Journal of Hypertension:
Antihypertensive treatments in obese patients: the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial experience
Jordan, Jens; Engeli, Stefan
Institute of Clinical Pharmacology, Medical School, Hannover, Germany
Correspondence to Jens Jordan, MD, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: firstname.lastname@example.org www.mh-hannover.de/klinpharm.html
The majority of hypertensive patients are overweight or obese . The issue is clinically relevant for several reasons. First, obesity and arterial hypertension can be additive in terms of cardiovascular and metabolic risk. For example, obesity and arterial hypertension predispose a person to left ventricular hypertrophy. The risk is increased further in patients burdened by both risk factors. Second, obesity can cause or exacerbate arterial hypertension. In the third National Health and Nutrition Examination Survey hypertension risk was increased in overweight and more so in obese individuals . Third, blood pressure control is more difficult to achieve, and treatment-resistant arterial hypertension is an important problem in obese patients. The latter topic has been the focus of a recent joint scientific statement by the European Society of Hypertension and the European Association for the Study of Obesity in this Journal . Indeed, the average BMI in the recently published controlled trial of renal denervation for resistant hypertension (SIMPLICITY HTN-3) was 34 kg/m2. Approximately 75% of the patients featured a BMI 30 kg/m2 at least, which is the diagnostic cutoff value for obesity in Western societies. Similarly, in a trial testing electrical carotid sinus stimulation in patients with treatment-resistant arterial hypertension, the average BMI exceeded 32 kg/m2.
The European Society of Hypertension/European Society of Cardiology guidelines 2013 emphasize that obesity can affect cardiovascular risk and that BMI as well as waist circumference should be routinely measured . Waist circumference serves as surrogate marker for abdominal visceral fat mass. Once the diagnosis is made, clinicians are left with surprisingly little guidance on how to best achieve blood pressure control in their obese hypertensive patients. Although weight loss is often advocated in obese hypertensive patients, the evidence that this treatment ameliorates blood pressure in the long term is rather limited . In fact, weight loss through dietary, pharmacological, or surgical interventions has not been sufficiently tested in patients with more advanced stages of arterial hypertension. During the long-term follow-up, severely obese patients treated with bariatric surgery exhibited sustained body weight reductions without a long-term effect on the incidence of arterial hypertension . Moreover, an intense lifestyle intervention focusing on weight loss in patients with type 2 diabetes mellitus in the Look AHEAD (Action for Health in Diabetes) trial did not reduce the rate of cardiovascular events . The observation that aerobic exercise improved blood pressure in patients with treatment-resistant hypertension is nevertheless promising, although weight loss was not achieved in this study . Regarding the role of weight loss interventions in the management of obese hypertensive patients, the jury is still out.
Ultimately, most obese hypertensive patients require antihypertensive medications. Although the underlying pathophysiology of the hypertension may differ between lean and obese patients, current guidelines provide limited specific antihypertensive treatment recommendations for obese hypertensive patients. The main question when choosing antihypertensive medications in these patients is which treatment is more effective in lowering blood pressure? Could the medication affect cardiovascular or metabolic risks independently of blood pressure? Has the impact of such a treatment on hard endpoints been tested in outcome trials?
Given the limited number of clinical studies specifically assessing antihypertensive medications in obese individuals, post-hoc analysis of large-scale clinical trials is a useful approach. In this issue, Reisin et al. report data from a retrospective analysis of Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) data. ALLHAT enrolled 42 418 hypertensive patients age 55 years or older with at least one additional cardiovascular risk factor. Patients were randomized to treatment regimens based on chlorthalidone, amlodipine, or lisinopril and studied for approximately 5 years. A treatment arm with doxazosin was terminated early and not included in the present analysis. In patients whose blood pressure was not controlled on the assigned antihypertensive medication, open-label drugs were added. In the first step, atenolol, clonidine, or reserpine could be used. In the second step, hydralazine could be added.
To assess adiposity influences on treatment outcomes, the investigators stratified patients according to established BMI criteria in a normal weight, overweight, and obese group. In the event, approximately 80% of the patients were overweight or obese. At 5 years follow-up, two-thirds of the patients had their blood pressure controlled regardless of the BMI category. However, the number of drugs required to control blood pressure was greater in overweight and more so in obese patients, thereby, confirming earlier analyses of ALLHAT data and a real-life experience [1,12]. Chlorthalidone-based therapy was particularly efficacious in lowering blood pressure in all three BMI groups compared with the other treatment arms. The analysis of clinical endpoints according to BMI category and treatment assignment was particularly interesting. The analysis suggested a reduced coronary heart disease risk in obese patients on lisinopril compared with chlorthalidone-treated patients. Obese patients treated with amlodipine were at higher risk for end-stage renal disease compared with chlorthalidone-treated patients. However, these retrospective findings should be interpreted with caution.
The important information provided by the analyses of Reisin et al. is that obese hypertensive patients require more attention in the hypertension clinic and more antihypertensive medications. The good news is that good blood pressure control rates can be attained in these patients. However, in one-third of the patients blood pressure remained elevated despite antihypertensive treatment escalation. Although providing important insight, the analysis may not have a major impact on the choice of antihypertensive medications in obese hypertensive patients. In fact, drug combinations in ALLHAT do not reflect clinical practice in European countries. For example, in patients whose blood pressure is not controlled with angiotensin-converting enzyme inhibitors, most physicians would add calcium-channel blockers or thiazide-like diuretics rather than the second-line drugs applied in ALLHAT. In obese patients at risk for type 2 diabetes mellitus without a compelling indication, many experts would avoid the combination of thiazide diuretics and β-blockers. Limitations for the use of β-blockers are related to their potential negative effects on glucose metabolism and body weight . In the future, treatment recommendations should rely more on clinical trial data and less on expert opinion or wishful thinking. The observation that overweight and obesity may modulate the clinical outcome to antihypertensive medications strongly supports the idea .
Comprehensive cardiovascular risk management in an obese hypertensive patient requires more than the prescription of antihypertensive medications, particularly in patients with difficult-to-control blood pressure. Surprisingly, the question how to combine weight loss interventions and antihypertensive medications received little attention. Are there antihypertensive drugs that are more or less likely to interfere with weight loss? Are there synergistic or, perhaps, antagonistic interactions between weight loss and specific antihypertensive drug classes? Because many patients do not attain long-term reductions in body weight with dietary interventions with or without physical exercise, weight loss medications, or bariatric surgery could be tested for their additive effect on blood pressure in patients not sufficiently responding to lifestyle interventions. Compared with placebo, the intestinal lipase inhibitor orlistat, which is approved as weight loss drug, induced an additional 2.7 kg weight loss together with a 2.2-mmHg greater reduction in DBP . The phentermine and topiramate controlled-release combination is approved for weight loss in the United States as an adjunct to diet and lifestyle modification . In patients with hypertension, blood pressure decreased 4.9/3.9 mmHg in the placebo group, 6.9/5.2 mmHg with the lower phentermine/topiramate dose, and 9.1/5.8 mmHg with the higher phentermine/topiramate dose . Blood pressure reduction as well as weight loss are side-effects of some antidiabetic medications, particularly glucagon-like peptide 1 analogues , and sodium glucose transporter 2 inhibitors . We would like to see properly conducted hypertension trials incorporating these treatment modalities in the management of obese hypertensive patients. Given the sheer number of obese hypertensive patients, the associated excess cardiovascular and metabolic risk, and the difficulties in controlling blood pressure in these patients, such studies would address an important clinical question.
Conflicts of interest
There are no conflicts of interest.
1. Bramlage P, Pittrow D, Wittchen HU, Kirch W, Boehler S, Lehnert H, et al. Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am J Hypertens
2. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA
3. Jordan J, Yumuk V, Schlaich M, Nilsson PM, Zahorska-Markiewicz B, Grassi G, et al. Joint statement of the European Association for the Study of Obesity and the European Society of Hypertension: obesity and difficult to treat arterial hypertension. J Hypertens
4. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med
5. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol
6. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens
7. Straznicky N, Grassi G, Esler M, Lambert G, Dixon J, Lambert E, et al. European Society of Hypertension Working Group on Obesity antihypertensive effects of weight loss: myth or reality? J Hypertens
8. Sjostrom CD, Peltonen M, Wedel H, Sjostrom L. Differentiated long-term effects of intentional weight loss on diabetes and hypertension. Hypertension
9. Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med
10. Dimeo F, Pagonas N, Seibert F, Arndt R, Zidek W, Westhoff TH. Aerobic exercise reduces blood pressure in resistant hypertension. Hypertension
11. Reisin E, Graves JW, Yamal J-M, Barzilay JI, Pressel SL, Einhorn PT, et al. Blood pressure control and cardiovascular outcomes in normal-weight, overweight, and obese hypertensive patients treated with three different antihypertensives in ALLHAT. J Hypertens
12. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich)
13. Sharma AM, Pischon T, Hardt S, Kunz I, Luft FC. Hypothesis: beta-adrenergic receptor blockers and weight gain: a systematic analysis. Hypertension
14. Bakris G, Calhoun D, Egan B, Hellmann C, Dolker M, Kingma I. Orlistat improves blood pressure control in obese subjects with treated but inadequately controlled hypertension. J Hypertens
15. Jordan J, Astrup A, Engeli S, Narkiewicz K, Day WW, Finer N. Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity. J Hypertens
16. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet
17. Katout M, Zhu H, Rutsky J, Shah P, Brook RD, Zhong J, et al. Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression. Am J Hypertens
18. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: A systematic review and meta-analysis. J Am Soc Hypertens
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