Initial attempts at BP reduction through nonpharmacological behavioral modification are emphasized in guidelines for the management of hypertension worldwide in individuals with or without diabetes. These principally focus on increasing physical activity, reducing body weight and/or adiposity, and dietary modification, including sodium restriction and adequate potassium consumption. Although a number of studies have evaluated the effects of lifestyle interventions on diabetes incidence, the Look AHEAD (Action for Health in Diabetes) trial examined the sustained effects of an intensive lifestyle intervention compared to diabetes support and education in 5145 overweight or obese adults with T2DM. The trial was prematurely discontinued on the basis of futility after a median of 9.6 years follow-up with respect to the primary composite cardiovascular disease outcome. The intensive lifestyle intervention was associated with significant improvements for a number of vascular risk factors, including net reductions in BP that diminished over time with an average postrandomization difference in SBP of −1.9 mm Hg. The intervention evaluated and targeted both physical activity and diet, and separate effects of individual components of the lifestyle intervention on BP cannot be estimated (see also Chapters 5 and 12 ).

Although not restricted to people with diabetes, the Dietary Approaches to Stop Hypertension (DASH) trials provide some indication of the likely effects of certain diets on BP. Allocation to the DASH diet (rich in fruits, vegetables, and low-fat dairy foods and with reduced saturated and total fat) in 459 adults over an 8-week intervention period was associated with significant reductions in SBP and DBP of 5.5 and 3.0 mm Hg, respectively, compared with a “typical” control diet. In the subsequent DASH-sodium trial, participants were randomly assigned different levels of sodium intake, within DASH or control diets. The effects of different levels of sodium intake in addition to the DASH diet were evaluated. Greatest benefits were observed with a low-sodium DASH diet, which compared with a control high-sodium diet, reduced SBP by 11.5 mm Hg in participants with hypertension and 7.1 mm Hg in those without a diagnosis of hypertension. With small numbers of participants, analysis in the subgroup with diabetes was not possible. Recent systematic reviews have concluded that reductions in dietary sodium were associated with significant reductions in BP, with a dose-response relationship and greater effects among older people, those with higher blood pressure and in non-White populations. In a cluster randomized trial of salt substitute (75% sodium chloride and 25% potassium chloride) versus regular salt (100% sodium chloride) conducted among 20,995 participants with a history of stroke or who were aged 60 years and older with hypertension in rural China, salt substitute was associated with significant relative risk reductions over 4.7 years in stroke (14%), major cardiovascular events (13%), and death (12%). Salt substitute was also associated with reduced rates of nonfatal acute coronary syndrome, without any excess in serious adverse events attributed to hyperkalemia. The mean reduction in systolic BP with salt substitute was 3.3 mm Hg. In prespecified subgroup analyses, there was no evidence of heterogeneity of intervention effect by baseline diabetes status.

Several meta-analyses have examined the relationship between pharmacological BP lowering and incident cardiovascular events. The most comprehensive overview of the effects of BP-lowering medications on vascular outcomes is provided by individual participant data (IPD) meta-analyses conducted in the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC). The most recent analyses, published in 2022, included IPD from 51 studies and 358,533 individuals (29% with T2DM). Over a median of 4.2 years follow-up, each 5 mm Hg reduction in systolic blood pressure resulted in a 6% relative reduction in major cardiovascular events in those with T2DM (HR, 0.94; 95% CI, 0.91–0.98) with a greater reduction observed in those without T2DM (HR, 0.89; 95% CI, 0.87–0.92; P for interaction 0.001). This heterogeneity was driven primarily by a smaller reduction in fatal and nonfatal coronary events in those with T2DM. Absolute risk reductions, however, were similar across those with and without T2DM due to the higher baseline risk of the T2DM cohort ( Fig. 18 2 ).

Absolute treatment effects of blood pressure ( BP )-lowering regimens on ischemic heart disease and other cardiovascular outcomes in people with and without diabetes.

Absolute risk reduction was estimated using a Poisson regression model with identity link. The unit is the percentage of absolute risk difference (treatment vs. comparator) over follow-up time and reflects the mean of blood pressure reduction across all trials. p _interaction was adjusted for multiple comparisons.

Reproduced from Nazarzadeh M, Bidel Z, Canoy D, et al. Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis. Lancet Diabetes Endocrinol . 2022;10:645–654.

While most trials of BP lowering in diabetes focused on patients with hypertension, ADVANCE, the largest ever conducted placebo-controlled trial of BP lowering among individuals with T2DM ( n = 11,140) addressed a question of routine BP lowering, regardless of initial BP level. Participants with known cardiovascular or microvascular disease or with at least one major risk factor for cardiovascular disease and any initial level of BP were randomly assigned to a fixed combination of the ACE inhibitor perindopril and the thiazide-like diuretic indapamide (4/1.25 mg) or matching placebo. The mean BP of participants at study baseline was 145/81 mm Hg. Over the course of active treatment, BP was reduced by a mean of 5.6/2.2 mm Hg compared with a placebo. At the end of a mean 4.3 years follow-up, active treatment reduced the risk of the combined composite primary outcome of major microvascular and macrovascular (cardiovascular) events by 9% (95% CI, 0%–17%, P = 0.043). For prespecified secondary outcomes, there was an 18% (2%–32%; P = 0.027) reduction in cardiovascular mortality and a 14% (2%–24%; P = 0.020) reduction in CHD events (defined as death caused by CHD, nonfatal MI, silent MI, coronary revascularization, or hospital admission for unstable angina). The effects of the combination of perindopril and indapamide treatment were similar across a range of initial BP levels, pointing to an alternative strategy for the provision of BP therapy to patients with T2DM, not limited to those with arbitrarily defined “hypertension.”

There has been considerable debate about the potential existence of BP-independent beneficial effects of various classes of drugs used to lower BP in a broad group of high-risk patients, including those with diabetes and with respect to different vascular beds. Data from both large clinical trials and meta-analyses help to inform this debate and are summarized below.

Although not limited to patients with diabetes, the results of three large trials raised questions about potential differential effects of BP-lowering regimens in patients with T2DM. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) investigated 19,257 people with hypertension and additional risk factors for cardiovascular disease (27% with diabetes), and compared the effects of combinations of atenolol with a thiazide diuretic versus amlodipine with perindopril on the primary outcome of fatal and nonfatal CHD events. The point estimate of treatment effect favored the amlodipine-perindopril combination for the primary outcome, but this was not statistically significant. However, there were significant reductions in all secondary outcomes associated with the amlodipine-perindopril combination, ranging from a relative risk reduction of 11% to 24%, and including all-cause mortality (which led to early termination of the trial), all coronary events, and nonfatal MI and fatal CHD. However, the amlodipine-based regimen was associated with a significant 2.7/1.9 mm Hg lower BP over the duration of follow-up. There was no evidence of heterogeneity of the treatment effect by the presence or absence of diabetes, evaluated on the basis of total cardiovascular outcomes.

The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) included 25,620 patients (~40% with diabetes) at increased risk for cardiovascular disease. Patients were randomized to ramipril alone, to telmisartan alone, or to both drugs. The mean BP level at study entry was 142/82 mm Hg. Over the course of follow-up, BP was 2.4/1.4 mm Hg lower in the combination therapy group compared with the ramipril-alone group. The incidence of the primary outcome (cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalized heart failure) did not differ between the ramipril-alone group and each of the other randomized groups. As expected, participants allocated to telmisartan alone experienced less cough and angioedema than those who were randomized to ramipril. However, symptoms of hypotension occurred more frequently in the telmisartan group (2.7%) and in the combination group (4.8%) compared with the ramipril-alone group (1.7%). Renal dysfunction was observed most often in the combination group. There was no heterogeneity in treatment effects by diabetes status for the primary outcome. In summary, the results of ONTARGET confirmed comparable efficacy of the ACE inhibitor and the ARB, with evidence of no additional benefit and increased harm from combination therapy.

The Avoiding Cardiovascular Events through Combination Therapy to Patients Living with Systolic Hypertension (ACCOMPLISH) trial included 11,506 high-risk patients (~60% with diabetes) with hypertension. Participants were randomly allocated to receive one of two combination drug regimens—the ACE inhibitor benazepril plus the calcium channel blocker amlodipine, or benazepril with the diuretic hydrochlorothiazide (HCT). The mean baseline BP level was 145/80 mm Hg. Over the duration of follow-up, a 0.9/1.1 mm Hg lower BP was observed in the benazepril-amlodipine group compared with the benazepril-HCT group. This study was stopped prematurely after a mean follow-up period of 3 years because of an observed statistically significant 20% reduction in the primary outcome (cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after cardiac arrest, and coronary revascularization) in the benazepril-amlodipine group compared with the benazepril-HCT group. There was no evidence of heterogeneity based on the baseline diagnosis of diabetes. Although early concerns had been expressed about potential underestimation of the BP difference between treatment arms using on-trial measurements, subsequent results of 24-hour ambulatory BP monitoring in a subset of 573 participants did not show any significant differences.

A 2015 systematic review restricted to trials of patients with diabetes identified few differences of the effects on clinical outcomes based on drug regimen, the key exceptions being for heart failure and stroke ( Fig. 18 3 ). In a more recent BPLTTC meta-analysis using IPD from 51 randomized trials, the magnitude of benefits on clinical outcomes produced by different regimens of BP-lowering therapy was assessed using a network meta-analysis by drug class and meta-regression stratified by T2DM status. In this overview, a smaller relative risk reduction in clinical events in those with T2DM, compared to those without T2DM, was consistently seen, irrespective of individual antihypertensive drug class, with no heterogeneity of treatment effect observed between drug classes.

Blood pressure-lowering drug class effects on CHD and other clinical outcomes from trials of participants with diabetes.

^a Systolic blood pressure ( SBP ) reduction is reported as a 95% CI for the mean reduction at the trial level, not a range of reduction among trials. The area of each square is proportional to the inverse variance of the estimate. Horizontal lines indicate 95% CIs of the estimate. ACE , Angiotensin-converting enzyme; ARB , angiotensin II receptor blocker; CCB , calcium channel blocker; CHD , coronary heart disease; CI , confidence interval.

Reproduced from Emdin CA, Rahimi K, Neal B, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA . 2015;313(6):603–615. https://doi.10.1001/jama.2014.18574 .

By and large, current hypertension and diabetes management guidelines worldwide acknowledge that achieving BP reduction is more pressing than decisions about which class of drug should be used, particularly given that two or more agents are frequently required in patients with diabetes. In general, the use of a regimen that includes an ACE inhibitor or an ARB is recommended, particularly in the presence of albuminuria. Although thiazide or thiazide-like diuretics as well as beta-blockers have been associated with adverse effects on glucose homeostasis, the clinical relevance of this is doubtful and it does not preclude the use of these drugs in people with T2DM. Indeed, the indications for use of beta-blockers in patients with existing CHD or systolic heart failure (particularly vasodilating or cardioselective beta-blockers, such as carvedilol, nebivolol, or metoprolol succinate, which may also have more favorable metabolic effects than older beta-blockers) and thiazide or thiazide-like diuretics in those with cerebrovascular disease are compelling. For much of the world, affordability is also a key issue that must be considered in the choice of antihypertensive therapy.

Most guidelines worldwide currently recommend more aggressive management of hypertension (mostly, a target of 130/80 mm Hg or lower) among people with diabetes compared with those without diabetes.

The BPLTTC evaluation of the effects of more versus less BP lowering included 48 trials and 344,716 patients, of whom 28% had T2DM. For the primary outcome of major adverse CV events (MACE), the relative effects of BP lowering were shown on a meta-regression analysis to be proportional to the degree of SBP reduction achieved. These analyses were not undertaken separately in those with T2DM; however, in meta-regression analyses performed in the most recent BPLTTC overview, similar correlations between the degree of BP lowering achieved and reductions in CV events were observed for individuals with and without diabetes ( Fig. 18 4 ).

Meta-regression of intensity of blood pressure reduction and hazard ratio of major cardiovascular events by diabetes status at baseline.

The hazard ratio for each trial is shown by the center of the bubbles, with the size of the bubble inversely related to the respective standard error. The solid red line is the fitted regression line; the dotted blue lines represent the 95 percent confidence intervals; the dashed gray line represents the hazard ratio = 1. Regression coefficients and 95 percent confidence intervals in people with and without diabetes at the baseline were–0.007 (–0.036 to 0.0205) and–0.014 (–0.035 to 0.006), respectively.

Reproduced from Nazarzadeh M, Bidel Z, Canoy D, et al. Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis. Lancet Diabetes Endocrinol . 2022;10:645–654.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in people with T2DM and the Systolic Blood Pressure Intervention (SPRINT) trial, in those without T2DM, are two pivotal trials addressing optimal blood pressure targets.

ACCORD was a factorial randomized trial of 10,251 individuals with T2DM from 77 centers in North America. Participants with a hemoglobin A1c (HbA1c) of 7.5% or more and aged 40 years or older with cardiovascular disease or 55 years or older with anatomic evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two additional risk factors for cardiovascular disease (dyslipidemia, hypertension, smoking, or obesity) were randomized to two glucose control targets (see also Chapter 13 ). A subset of 4733 participants (with SBP between 130 and 180 mm Hg on three or fewer antihypertensive medications and with no evidence of greater than 1.0 g of proteinuria per day or the equivalent) were also included in a randomized evaluation of a BP-lowering intervention targeting two different SBP levels (an SBP target of 120 mm Hg or less, compared with 140 mm Hg or less). The BP-lowering regimen was at the physician’s discretion but included any class of drug therapy known to produce cardiovascular benefits (ACE inhibitors, ARBs, diuretics, calcium channel blockers, or beta-blockers). The primary outcome was a composite of major cardiovascular events defined as nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary outcomes included all coronary events, all stroke events, and all-cause death, considered separately. The mean baseline BP in ACCORD was 139/76 mm Hg, and at study entry, 87% of participants were already taking some form of antihypertensive therapy. Over a mean follow-up of 4.7 years, intensive therapy achieved a mean SBP of 119 mm Hg compared with 134 mm Hg in the standard therapy group, resulting in a mean between-group difference of 14.2 mm Hg. However, intensive therapy did not result in a statistically significant reduction in major cardiovascular events (relative risk reduction [RRR] 12%; 95% CI, −6% to 27%; P = 0.20). When the components of the composite outcome were considered separately, intensive therapy did not reduce major coronary events (which included unstable angina) or cardiovascular death, but significantly reduced major strokes by 41% (95% CI, 11%–61%). There was no statistically significant effect of intensive BP therapy on all-cause mortality or heart failure. There was no evidence of heterogeneity in treatment effect in subgroups of participants defined by age, sex, baseline history of cardiovascular disease, and the use of BP-lowering therapy at study entry.

Many have interpreted the ACCORD trial as being “negative” with respect to the BP-lowering component, stimulating discussion that the current target of 130/80 mm Hg or lower promulgated by many guidelines may not be justified. However, notwithstanding the clear benefits of a more aggressive approach to BP lowering for stroke well below this threshold, the study was not sufficiently powered to detect substantial and clinically important beneficial effects on other cardiovascular events, including CHD (approximately one-quarter reduction, which would be broadly consistent with a 14 mm Hg difference in SBP based on epidemiologic data). Intensive BP lowering in ACCORD was associated with an increased number of serious adverse events attributed to BP-lowering drugs, compared with the standard therapy group; however, overall rates over an average period of almost 5 years of follow-up were low (3.3% vs. 1.3%). Particular concerns have been raised about higher levels of serum creatinine and lower levels of estimated glomerular filtration rate postrandomization among intensive BP treatment participants. This did not translate to differences in end-stage renal disease (2.5% vs. 2.4%), and intensive BP-lowering therapy was associated with the development of numerically fewer cases of microalbuminuria and macroalbuminuria, the latter being significantly lower than the rates observed in the standard therapy group.

The SPRINT trial also evaluated the cardioprotective value of intensive (<120 mm Hg systolic) versus standard blood pressure (<140 mm Hg systolic) control in 9361 individuals at elevated baseline cardiovascular risk; however, people with T2DM were excluded. Over 3.3 years, median follow-up SBP separation between groups was achieved (mean of 121.5 vs. 134.6 mm Hg), with intensive treatment resulting in a 25% lower rate of cardiovascular events (defined as MI, acute coronary syndromes, stroke, heart failure, and CV death) compared to the standard control (HR, 0.75; 95% CI, 0.64–0.89; P < 0.001). As was seen in the ACCORD trial, there was an increase in serious adverse events with intensive treatment, including hypotension, syncope, acute kidney injury/failure, and electrolyte abnormalities.

A post hoc analysis combining participants from the SPRINT trial with prediabetes and “SPRINT-eligible” participants from ACCORD with T2DM suggested a benefit for intensive systolic blood pressure control. These analyses reported a 21% reduction (HR, 0.79; 95% CI, 0.65–0.96) in composite cardiovascular events (nonfatal MI, nonfatal stroke, CV death, revascularization, and heart failure) with intensive as compared to standard control. Again, an increase in adverse events was noted with intensive control (4.1% vs. 2.1%; P = 0.003).

In addition, a post hoc high-CV-risk subgroup analysis of the ACCORD trial and of the long-term observational follow-up “ACCORD Follow-on” (ACCORDION) was performed to determine the longer-term cardiovascular impacts of intensive BP control in those with T2DM. Over 9 years of follow-up, intensive BP control as compared to standard control, reduced MACE by 25% (HR, 0.75; 95% CI, 0.60–0.95), mainly driven by a reduction in nonfatal MI.

Taken together, these data suggest a likely cardiovascular benefit for intensive systolic BP control in those with T2DM, which must be balanced against an increase in adverse events.

In 2008 the UKPDS study reported data from posttrial annual follow-up for an additional 6 years undertaken for all study participants, without attempts to maintain therapies based on the original randomization. Long-term posttrial observational follow-up of the blood glucose-lowering arm demonstrated sustained, and in some cases newly emerged, reductions in clinical events associated with original randomization to intensive glucose control (see also Chapter 13 ). These benefits were observed despite convergence of HbA1c values within a year of posttrial monitoring. Similarly, the BP difference achieved between randomized arms during the trial was no longer apparent within 2 years of the longer-term follow-up. However, unlike the blood glucose intervention, the significant reductions in clinical events were lost during the additional observational period, without the emergence of any new benefits. Long-term observational data are also available for the ADVANCE trial. With posttrial follow-up of 5.9 years in the ADVANCE cohort, between-group BP differences were no longer evident, and the hazard ratios in favor of routine BP lowering for the outcomes of all-case and CV death were still significant but attenuated.

Overall, notwithstanding post hoc subgroup analyses of ACCORDION, a reasonable interpretation of these findings is that BP reduction needs to be maintained for the long-term benefits of such treatment to continue.

Over the last 2 years, potential new drug classes specifically developed for BP lowering have emerged from early-phase clinical trials. There have also been some important developments in pharmacological management of hypertension related to the use of fixed dose combination therapies and “off-target” BP-lowering effects of newer treatments initially developed for blood glucose lowering or other cardiometabolic disease indications.

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