This post hoc analysis of the FORSAGE study provides important data on the cardiovascular risk profile of patients treated for hypertension in routine clinical practice in the Russian Federation by BMI category, and the influence that this may have on treatment efficacy. There was a higher incidence of concomitant diseases associated with the metabolic syndrome among overweight and obese participants, including diabetes mellitus, higher BP levels, serum cholesterol and creatinine, and lower GFR. When patients with BP uncontrolled on their previous antihypertensive regimen were switched to perindopril arginine/indapamide SPC, statistically significant reductions in BP and higher rates of target BP achievement were observed in all BMI groups. At M3, over 70% of patients treated with the SPC had achieved target BP, including overweight and obese subjects who had the highest BP at baseline.
Worldwide, nearly a third of the population is now classified as overweight or obese . In the current study, 48.7% of patients had a BMI in the overweight range, while 34.7% were obese. Similar findings have been observed in a recent large epidemiological study from the Russian Federation, where the prevalence of BMI-defined obesity was estimated as 33.4% . In addition to hypertension, overweight is associated with multiple CVD risk factors, including hypercholesterolemia, diabetes, and metabolic syndrome. Pooled data from a number of US longitudinal population-based cohort studies have been used to estimate lifetime risk estimates of CVD by weight status . The results showed that overweight and obesity were associated with earlier onset of CVD, and a greater proportion of life lived with CVD morbidity. Obesity was additionally associated with shorter overall survival compared with adults with normal BMI.
The FORSAGE findings are in line with previously reported studies. The Global Cardiometabolic Risk Profile in patients with Hypertension Disease (GOOD) survey, which included 3370 patients from 12 European countries, showed that patients with uncontrolled BP had a higher BMI, greater waist circumference, and other impaired metabolic parameters (increased fasting plasma glucose, total cholesterol, and triglyceride levels), as well as lower levels of high-density lipoprotein (HDL) cholesterol in women . In the GOOD survey, the prevalence of metabolic syndrome (ATP III criteria) was significantly higher in patients with uncontrolled versus controlled BP (66.5 vs. 35.5%, respectively). Multivariate analysis revealed that the metabolic syndrome was associated with a 2.6-fold greater likelihood of poor BP control . Further analysis of the GOOD survey reported that it was the visceral obesity and dyslipidemia components of the metabolic syndrome that were associated with the poor response to antihypertensive treatment and not impaired glucose tolerance .
Regardless of BMI group, switching from previous therapy with ACEI, ARB, and diuretics to SPC perindopril arginine/indapamide at full dose (10 mg/2.5 mg) was associated with statistically significant decreases in BP and higher rates of target BP achievement (despite the fact that most patients had been receiving combination therapy including renin–angiotensin–aldosterone system (RAAS) inhibitors and diuretics at baseline). However, although the overall proportion of patients achieving target BP was quite high (70–80%), fewer obese subjects achieved target BP compared with subjects in the overweight and normal BMI groups at all study time points.
The reduced efficacy of antihypertensive therapy in obese subjects may relate to the fact that hypertension in these individuals has different pathogenetic features . In people with obesity, the kidneys are subject to outer compression by intra-abdominal adipose tissue and increased intra-abdominal pressure, as well as inner compression of renal medullary sinuses by penetrating adipose tissue and increased intrarenal tissue compression. The result is impaired blood supply to the kidneys and subsequent activation of the renin–angiotensin and sympathetic nervous systems . The adipose tissue itself also plays an important role in the activation of RAAS. Individual adipocytes have all the components of the RAAS, and an accumulation of fat mass leads to an increase in angiotensinogen followed by increased angiotensin II levels, higher expression of angiotensin II type 1 receptors, and aldosterone production. This causes a significant change in the structural and functional state of the cardiovascular system (left ventricular hypertrophy, vascular remodeling, and endothelial dysfunction) on the one hand, and an increase in salt sensitivity and an increase in the reabsorption of sodium and fluid on the other, with a resultant increase in fluid volume .
Adipocytes are hormonally active cells that trigger the production of leptin, adipsin, adiponectin, and proinflammatory cytokines (TNF-α, interleukins, transforming growth factor-β, and monocyte chemoattractant protein 1), and the release of fatty acids . The fasting level of leptin secreted by adipocytes becomes higher with increased grade of obesity. At the same time, leptin increases the activity of the sympathetic nervous system, particularly in the kidneys. The consequences of sustained sympathetic overdrive include increases in cardiac output and heart rate, tubular reabsorption of sodium, and intravascular blood volume . The combination of perindopril and indapamide therefore acts on the major mechanisms involved in obesity-related hypertension: adipocyte-associated RAAS activation (inhibited by perindopril) and distal tubule sodium reabsorption (blocked by indapamide).
Greater attention is now also being paid to the association between oxidative stress and hypertension in obese patients. Oxidative stress and increased production of reactive oxygen species in glomerular podocytes, endothelial cells, and mesangial cells are known to lead to the development and progression of kidney damage in metabolic disorders . Increased arterial stiffness and early return of reflected waves represent a rise in central systolic BP, a drop in diastolic BP, and an increase in pulse pressure, and mediate at least some of the effects of CKD on cardiac function . Arterial stiffness can be improved by a few classes of antihypertensive drugs, such as ACEI, ARB, and direct renin inhibitors. These are able to reduce arterial stiffness independently of BP changes, which may explain the effectiveness of the fixed-dose combination of perindopril/indapamide in this category of patient. It was noted that the incidence of glomerulopathy associated with obesity increased tenfold between 1986 and 2000 . Obesity is considered to be a powerful factor in the initiation and progression of chronic kidney disease [22, 23]. Importantly, in the FORSAGE study, perindopril/indapamide treatment was not associated with acute increases in serum creatinine or a sudden decline in GFR. The combination was well tolerated, with adverse events in line with those reported in previous studies in a variety of patient groups [24,25,26].
The complex pathogenesis of obesity-related hypertension highlights the need for specific pharmacological recommendations in the form of combination antihypertensive therapy . Subgroup analysis of obese patients from the large randomized ASCOT BPLA (Anglo-Scandinavian Cardiac Outcomes Trial, Blood Pressure Lowering Arm) trial, suggests that drugs such as thiazide diuretics and ACEI are superior for preventing cardiovascular events in obesity-related hypertension , and it has been suggested that this combination should be considered as first-line antihypertensive drug therapy in obesity . In the FORSAGE study, patients were initially receiving combination therapy, but it is likely that the specific components of the combination therapy regimen may provide an explanation for the differences in the efficacy of treatment.
No significant difference was observed between the mean number of drugs taken by patients with normal BMI (3.9) and by overweight subjects (4.1), but obese patients were using statistically more drug classes (4.4; P = 0.0001). The proportion of patients taking CCB was low (13.4, 16.1, and 16.1% in the normal, overweight, and obese BMI groups, respectively), and as these numbers did not change during the study, CCB use could not have influenced the antihypertensive effect.
There is evidence that perindopril leads to a more pronounced decrease in BP than other ACEI in most patients  and greater BP-lowering effect than with the ARB, particularly in obesity . In patients with a large number of cardiovascular risk factors such as in the current study, the effect of perindopril is reported to be even more pronounced . Perindopril, in contrast to ARB such as losartan, also increases insulin sensitivity in overweight patients . Furthermore, recent data indicate that a fixed combination of perindopril and indapamide not only leads to a decrease in BP in patient groups achieving and not achieving target BP on preceding therapy, but also to decreases in leptin levels of 14.4 and 10.0%, and high-sensitivity C-reactive protein by 17.7 and 11.0%, and an increase in adiponectin levels of 6.7 and 9.9%, respectively (P < 0.01) .
The switch to a perindopril/indapamide SPC led to an increase in the number of patients taking a diuretic, a required and pathogenetically substantiated component of treatment for obesity-related hypertension. The observed beneficial effect with the perindopril/indapamide SPC may also be partially explained by the replacement of hydrochlorothiazide, which is often used for the treatment of hypertension, with indapamide. Indapamide is considered a preferred drug for obesity-related hypertension because of its marked antihypertensive effect, as well as multiple organ-protective properties [16,17,18, 33].
Given the increasing rates of overweight and obesity, substantial improvements in CVD risk factor treatment and control rates among obese individuals are needed to prevent future cardiovascular events. Weight loss remains important in patients with obesity-associated hypertension to reduce circulating leptin, decrease sympathetic activation, and improve BP and other risk factors, but weight loss as a result of lifestyle changes is often modest and difficult to maintain. When treating people with obesity, careful attention should be paid to the selection of appropriate antihypertensive therapy. The current study suggests that this should more systematically be brought to the attention of physicians, as in clinical practice, BMI levels in the overweight or obese range appear to have little impact on the type of antihypertensive drugs prescribed. There is currently a lack of clinical trial data evaluating interventions in obese subgroups to determine whether obesity-specific treatments would result in decreased CVD outcomes. No specific recommendations for high BP management in patients with excess weight are discussed in international guidelines, and until the results of randomized clinical trials become available, observational studies such as FORSAGE will continue to inform physicians on the optimal management of their patients.
In addition to the limitations regarding the study design (open-label, observational, non-randomized, lack of control group) and post hoc analysis, limitations of the study include the fact that adherence was not assessed in the post hoc analysis, and LVH measurement techniques were not unified. Only descriptive statistics were used, and there was no calculation of sample size. In addition, as the study reflected routine clinical practice, patients could receive concomitant therapy, which may have introduced bias.