Antihypertensive medication needs and blood pressure control with weight loss in the Diabetes Remission Clinical Trial (DiRECT)

Until recently, type 2 diabetes was viewed as a discrete endocrine disease, and its management was largely limited to prescribing medications that lower blood glucose and HbA_1c, with a target, representing ‘good control’ of HbA_1c < 53 mmol/mol (7%). It is well established that lowering blood glucose and HbA_1c will delay or prevent microvascular complications [1‐3], but life expectancy for people with type 2 diabetes remains reduced despite best practice treatments directed at clinical guideline targets [4]. The excess morbidity and early mortality are importantly accounted for by vascular complications inherent in the underlying metabolic syndrome, and particularly related to high BP, which commonly accompanies type 2 diabetes [5].

Our understanding of type 2 diabetes is changing, as evidence accumulates that it is primarily a nutritional disease process. It is driven by weight gain; in susceptible or predisposed individuals, body fat accumulates in ectopic sites, specifically liver, pancreas and muscle including heart muscle. A linked underlying genetic or epigenetic predisposition underpins the development of hypertension and dyslipidaemia, the main features of the metabolic syndrome, and also microalbuminuria and hyperuricaemia, commonly in the same individuals. About 85% of people with type 2 diabetes have or will develop hypertension, which requires treatment under current guidelines (systolic BP [SBP] ≥140 mmHg, diastolic BP [DBP] ≥90 mmHg) [6, 7].

As the vascular complications of type 2 diabetes, which still affect most patients, are strongly predicted by BP, clinical guidelines now stress the need for effective antihypertensive treatments [7]. Unfortunately, some medications to treat high BP can aggravate glucose tolerance [8‐10] and some anti-obesity medications used in the past to treat type 2 diabetes can elevate BP [11, 12]. All the features of cardiometabolic conditions, including both type 2 diabetes, dyslipidaemia and hypertension, are improved by weight loss [13‐15]. However, clinicians and guidelines have been reluctant to recognise weight loss as an effective alternative treatment for hypertension in individuals who are overweight, or to consider a therapeutic trial of withdrawing antihypertensive drug treatment when effective weight management is provided.

The present study is a secondary analysis of the changes in BP and in antihypertensive medication use during the initial total diet replacement (TDR) phase in the intervention arm of the Diabetes Remission Clinical Trial (DiRECT), after a planned withdrawal of all antihypertensive and diuretic medications at the start of an evidence-based weight management programme [16]. Our aim was to determine the safety of stopping BP medications as well as the extent of BP change in each group. We also wanted to assess to what extent BP would fall with weight reduction in our non-hypertensive participants. The per-protocol withdrawal of antihypertensive medications in DiRECT was informed by observation of postural hypotension necessitating withdrawal of antihypertensive agents [17] and the subsequent early results of omitting all antihypertensive agents [18].

Not all people prescribed antihypertensive drugs need to remain on them indefinitely. Indeed, a systematic review of 66 published studies reporting on withdrawal of antihypertensive drugs found that about 40% of people remain below the treatment threshold at 1 year, and 26% of over 1000 individuals remained normotensive and off medication for 2 years or longer, without evidence for adverse clinical outcomes [26]. However, the strong association between hypertension, affecting 50% or more people with type 2 diabetes [27, 28] as related features of the metabolic syndrome, may point to greater need to continue antihypertensive medication. It is well known that weight loss usually reduces BP, often substantially, as shown for our participants without previous antihypertensive treatment (ESM Table 3). Previous studies have reported reductions in use of antihypertensive drugs with weight loss, but their protocols have not previously included a proactive therapeutic trial of withdrawing medication. Discontinuation of antihypertensive medications at baseline was included in the DiRECT protocol primarily as a safety measure to avoid symptoms and injuries from postural hypotension, (a condition responsible for around 30,000 UK hospital admissions annually [29]). Although modern antihypertensive drugs are effective, it is well known that adherence to prescriptions for both diabetes and hypertension can be poor [30, 31] and the potential to be able to stop both antihypertensive and glucose-lowering medications legitimately was a major practical motivation for participants’ achieving substantial weight loss and remission of diabetes [32, DiRECT unpublished data, paper in preparation].

Withdrawing antihypertensive medications was initially a concern for some GPs in practices participating in DiRECT, uncertain whether weight loss would be achieved, or could provide good alternative treatment for hypertension. However, the results from Counterbalance, showing a fall in BP despite withdrawal of antihypertensive medications, were persuasive [18].

In the event, after withdrawing antihypertensive medications on commencing TDR, no severe postural hypotension was experienced by participants. Importantly, there was no worrying early rebound rises in BP. Indeed, with the combined effects of negative energy balance and weight loss, blood pressures actually fell below the baseline TDR values by about 9 weeks. The decrease in BP on commencing rapid weight loss, with withdrawal of antihypertensive medication, was similar in the community setting of DiRECT to that reported in the research centre-based Counterbalance study [18]. Weight loss was a strong determinant of fall in BP; however, reintroduction of medication was required for about one-third of participants during TDR, despite some weight loss. The protocol in place in DiRECT for monitoring BP and reintroduction of antihypertensive medications [19] allowed these participants to be identified quickly and managed safely. No serious adverse events related to rises in BP occurred.

The ability to provide, within routine primary care, a safe non-surgical intervention to achieve remission of type 2 diabetes without the need for medication is attractive to many people currently living with type 2 diabetes, and at risk of its progressive complications. The DiRECT study has proved that this is possible, with sustained remissions for over 80% at 2 years if weight loss of 10–15 kg is achieved. The present analysis shows a bonus for those individuals who achieved remission, from the high likelihood of being able to withdraw antihypertensive and diuretic medications completely. As with drug treatments, the clinical effects from weight loss do vary between patients, so it is necessary to monitor blood glucose and BP, and respond quickly to any deterioration. This entails a small commitment from either healthcare staff or potentially patients themselves using home monitoring. Applying the simple protocol used in DiRECT for reintroduction of anti-diabetes and/or antihypertensive medications [19] proved safe and effective. The overall effect of the DiRECT intervention at 12 and 24 months was to achieve improvements in mean BP which did not differ significantly between the intervention and the well-controlled control group at 12 months [13] but were significantly lower in the intervention group than in the control group at 24 months [33]. At both 12 and 24 months, fewer participants in the intervention group were being prescribed antihypertensive medications than at baseline (baseline 54% [81/149], 12 months: 32% [47/148], 24 months: 47% [61/129]). This differed significantly from the control group at both time points [13, 33].

It is important that BP continues to be monitored, at least annually along with HbA_1c, as even without weight regain, BP often rises with age [34].

Those who needed to restart antihypertensive medications were more often those who had been treated with two or more medications at baseline. It is possible that some of these might be at greater risk of postural hypotension if the drugs are not withheld during TDR, and BP monitoring is particularly important for this group. If BP is poorly controlled, and with multiple antihypertensive medications, maintaining some antihypertensive drugs during TDR might be safe, provided that lying and standing BP is checked if there are symptoms suggesting postural hypotension. Non-adherence with antihypertensive medications is reported at 45% overall, and 84% in patients with poorly controlled BP [31]. In some cases, patients adopting new health behaviours may increase their compliance with their prescribed drugs, and the combination with the antihypertensive effect of weight loss can be profound.

The overall effect on BP observed from weight loss in DiRECT was substantial, incorporating both the observed mean fall in BP and the reduced numbers of drugs being prescribed to fewer people, probably of a similar order to that achieved by many of the commonly prescribed antihypertensive medications. There are two separate major mechanisms which probably contribute to the observed reduction in BP. First, there was an acute, relatively large direct effect of the negative energy balance [35], together with the profound decrease in sodium intake on commencing the liquid formula diet which provided approximately 2.0–4.1 g daily, depending on the exact combination of soups and shakes chosen. Baseline salt intake has recently been estimated at 8 g per day in the UK [36, 37]. The decrease in BP following acute reduction of salt intake is greater in hypertensive people [38], although in DiRECT a fall in BP was observed in the whole intervention group. Both the acute and lesser longer-term effects from diet changes can be identified from the data collected during TDR in DiRECT, as shown in Fig. 3. It is well-recognised that for each 1 kg of sustained weight loss, BP falls by about 1 mmHg [39]. The step-change onto a 3470 kJ/day (830 kcal) TDR, necessarily low in all macronutrients albeit relatively high in carbohydrate, induced marked reductions in BP. The mechanisms may include metabolic effects, perhaps related to the expected reduction in plasma insulin concentrations for those who adhered to the TDR programme. Plasma insulin was not measured frequently in this primary care study, and specifically not over the first few weeks of TDR The median baseline fasting plasma insulin was only 19.8 mIU/ml (IQR 13.8 to 31.9) (DiRECT unpublished data), so any reduction would be unlikely to account for the large BP effects we observed. For the WLM phase of DiRECT, beyond 3–4 months, participants aimed for energy balance, and there was no restriction in carbohydrate intake. Median fasting plasma insulin at 24 months was 12.9 (7.4 to 20.1) mIU/ml, (DiRECT unpublished data). This very modest fall from baseline, again could not account for the large BP effects observed with sustained weight loss. As well as reduction in sodium consumption, reductions in perivascular ectopic fat might contribute to BP lowering with weight loss, via improved vasocrine signalling [40].

Remission from type 2 diabetes is a highly desired goal for people currently living with diabetes [41], and the intervention is highly cost-effective, indeed cost saving, for healthcare as well as increasing Quality-Adjusted Life Years [42]. The conclusion from this secondary analysis of DiRECT data is that a therapeutic trial of replacing antihypertensive medications with an effective weight management programme to achieve marked negative energy balance and rapid weight loss, and with regular BP monitoring and the DiRECT antihypertensive reintroduction protocol, was safe with no worrying rises or falls in BP. It was not possible to identify reliably at baseline the patients who would fail to lose weight or those whose BP responded less well to weight loss. The present analysis used measured data, following standard measurement procedures, so is unlikely to be affected by bias. We conducted the analyses with appropriate adjustments to avoid confounding. The sample studied was very typical of the type 2 diabetes population within 6 years of diagnosis and with typical prevalence of hypertension that was well controlled at baseline. Participants were not selected for high BP, so regression to the mean is not a factor behind the observed changes. The DiRECT control group, with no alterations in routine management, had similar BP to the intervention group at baseline, and these did not change significantly at 12 months [12]. The results can therefore reasonably be extrapolated to the wider type 2 diabetes population.