spironolactone, are shown in Supplementary Figs. 8 and 9.

Change in risk factors

Reductions in mean (SD) weight, waist circumference, and BMI were observed from baseline in patients with and without hypertension at baseline and were maintained over long-term treatment (see Supplementary Fig. 10 for further details).

Change in glycemic parameters over timeChange in FPG and HbA1c by presence/absence of diabetes at baseline

In patients with and without diabetes at baseline, mean (SD) FPG decreased from 110.7 (32.3) and 89.7 (17.1) mg/dL, respectively, at baseline to 96.8 (24.3) and 85.2 (9.8) mg/dL at W12 and 97.4 (24.2) and 83.6 (10.1) mg/dL at W72 (Fig. 2a). Corresponding values for HbA1c were 6.5% (1.1) and 5.5% (0.5), 5.9% (0.7) and 5.4% (0.5), and 5.9% (0.8) and 5.3% (0.4; Fig. 2b).

Fig. 2

Mean (a) FPG and (b) HbA1c over time in patients with and without diabetes at baseline. Shift over time in (c) FPG in patients with high FPG (≥ 100 mg/dL) at baseline and (d) HbA1c in patients with high HbA1c (≥ 6.5%) at baseline. Mean (e) FPG and (f) HbA1c over time in patients with diabetes at baseline, according to antihyperglycemic medication use during the studies. For panels a and e, the dashed gray lines indicate the FPG thresholds for pre-diabetes (100 mg/dL [5.6 mmol/L]) and diabetes (126 mg/dL [7.0 mmol/L]). For panels b and f, the dashed gray lines indicate the HbA1c threshold for diabetes (6.5% [47.5 mmol/mol])

In patients with FPG ≥ 100 mg/dL at baseline, 33.3% (n = 20/60) had levels < 100 mg/dL at W72 (Fig. 2c). In those with HbA1c ≥ 6.5% at baseline, 61.5% (n = 16/26) had levels < 6.5% at W72 (Fig. 2d). Overall, 5.7% (n = 7/123) of patients with FPG < 100 mg/dL at baseline had FPG ≥ 100 mg/dL at W12, and 0.7% (n = 1/137) of patients with HbA1c < 6.5% at baseline had HbA1c ≥ 6.5% at W12. At W72, these proportions were 4.3% (n = 6/140) for FPG and 1.7% (n = 2/120) for HbA1c.

The largest decreases in FPG and HbA1c occurred in patients with the highest baseline values (see Supplementary Fig. 11 for further details).

Change in FPG and HbA1c in patients with diabetes at baseline, by antihyperglycemic medication use

Overall, 21.9% (n = 46/210) of patients received antihyperglycemic medication at baseline, most commonly (≥ 10% of patients) insulin (73.9% [n = 34/46]), metformin (56.5% [n = 26/46]), metformin hydrochloride (41.3% [n = 19/46]), sitagliptin (13.0% [n = 6/46]), and liraglutide (10.9% [n = 5/46]). Among patients not taking antihyperglycemic medication at baseline, three and three patients received antihyperglycemic medication at W48 and W72, respectively.

The proportion of patients receiving antihyperglycemic medication generally remained stable from baseline to W12 (23.7% [n = 41/173]) then decreased over long-term treatment (W72: 17.1% [n = 22/129]). At W12, 48.0% (n = 24/50) of patients had stopped or reduced their dose, 50.0% (n = 25/50) had no change, and 2.0% (n = 1/50) had increased their dose or started a new antihyperglycemic medication. Corresponding values at W72 were 35.7% (n = 10/28), 53.6% (n = 15/28), and 10.7% (3/28), respectively.

In patients with diabetes at baseline, mean FPG and HbA1c decreased from baseline to W72, regardless of whether patients received antihyperglycemic medication (Fig. 2e–f). Reductions in mean FPG and HbA1c levels were similar in patients irrespective of any change in their antihyperglycemic medication (Supplementary Fig. 12).

Change in FPG and HbA1c by baseline mUFC severity and mUFC control

Baseline mean (SD) FPG and HbA1c levels in patients with diabetes at baseline were higher in patients with severe mUFC elevation (120.3 [39.4] mg/dL and 6.5% [1.0], respectively) than in those with mild (100.2 [25.3] mg/dL and 6.3% [0.9]) or moderate elevation (111.9 [30.4] mg/dL and 6.7% [1.1]). Reductions in FPG were greater in those with baseline mUFC > 5 x ULN than in those with baseline mUFC 2–5 or < 2 x ULN. Reductions in HbA1c were greater in those with baseline mUFC 2–5 and > 5 x ULN than in those with baseline mUFC < 2 x ULN (Fig. 3).

Fig. 3

Mean (a) FPG and (b) HbA1c over time in patients with diabetes at baseline, by baseline mUFC severity. For part a, the dashed gray lines indicate the FPG thresholds for pre-diabetes (100 mg/dL [5.6 mmol/L]) and diabetes (126 mg/dL [7.0 mmol/L]). For part b, the dashed gray line indicates the HbA1c threshold for diabetes (6.5% [47.5 mmol/mol])

Of patients with diabetes at baseline, 76.6% (n = 59/77) and 71.0% (n = 49/84) had mUFC ≤ ULN at W12 and W72, respectively. Corresponding proportions for patients without diabetes were 70.4% (n = 76/108) and 75.5% (n = 77/126). In patients with diabetes at baseline, FPG decreased from baseline to W72 in patients with mUFC ≤ ULN but generally remained stable in patients with partial mUFC control or uncontrolled mUFC, while HbA1c decreased from baseline to W72 irrespective of mUFC control (Supplementary Fig. 13). There was a weak correlation between changes in FPG and HbA1c and change in mUFC from baseline to W72 (FPG: r = 0.31, P = 0.005; HbA1c: r = 0.21, P = 0.044). There was no correlation between FPG and HbA1c and mUFC at W72.

In patients with diabetes at baseline who used antihyperglycemic medication during the studies, the proportion who reduced or stopped their dose was higher in those with mUFC ≤ ULN and partial mUFC control than in those with uncontrolled mUFC at W12 and W72 (Supplementary Fig. 14a). Changes in antihyperglycemic medication according to mUFC control in 12 patients without diabetes at baseline who started antihyperglycemic medication during the studies are shown in Supplementary Fig. 14b.

Change in risk factors

Reductions in mean weight, waist circumference, and BMI were observed from baseline in patients with and without diabetes at baseline, which were maintained over long-term treatment in both subgroups (see Supplementary Fig. 15 for further details).