Baseline characteristics (at recruitment)
One hundred and forty-three participants (79 male, 64 female) from 23 practices allocated to intervention attended the first TDR appointment (visit 1, week 0) and commenced TDR (Fig. 1).
Just over half of all participants (n = 81) in the intervention arm had diagnosed hypertension (Table 2). The majority (96%) of those with diagnosed hypertension were on antihypertensive medications, with 54% (44/81) on two or more medications. Baseline weight and BP were lower in those with no history of hypertension in comparison with those with a history of hypertension and to the group as a whole. Baseline BP in those prescribed antihypertensive medications at recruitment (n = 78) varied slightly according to the number of medications prescribed:
One medication (n = 34), 136.5 (SD 17.7) mmHg systolic, 85.7 (SD 11.6) diastolic
Two medications (n = 28), 141.4 (SD 21.5) mmHg systolic, 87.0 (SD 11.1) diastolic
Three medications (n = 10), 123.0 (SD 10.7) mmHg systolic, 82.8 (SD 5.7) diastolic
Four medications (n = 6) 135.8 (SD 19.2) mmHg systolic, 82.4 (SD 9.1) diastolic
Nineteen participants withdrew from the intervention from visit 1 to 12 (inclusive) (Fig. 2). Four attended only the first TDR appointment. Of those who withdrew, 15 were still in the TDR phase of the study. Mean baseline BP of these 15 was 122.8 (SD11.9) mmHg systolic, 82.8 (SD 9.2) mmHg diastolic, with five on antihypertensive medications.
Discontinuation of antihypertensive medications
All antihypertensive medications were discontinued at the start of TDR, as per DiRECT protocol, in the majority of participants on treatment for hypertension (65/78; 83%). In four participants (5%) only some of the prescribed medications were discontinued (Fig. 1), the reasons given for continuing medications were ‘GP decision’ (2), CHD (1), unknown (1).
In 9 (11.5%) participants none of the antihypertensive medications were stopped on commencing TDR. Their baseline characteristics are shown, compared with the whole group, in Table 2. The reasons given for not stopping antihypertensive medications were: heart failure (1), ‘high BP’ (5), patient reluctant (1), and reason unknown (2). For three of these nine participants, antihypertensive medications were subsequently discontinued during TDR, as BP control improved with weight loss.
Similar significant weight losses were seen during TDR in the intervention group as a whole and those who withdrew antihypertensives (Table 3, Fig. 3, electronic supplementary material [ESM] Table 1). Weight loss was similar for those with no history of hypertension and who discontinued 1 and ≥2 antihypertensives (ESM Fig. 1).
Changes in BP
In the intervention group as a whole (n = 143) significant reductions in mean BP were seen during TDR: SBP fell significantly from week 1 (−3.6 [14.2] mmHg p = 0.003), DBP from week 3 (−1.9 [8.7] mmHg, p = 0.009) (Fig. 4, ESM Table 2). The falls in BP through TDR were immediate and quite substantial for those with no history of hypertension (Fig. 4, ESM Table 3). In those previously treated for hypertension, and who discontinued antihypertensives, there were no significant changes in BP until visit 6 (~week 9), when both SBP and DBP fell: −4.5 (15.9) mmHg, p = 0.03 and −2.5 (9.5) mmHg, respectively (p = 0.03) (Fig. 3, ESM Table 2). Changes in BP were slower for those who stopped two or more antihypertensives at the start of TDR (Fig. 4, ESM Table 2). The lowest BP recorded at study visits during TDR was 100/70 mmHg in one participant who had previously been hypertensive, and 95/58 mmHg for one participant without previously treated hypertension. These low BP measurements occurred at visit 6, around week 9 of TDR.
In linear mixed effects regression models predicting change in SBP from week 1, there was a significant difference between those who were and were not on antihypertensive treatment at baseline. Mean SBP was higher by 10.6 mmHg (95% CI 7.2, 14.0; p < 0.0001) and mean DBP higher by 4.2 mmHg (95% CI 2.1, 6.3; p < 0.0001) for those on antihypertensive treatment at baseline (Table 4). Whether or not a participant was still on TDR was not a significant predictor of SBP or DBP (p = 0.1350 and p = 0.4868, respectively). There was no significant interaction with treatment visit (p = 0.45 for SBP, p = 0.73 for DBP), which means the trajectory is similar between both groups.
Analysing all intervention patients who started TDR in a linear mixed effects regression model, weight change was a significant predictor of change in BP (with a decrease of 0.53 [0.41, 0.65] mmHg in SBP and 0.34 [0.26, 0.41] mmHg in DBP per kg lost, p < 0.0001 for both) (Table 5). The association did not vary significantly by visit (p for interaction of weight change with visit = 0.107 for SBP and 0.656 for DBP, p for visit number = 0.2871 and 0.3579), so visit number was therefore removed from the model.
Fifty-one participants (36%) reported experiencing dizziness, potentially suggesting postural hypotension, on at least one occasion during the 12–20-week TDR phase, of whom 23 (45%) had been on antihypertensive medications and two had continued them. In most participants (n = 42/51, 82%), the reported dizziness was mild, not interfering with daily activities. Only two participants reported experiencing severe dizziness, one of whom had a history of hypertension and had discontinued all antihypertensive medications at the start of TDR. Recorded BP at the time severe dizziness was reported (week 3) was 150/110 mmHg and the participant was recommenced on antihypertensive medication.
Dizziness was reported at baseline (visit 1), before the start of TDR, in 15 participants, of whom nine were taking antihypertensive medications, and two took diuretics which were stopped at the start of TDR. Dizziness, which recurred in most of these 15 participants, could not be attributed fully to the TDR intervention.
Recommencement of antihypertensive medications
In two-thirds of the participants who discontinued antihypertensive medications (46/69; 66.6%) antihypertensive medications had to be recommenced using the DiRECT reintroduction protocol (Table 1). Antihypertensive drug reintroduction was during TDR for 20/69 participants (29%), mainly among those previously prescribed ≥2 antihypertensives at baseline (14/20). For one participant, this was because of withdrawal from the trial. Changes in BP for the 19 participants who recommenced antihypertensives during TDR because of increases in BP are shown in ESM Table 4. For 11 participants, antihypertensive medications were recommenced around week 3 of TDR, with mean weight change −4.6 (SD 2.1) kg (p < 0.001), mean SBP 158.7 (11.7) mmHg and mean DBP 94.0 (10.4) mmHg. In 26 participants, BP remained acceptable throughout TDR, and antihypertensive medications remained withheld, but were recommenced because BP rose later on (Fig. 1). Among those who restarted antihypertensives during WLM, seven did so in year 1 and 12 in year 2.
Of the 46 participants who recommenced antihypertensive medications, around one-third (16/46; 34.8%) had stopped these at 12 months (Table 6). Blood pressure remained well controlled, on fewer medications, at both 12 and 24 months (Table 6).
Twenty-three (33.3%) of the 69 participants who discontinued antihypertensive medications at TDR baseline remained off the discontinued antihypertensive and diuretic medications through to the end of TDR (Fig. 1). Changes in BP while on TDR are shown in ESM Table 4.
Mean weight loss by week 20 in this group was −16.6 (SD 7.8) kg, SBP 129.5 (SD 14.9) mmHg, at which time most participants were in FR (n = 16; 70%). Of these 23, 19 were able to remain off medications at 2 years.
Of the 53 patients in the intervention group who were in remission after 2 years, and with a mean weight loss of 11.4 kg, 31 had been hypertensive at baseline. Of these 31, 27 had all their medication stopped, one had some medication stopped and three had not had their medication stopped at baseline. Of these 27, 12 remained off antihypertensive medication at the end of year 2.