Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Fast track – ISH2022 KYOTO
  • Published:

Reduced efficacy of blood pressure lowering drugs in the presence of diabetes mellitus—results from the TRIUMPH randomised controlled trial

Hypertension Research volume 46, pages 128–135 (2023)Cite this article

Abstract

We investigated whether diabetes mellitus (DM) affects the efficacy of a low-dose triple combination pill and usual care among people with mild-moderate hypertension. TRIUMPH (TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension) was a randomised controlled open-label trial of patients requiring initiation or escalation of antihypertensive therapy. Patients were randomised to a once-daily low-dose triple combination polypill (telmisartan-20mg/amlodipine-2.5 mg/chlorthalidone-12.5 mg) or usual care. This analysis compared BP reduction in people with and without DM, both in the intervention and control groups over 24-week follow-up. Predicted efficacy of prescribed therapy was calculated (estimation methods of Law et al.). The trial randomised 700 patients (56 ± 11 yrs, 31% DM). There was no difference in the number of drugs prescribed or predicted efficacy of therapy between people with DM and without DM. However, the observed BP reduction from baseline to week 24 was lower in those with DM compared to non-diabetics in both the triple pill (25/11 vs 31/15 mmHg, p ≤ 0.01) and usual care (17/7 vs 22/11 mmHg, p ≤ 0.01) groups, and these differences remained after multivariable adjustment. DM was a negative predictor of change in BP (β-coefficient −0.08, p = 0.02). In conclusion, patients with DM experienced reduced efficacy of BP lowering therapies as compared to patients without DM, irrespective of the type of BP lowering therapy received.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

Data availability

The data underlying this article are available in the article and in its online supplementary material.

References

  1. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434–44.

    Article  Google Scholar 

  2. Action to Control Cardiovascular Risk in Diabetes Study Group GH, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    Article  Google Scholar 

  3. Fox CS, Golden SH, Anderson C, Bray GA, Burke LE, de Boer IH, et al. American heart association diabetes committee of the council on lifestyle and cardiometabolic health; council on clinical cardiology, council on cardiovascular and stroke nursing, council on cardiovascular surgery and anesthesia, council on quality of care and outcomes research; American diabetes association. update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American heart association and the American diabetes association. Diabetes Care. 2015;38:1777–803.

    Article  Google Scholar 

  4. DeStefano F, Ford ES, Newman J, Stevenson JM, Wetterhall SF, Anda RF, et al. Risk factors for coronary heart disease mortality among persons with diabetes. Ann Epidemiol. 1993;3:27–34.

    Article  Google Scholar 

  5. Emerging Risk Factors Collaboration, Sarwar NGP, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–22.

    Article  Google Scholar 

  6. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK prospective diabetes study group. BMJ. 1998;317:703–13.

    Article  Google Scholar 

  7. Deedwania P. Diabetes and hypertension, the deadly duet: importance, therapeutic strategy, and selection of drug therapy. Cardiol Clin. 2005;23:139–52.

    Article  Google Scholar 

  8. Brown MJ, Castaigne A, de Leeuw PW, Mancia G, Palmer CR, Rosenthal T, et al. Influence of diabetes and type of hypertension on response to antihypertensive treatment. Hypertension. 2000;35:1038–42.

    Article  Google Scholar 

  9. Patel A, ADVANCE Collaborative Group, MacMahon S, Chalmers J, Neal B, Woodward M, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829–40.

    Article  Google Scholar 

  10. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A, et al. Blood pressure lowering in type 2 diabetes: A systematic review and meta-analysis. JAMA. 2015;313:603–15.

    Article  Google Scholar 

  11. Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, et al. HOT Study Group.Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755–62.

    Article  Google Scholar 

  12. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2018;71:2199–269.

    Article  Google Scholar 

  13. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J. 2018;39:3021–104.

    Article  Google Scholar 

  14. Webster R, Salem A, de Silva HA, Selak V, Stepien S, Rajapakse S, et al. TRIUMPH study group. fixed low-dose triple combination antihypertensive medication vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: a randomized clinical trial. JAMA. 2018;320:566–79.

    Article  Google Scholar 

  15. Gnanenthiran SR, Wang N, Di Tanna GL, Salam A, Webster R, De Silva HA, et al. Association of low-dose triple combination therapy vs usual care with time at target blood pressure: a secondary analysis of the TRIUMPH randomized clinical trial. JAMA Cardiol. 2022;7:645–50.

    Article  Google Scholar 

  16. Law M, Morris JK, Wald N. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:1–19.

    Article  Google Scholar 

  17. Blood Pressure Lowering Treatment Triallists Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus. Arch Intern Med. 2005;165:1410–9.

    Article  Google Scholar 

  18. Sung KC, Oh YS, Cha DH, Hong SJ, Won KH, Yoo KD, et al. Efficacy and tolerability of telmisartan/amlodipine + hydrochlorothiazide versus telmisartan/amlodipine combination therapy for essential hypertension uncontrolled with telmisartan/amlodipine: the phase III, multicenter, randomized, double-blind TAHYTI study. Clin Ther. 2018;40:50–63.e53.

    Article  Google Scholar 

  19. Doménech M, Coca A. Role of triple fixed combination valsartan, amlodipine and hydrochlorothiazide in controlling blood pressure. Patient Prefer Adherence. 2010;4:105–13.

    Google Scholar 

  20. Giacchetti G, Sechi LA, Rilli S, Carey RM. The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends Endocrinol Metab. 2005;16:120–6.

    Article  Google Scholar 

  21. Simonson DC. Etiology and prevalence of hypertension in diabetic patients. Diabetes Care. 1988;11:821–7.

    Article  Google Scholar 

  22. Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DA. Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension. Circulation. 2003;108:3097–101.

    Article  Google Scholar 

  23. Eguchi K, Pickering TG, Kario K. Why is blood pressure so hard to control in patients with type 2 diabetes? J Cardiometab Syndr. 2007;2:114–8.

    Article  Google Scholar 

  24. Wong WT, Tian XY, Huang Y. Endothelial dysfunction in diabetes and hypertension: cross talk in RAS, BMP4, and ROS-dependent COX-2-derived prostanoids. J Cardiovasc Pharm. 2013;61:204–14.

    Article  Google Scholar 

  25. Reichmuth KJ, Austin D, Skatrud JB, Young T. Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med. 2005;172:1590–5.

    Article  Google Scholar 

  26. Sawicki P, Kaiser S, Heinemann L, Frenzel H, Berger M. Prevalence of renal artery stenosis in diabetes mellitus-an autopsy study. J Intern Med. 1991;229:489–92.

    Article  Google Scholar 

  27. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: An integrated index of vascular function? Circulation. 2002;106:2085–90.

    Article  Google Scholar 

  28. American Diabetes Association Professional Practice Committee; American Diabetes Association Professional Practice Committee, Aroda DB, Bakris VR, Benson G, Brown G, Freeman FM, et al. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2022. Diabetes Care. 2022;45:S144–74.

    Article  Google Scholar 

  29. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ (Clin Res Ed). 2003;326:1427.

    Article  Google Scholar 

Download references

Acknowledgements

The data and safety monitoring committee chair was Neil Poulter, FRCP (Imperial College, London, England). The other members of the committee were Chris Reid, PhD (Curtin University, Perth, Australia), and Nikhil Tandon, FRCP (All India Institute of Medical Sciences, New Delhi). The data and safety monitoring committee was not compensated for its work. Jayanthi Mysore and Sandrine Stepien provided statistical support and were compensated as part of their salaries (The George Institute for Global Health). Site management was provided by RemediumOne, which coordinated project execution and data collection. George Clinical (Bangalore, India) provided project management, monitoring, and data management services.

The TRIUMPH Study Group

Keshinie Samarasekara7, Chiranthi Kongala Liyanage7, Verni Sopan7, Wasantha Kumara7, Hansika Pathirana7, Lumbini Perera7, Manisha Somasiri7, Aruna Wijesinghe7, Jayamini Jayantha7, Sonali Liyanagamage7, Muditha de Silva7, Chandika Jayawardena7, Dilini Karunarathna7, Mitrakrishnan Rayno Navinan7, Zumra Shukri7, Charitha Herath7, Nadeeja Seneviratne7, Amila Isurangana7, Zulaiha Liyakath7, Thamal Dasitha7, Gerald Rajakulenthiran7, Aaisha Azam7, Chandika Jayawardena7, Manori Jayawardena7, Vinodhan Sunderalingam7, Milinda Withana7, Anushiya Annaraja7, Keshini Soza7, Dulani Dasanayake7, Keshini Soza7, Dhanushka de Silva7, Shakoor Niyasdeen7, Uthpala Chandradeva8, Safiya Fathima8, Aruna Jayawardana8, Ranasinghe Chathurika9, Manik de Mel9, Tharini Mendis9, Saumya Withanage9, Kandula Pieris9, Manik de Mel9, Gayathri Fernando9, Chamila Mettanda9, Saumya Withanage9, Kandula Pieris9, Eshani de Silva10, Imali Wijerathna10, Jeevaraj Thanushanthan11, Devaki Dharmawardena11, Shehan Gnanapragasam11, Shalomi Weerawardena11, Matheesha Suduwelikandage11, Ingrid de Silva11, Sachini Wathsala11, Ruchiranga Ekanayaka11, Anuradha Dahanayaka11, Vindhya Fernando11, Lakmal Jayaweera11, Namal Wijesinghe11, Murali Dhakshinamurthy12, Ullas Arabhavi12, Harish Sankarankutty12, Mohammed Muddaseer12, Sarath Gudivada12, Aditi Moitra12, Ayesha Tazeen12, Karuna Acharya12, Prakash Velappan12, Ambika Yoganathan12, Vipin Jose12

Funding

The study was funded by grants from the Australian National Health and Medical Research Council (NHMRC) Global Alliance for Chronic Disease programme and National Health and Medical Research Council programme grant [grants APP1041052, APP1052555]. The funding sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia

    Sonali R. Gnanenthiran, Ruth Webster, Aletta E. Schutte, Anushka Patel & Anthony Rodgers

  2. School of Population Health, UNSW, Sydney, Australia

    Ruth Webster

  3. Clinical Trials Unit, Department of Pharmacology, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka

    Asita de Silva

  4. The George Institute for Global Health, Hyderabad, India

    Pallab K. Maulik & Abdul Salam

  5. Department of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand

    Vanessa Selak

  6. Department of Population Medicine and Lifestyle Diseases Prevention, Faculty of Medicine with the Division of Dentistry and Division of Medical Education in English, Medical University of Bialystok, Bialystok, Poland

    Rama K. Guggilla

  7. National Hospital, Colombo, Sri Lanka

    Keshinie Samarasekara, Chiranthi Kongala Liyanage, Verni Sopan, Wasantha Kumara, Hansika Pathirana, Lumbini Perera, Manisha Somasiri, Aruna Wijesinghe, Jayamini Jayantha, Sonali Liyanagamage, Muditha de Silva, Chandika Jayawardena, Dilini Karunarathna, Mitrakrishnan Rayno Navinan, Zumra Shukri, Charitha Herath, Nadeeja Seneviratne, Amila Isurangana, Zulaiha Liyakath, Thamal Dasitha, Gerald Rajakulenthiran, Aaisha Azam, Manori Jayawardena, Vinodhan Sunderalingam, Milinda Withana, Anushiya Annaraja, Keshini Soza, Dulani Dasanayake, Dhanushka de Silva & Shakoor Niyasdeen

  8. Colombo South Teaching Hospital, Colombo, Sri Lanka

    Uthpala Chandradeva, Safiya Fathima & Aruna Jayawardana

  9. Colombo North Teaching Hospital, Colombo, Sri Lanka

    Ranasinghe Chathurika, Manik de Mel, Tharini Mendis, Saumya Withanage, Kandula Pieris, Gayathri Fernando & Chamila Mettanda

  10. Sri Jayawardenapura General Hospital, Nugegoda, Sri Lanka

    Eshani de Silva & Imali Wijerathna

  11. RemediumOne, Colombo, Sri Lanka

    Jeevaraj Thanushanthan, Devaki Dharmawardena, Shehan Gnanapragasam, Shalomi Weerawardena, Matheesha Suduwelikandage, Ingrid de Silva, Sachini Wathsala, Ruchiranga Ekanayaka, Anuradha Dahanayaka, Vindhya Fernando, Lakmal Jayaweera & Namal Wijesinghe

  12. George Clinical, Bangalore, India

    Murali Dhakshinamurthy, Ullas Arabhavi, Harish Sankarankutty, Mohammed Muddaseer, Sarath Gudivada, Aditi Moitra, Ayesha Tazeen, Karuna Acharya, Prakash Velappan, Ambika Yoganathan & Vipin Jose

Authors
  1. Sonali R. Gnanenthiran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruth Webster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Asita de Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pallab K. Maulik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdul Salam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vanessa Selak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rama K. Guggilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aletta E. Schutte
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anushka Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anthony Rodgers
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the TRIUMPH Study Group

  • Keshinie Samarasekara
  • , Chiranthi Kongala Liyanage
  • , Verni Sopan
  • , Wasantha Kumara
  • , Hansika Pathirana
  • , Lumbini Perera
  • , Manisha Somasiri
  • , Aruna Wijesinghe
  • , Jayamini Jayantha
  • , Sonali Liyanagamage
  • , Muditha de Silva
  • , Chandika Jayawardena
  • , Dilini Karunarathna
  • , Mitrakrishnan Rayno Navinan
  • , Zumra Shukri
  • , Charitha Herath
  • , Nadeeja Seneviratne
  • , Amila Isurangana
  • , Zulaiha Liyakath
  • , Thamal Dasitha
  • , Gerald Rajakulenthiran
  • , Aaisha Azam
  • , Chandika Jayawardena
  • , Manori Jayawardena
  • , Vinodhan Sunderalingam
  • , Milinda Withana
  • , Anushiya Annaraja
  • , Keshini Soza
  • , Dulani Dasanayake
  • , Keshini Soza
  • , Dhanushka de Silva
  • , Shakoor Niyasdeen
  • , Uthpala Chandradeva
  • , Safiya Fathima
  • , Aruna Jayawardana
  • , Ranasinghe Chathurika
  • , Manik de Mel
  • , Tharini Mendis
  • , Saumya Withanage
  • , Kandula Pieris
  • , Manik de Mel
  • , Gayathri Fernando
  • , Chamila Mettanda
  • , Saumya Withanage
  • , Kandula Pieris
  • , Eshani de Silva
  • , Imali Wijerathna
  • , Jeevaraj Thanushanthan
  • , Devaki Dharmawardena
  • , Shehan Gnanapragasam
  • , Shalomi Weerawardena
  • , Matheesha Suduwelikandage
  • , Ingrid de Silva
  • , Sachini Wathsala
  • , Ruchiranga Ekanayaka
  • , Anuradha Dahanayaka
  • , Vindhya Fernando
  • , Lakmal Jayaweera
  • , Namal Wijesinghe
  • , Murali Dhakshinamurthy
  • , Ullas Arabhavi
  • , Harish Sankarankutty
  • , Mohammed Muddaseer
  • , Sarath Gudivada
  • , Aditi Moitra
  • , Ayesha Tazeen
  • , Karuna Acharya
  • , Prakash Velappan
  • , Ambika Yoganathan
  •  & Vipin Jose

Contributions

Concept and design: SRG, AR. Acquisition, analysis, or interpretation of data: SRG, RW, AS, HAdS, VS, HRKG, PKM, AES, AP, AR. Drafting of the manuscript: SRG, RW, AS, AES, AP, AR. Critical revision of the manuscript for important intellectual content: SRG, RW, AS, HAdS, VS, HRKG, PKM, AES, AP, AR. Statistical analysis: SRG. Obtained funding: RW, HRKG, PKM, AR, AP. Administrative, technical, or material support: RW, AS, HAdS, VS, HRKG, PKM.

Corresponding author

Correspondence to Anthony Rodgers.

Ethics declarations

Conflict of interest

RKG is a minority shareholder in three Indian multinational pharmaceutical companies (Ajanta Pharma, Divis Laboratories, and NATCO Pharma). RW, AR reported receiving a salary from George Health Enterprises, which is the social enterprise arm of the George Institute for Global Health. The George Institute for Global Health is a majority shareholder of George Health Enterprises, which has received investment funds to develop fixed-dose combination products containing aspirin, statin, and blood pressure lowering drugs and has submitted a patent for the treatment of hypertension. AR is listed as an inventor on this patent; however, he does not have a financial interest in it. PKM is supported by MRC grant (MR/S023224/1) - Adolescents’ Resilience and Treatment nEeds for Mental health in Indian Slums (ARTEMIS), NHMRC/GACD grant (APP1143911) - Systematic Medical Appraisal, Referral and Treatment for Common Mental Disorders in India - SMART Mental Health.

Ethics approval

The study complies with the Declaration of Helsinki, that the locally appointed ethics committee has approved the research protocol and that informed consent has been obtained from the subjects.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gnanenthiran, S.R., Webster, R., Silva, A.d. et al. Reduced efficacy of blood pressure lowering drugs in the presence of diabetes mellitus—results from the TRIUMPH randomised controlled trial. Hypertens Res 46, 128–135 (2023). https://doi.org/10.1038/s41440-022-01051-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-022-01051-7

Keywords

This article is cited by

Search

Advanced search

Quick links