Clinical effectiveness of amlodipine/indapamide/perindopril fixed-dose combination in patients with metabolic disorders: results of post hoc analyzes of the TRICOLOR study

Aim. To describe antihypertensive effectiveness of triple fixed-dose combination of am lo dipine/indapamide/perindopril and assess predictors of its clinical effectiveness in pati ents depending on body mass index (BMI) and presence of type 2 diabetes (T2D).

Material and methods. This observational prospective study TRICOLOR (NCT03722524) (n=1247) demonstrated high antihypertensive effectiveness and good tolerability of amlodipine/indapamide/perindopril fixed-dose combination. Subgroup analyzes based on BMI included data from 1144 patients. In a second subgroup analysis, 1128 patients were stratified according to concomitant T2D.

Results. In patients with overweight/obesity and diabetes, good antihypertensive effectiveness of amlodipine/indapamide/perindopril was observed, comparable in blood pressure (BP) reduction with the comparison groups (patients with normal BMI and patients without diabetes). At the same time, patients with normal BMI, compared with patients with overweight and obesity, had significantly lower systolic BP (SBP) (after 4 and 12 weeks) and diastolic BP (DBP) (after 2 and 12 weeks). In the subgroups, depending on the diabetes status, there were no significant differences in the decrease in SBP and DBP levels at all follow-up points. By the 12th week, BP decrease in the group of patients with normal BMI was 32,9 (10,5)/15,3 (8,6) mm Hg, in the group with overweight — 33,2 (11,3)/14,2 (8,5) mm Hg, in the obesity group — 33,9 (12,3)/14,1 (8,8) mm Hg (p>0,05 for intergroup comparison). Target BP <140/90 mm Hg already after 2 weeks of therapy achieved a higher number of patients with a normal BMI compared to overweight group (50,8% vs 37,2%, p=0,009). By the 12th week, the vast majority of patients, regardless of BMI and diabetes status, achieved a target BP <140/90 mm Hg, which demonstrates a good and rapid response to triple fixed-dose therapy.

Conclusion. Thus, additional analyzes of the TRICOLOR study demonstrate the high antihypertensive effectiveness of amlodipine/indapamide/perindopril in hypertensive patients, regardless of the presence of diabetes, overweight or obesity.

1. NCD Risk Factor Collaboration (NCD­RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population­ representative studies with 104 million participants. Lancet. 2021; 398(10304):957­80. doi:10.1016/S0140­6736(21)01330­1. Erratm in: Lancet. 2022; 399(10324):520.

2. Balanova YuA, Drapkina OM, Kutsenko VA, et al. Hypertension in the Russian population during the COVID­19 pandemic: sex differences in prevalence, treatment and its effectiveness. Data from the ESSE­RF3 study. Cardiovascular Therapy and Prevention. 2023;22(8S):3785. (In Russ.) doi:10.15829/1728­8800­2023­3785.

3. Tanaka M, Itoh H. Hypertension as a Metabolic Disorder and the Novel Role of the Gut. Curr Hypertens Rep. 2019;21(8):63. doi:10.1007/s11906­019­0964­5.

4. Balanova YuA, Drapkina OM, Kutsenko VA, et al. Obesity in the Russian population during the COVID­19 pandemic and associated factors. Data from the ESSE­RF3 study. Cardiovascular Therapy and Prevention. 2023;22(8S):3793. (In Russ.) doi:10.15829/1728­8800­2023­3793.

5. Harsha DW, Bray GA. Weight Loss and Blood Pressure Control (Pro). Hypertension. 2008;51:1420­5. doi:10.1161/HYPERTENSIONAHA.107.09411.

6. Kotchen TA. Obesity­ related hypertension: epidemiology, pathophysiology, and clinical management. Am J Hypertens. 2010;23(11):1170­8. doi:10.1038/ajh.2010.172.

7. Przezak A, Bielka W, Pawlik A. Hypertension and Type 2 Diabetes — The Novel Treatment Possibilities. Int. J. Mol. Sci. 2022;23(12):6500. doi:10.3390/ijms23126500.

8. Expert panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med. 1998;158(17):1855­6. doi:10.1001/archinte.158.17.1855.

9. Whitlock G, Lewington S, Sherliker P, et al. Body­mass index and cause­ specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373(9669):1083­96. doi:10.1016/S0140­6736(09)60318­4.

10. Zou ZY, Yang YD, Wang S, et al. The importance of blood lipids in the association between BMI and blood pressure among Chinese overweight and obese children. Br J Nutr. 2016;116(1):45­51. doi:10.1017/S0007114516001744.

11. Chen Z, Smith M, Du H, et al. Blood pressure in relation to general and central adiposity among 5,00,000 adult Chinese men and women. Int J Epidemiol. 2015;44(4):1305­19. doi:10.1093/ije/dyv012.

12. Ninomiya T, Kubo M, Doi Y, et al. Impact of metabolic syndrome on the development of cardiovascular disease in a general Japanese population: The Hisayama study. Stroke. 2007;38:2063­9. doi:10.1161/STROKEAHA.106.479642.

13. Chen G, McAlister FA, Walker RL, et al. Cardiovascular outcomes in framingham participants with diabetes: The importance of blood pressure. Hypertension. 2011;57:8917. doi:10.1161/HYPERTENSIONAHA.110.162446.

14. Ndumele CE, Rangaswami J, Chow SL, et al.; American Heart Association. Cardiovascular­ Kidney­ Metabolic Health: A Presidential Advisory From the American Heart As socia tion. Circulation. 2023;148(20):1606­35. doi:10.1161/CIR.0000000000001184.

15. Karpov YuA, Gorbunov VM, Logunova NA. Triple fixed­dose combination in the treatment of hypertension: the results of the Russian observational study TRICOLOR. Russian Journal of Cardiology. 2020;25(10):4130. (In Russ.) doi:10.15829/1560­4071­2020­4130.

16. Messerli FH, Bangalore S, Schmieder RE. Wilder's principle: pre­treatment value determines post­treatment response. Eur Heart J. 2015;36(9):576­9. doi:10.1093/eurheartj/ehu467.

17. Kario K, Saito I, Kushiro T, et al. Persistent olmesartan­ based blood pressure— lowering effects on morning hypertension in Asians: the HONEST study. Hypertens Res. 2016;39:334­41. doi:10.1038/hr.2015.148.

18. Hu H, Zhang J, Wang Y, et al. Impact of baseline blood pressure on the magnitude of blood pressure lowering by nifedipine gastrointestinal therapeutic system: refreshing the Wilder's principle. Drug Des Devel Ther. 2017;11:3179­86. doi:10.2147/DDDT.S143551.

19. Barras M, Legg A. Drug dosing in obese adults. Aust Prescr. 2017;40(5):189­93. doi:10.18773/austprescr.2017.053.

20. Grassi G, Biffi A, Seravalle G, et al. Sympathetic Neural Overdrive in the Obese and Overweight State. Hypertension. 2019;74(2):349­58. doi:10.1161/HYPERTENSIONAHA.119.12885.

21. Lasserson DS, Buclin T, Glasziou P. How quickly should we titrate antihypertensive medication? Systematic review modelling blood pressure response from trial data. Heart. 2011;97(21):1771­5. doi:10.1136/hrt.2010.221473.

22. Ionov M, Zvartau N, Semakova A, et al. Response rate and patients' characteristics associated with effective antihypertensive monotherapy. Journal of Hypertension. 2019;37():p e105. doi:10.1097/01.hjh.0000571352.43815.03.

23. Bramlage P, Pittrow D, Wittchen HU, et al. Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am J Hypertens. 2004;17(10):90410. doi:10.1016/j.amjhyper.2004.05.017.

24. Fink JT, Magnan EM, Johnson HM, et al. Blood Pressure Control and Other Quality of Care Metrics for Patients with Obesity and Diabetes: A Population­ Based Cohort Study. High Blood Press Cardiovasc Prev. 2018;25(4):391­9. doi:10.1007/s40292­018­0284­x.

25. Larina VN, Fedorova EV, Mikhailusova MP, Golovko MG. Problems of insufficient control of target blood pressure levels in the outpatient practice. Terapevticheskii Arkhiv (Ter. Arkh.). 2021;93(1):7­14. (In Russ.) doi:10.26442/00403660.2021.01.200586.

26. Raji A, Seely EW, Bekins SA, et al. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care. 2003;26:172­8.

27. St John Sutton M, Rendell M, Dandona P, et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care. 2002;25(11):2058­64. doi:10.2337/diacare.25.11.2058.

28. Duggirala M, Cuddihy R, Cuddihy M, et al. Predictors of Blood Pressure Control in Patients With Diabetes and Hypertension Seen in Primary Care Clinics. American Journal of Hypertension. 2005;18(6):833­8. doi:10.1016/j.amjhyper.2004.12.016.

29. Fortuna RJ, Nagel AK, Rocco TA, et al. Patient experience with care and its association with adherence to hypertension medications. Am J Hypertens. 2017;31(3):340­5. doi:10.1093/ajh/hpx200.

30. Jankowska­ Polańska B, Świątoniowska­ Lonc N, Karniej P, et al. Influential factors in adherence to the therapeutic regime in patients with type 2 diabetes and hypertension. Diabetes Research and Clinical Practice. 2021;173:108693. doi:10.1016/j.diabres.2021.108693.

31. Daniel AC, Veiga EV. Factors that interfere the medication compliance in hypertensive patients. Einstein (Sao Paulo). 2013;11(3):331­7. doi:10.1590/s1679­45082013000300012.

32. Karakurt P, Kasikci M. Factors affecting medication adherence in patients with hypertension. J Vasc Nurs. 2012;30(4):118­26. doi:10.1016/j.jvn.2012.04.002.

33. Tibebu A, Mengistu D, Bulto LN. Adherence to prescribed antihypertensive medications and associated factors for hypertensive patients attending chronic follow­up units of selected public hospitals in Addis Ababa, Ethiopia. Int J Health Sci (Qassim). 2017;11(4):47­52.

34. Tilea I, Petra D, Voidazan S, et al. Treatment adherence among adult hypertensive patients: a cross­ sectional retrospective study in primary care in Romania. Patient Prefer Adherence. 2018;12:625­35. doi:10.2147/PPA.S162965.

35. Boytsov SA, Karpov YuA, Logunova NA, et al. Ways to increase adherence to antihypertensive therapy. Russian Journal of Cardiology. 2022;27(9):5202. (In Russ.) doi:10.15829/1560­4071­2022­5202.

36. Karpov YuA, Logunova NA, Kvasnikov BB, Khomitskaya YuV. New data from a subanalysis of the TRICOLOR study: antihypertensive effectiveness of the triple single­pill combina tion of amlodipine/indapamide/perindopril and predictors of effectiveness and blood pressure control in young patients. Russian Journal of Cardiology. 2023;28(10):5597. (In Russ.) doi:10.15829/1560­40712023­5597.

37. Burnier M, Polychronopoulou E, Wuerzner G. Hypertension and Drug Adherence in the Elderly. Front. Cardiovasc. Med. 2020;7:49. doi:10.3389/fcvm.2020.00049.

38. Johnson HM, Warner RC, Bartels CM, LaMantia JN. "They're younger... it's harder." Primary providers' perspectives on hypertension management in young adults: a multicenter qualitative study. BMC Res Notes. 2017;10:9. doi:10.1186/s13104­016­2332­8.

39. Hill M, Houston N. Adherence to antihypertensive therapy. Chapter. 2002;131:390­2.

40. Abegaz TM, Shehab A, Gebreyohannes EA, et al. Nonadherence to antihypertensive drugs: A systematic review and meta­analysis. Medicine (Baltimore). 2017;96(4):e5641. doi:10.1097/MD.0000000000005641.

41. Chapman RH. Predictors of Adherence With Antihypertensive and Lipid­Lowering Therapy. Archives of Internal Medicine. 2005;165(10):1147­52. doi:10.1001/archinte.165.10.