Skip to main content

Candesartan Cilexetil/Hydrochlorothiazide Treatment in High-Risk Patients with Type 2 Diabetes Mellitus and Microalbuminuria

The CHILI T2D Study

Abstract

Background: Arterial hypertension complicated by the presence of diabetes mellitus and microalbuminuria is a particularly hazardous risk-factor combination. Blockers of the renin-angiotensin system have been shown to be beneficial with respect to these risk factors in randomized clinical trials.

Objective: To provide proof of effectiveness for a fixed-dose combination such as candesartan cilexetil 16mg/hydrochlorothiazide (HCTZ) 12.5 mg in clinical practice within the context of a variety of concomitant diseases and medications.

Methods: CHILI T2D was a non-interventional, open-label, non-controlled, multicentre study in clinical practice that evaluated 4110 patients with type 2 diabetes, uncontrolled hypertension and microalbuminuria who were being prescribed a fixed-dose combination of candesartan cilexetil 16mg/HCTZ 12.5 mg (Biopress®). Documented outcomes included blood pressure (BP) reductions, metabolic changes, changes in albuminuria, and adverse events throughout the 12-week treatment period.

Results: Patients had a mean ±SD age of 64.0 ±10.3 years, 54.0% were male and the mean ±SD body mass index was 29.6 ±5.8 kg/m2. Coronary heart disease (34.3%), diabetic neuropathy (23.8%), retinopathy (18.6%) and heart failure (20.2%) were frequent co-morbidities. The use of candesartan cilexetil 16mg/HCTZ 12.5mg in patients with a mean ±SD baseline BP of 158.5±14.2/92.5 ±9.1 mmHg resulted in a substantial further reduction of office BP by a mean ±SD of −27.1 ±14.4/-13.1±9.5mmHg (p<0.001). The reduction was particularly pronounced in patients with severe hypertension (mean reduction of −44.7/−19.9 mmHg). Glucose (glycosylated haemoglobin [HbA1c], fasting blood glucose) as well as lipid parameters (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) were significantly improved (p< 0.001). Microalbuminuria, indicative of renal and cardiovascular risk, was significantly reduced by 28.8% (p< 0.001). Tolerability was excellent with only 16 out of 4110 patients experiencing any adverse event, of which six were considered to be serious.

Conclusions: The fixed-dose combination of candesartan cilexetil 16 mg/HCTZ 12.5 mg is highly effective in lowering blood pressure in type 2 diabetic patients with all stages of hypertension and microalbuminuria. The data indicate that low-dose HCTZ can safely be added to an existing drug regimen in this patient group to increase the BP-lowering effect, without compromising tolerability and the favourable metabolic profile of candesartan cilexetil monotherapy.

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

Table I
Table II
Fig. 1
Fig. 2
Fig. 3
Table III
Table IV
Table V
Table VI

References

  1. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press 2009; 18: 308–47

    PubMed  Article  CAS  Google Scholar 

  2. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321: 412–9

    PubMed  Article  CAS  Google Scholar 

  3. Bönner G, Fuchs W. Fixed combination of candesartan with hydrochlorothiazide in patients with severe primary hypertension. Curr Med Res Opin 2004; 20: 597–602

    PubMed  Article  Google Scholar 

  4. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003; 21: 875–86

    PubMed  Article  CAS  Google Scholar 

  5. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003

    PubMed  Article  CAS  Google Scholar 

  6. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759–66

    PubMed  Article  CAS  Google Scholar 

  7. Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870–8

    PubMed  Article  CAS  Google Scholar 

  8. Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002; 106: 672–8

    PubMed  Article  CAS  Google Scholar 

  9. Bramlage P, Schonrock E, Odoj P. Metabolic effects of an AT1-receptor blockade combined with HCTZ in cardiac risk patients: a non interventional study in primary care. BMC Cardiovasc Disord 2008; 8: 30

    PubMed  Article  Google Scholar 

  10. Mancia G, De Backer G, Dominiczak A, et al. 2007 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 2007; 25: 1105–87

    PubMed  Article  CAS  Google Scholar 

  11. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the Candesartan and Lisinopril Microalbuminuria (CALM) study. BMJ 2000; 321: 1440–4

    PubMed  Article  CAS  Google Scholar 

  12. Bilous R, Chaturvedi N, Sjolie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med 2009; 151(1): 11–20

    PubMed  Google Scholar 

  13. Oparil S, Michelson EL. Long term efficacy, safety, and tolerability of candesartan cilexitil added to hydrochlorothiazide in patients with severe hypertension [abstract]. Am J Hypertens 1999; 12: 120A

    Article  Google Scholar 

  14. Edes I. Combination therapy with candesartan cilexetil 32mg and hydrochlorothiazide 25mg provides the full additive antihypertensive effect of the components: a randomized, double-blind, parallel-group study in primary care. Clin Drug Investig 2009; 29: 293–304

    PubMed  Article  CAS  Google Scholar 

  15. Bramlage P, Schonrock E, Odoj P, et al. Importance of a fixed combination of AT1-receptor blockade and hydrochlorothiazide for blood pressure lowering in cardiac risk patients: a postmarketing surveillance study with candesartan/HCTZ. MMW Fortschr Med 2008; 149Suppl. 4: 172–81

    PubMed  Google Scholar 

  16. Uen S, Un I, Fimmers R, et al. Effect of candesartan cilexetil with hydrochlorothiazide on blood pressure and ST-segment depression in patients with arterial hypertension. Dtsch Med Wochenschr 2007; 132: 81–6

    PubMed  Article  CAS  Google Scholar 

  17. Bönner G. Antihypertensive efficacy and tolerability of candesartan-hydrochlorothiazide 32/12.5mg and 32/25mg in patients not optimally controlled with candesartan monotherapy. Blood Press 2008; 17Suppl. 2: 22–30

    Article  Google Scholar 

  18. Karlson BW, Zetterstrand S, Olofsson B, et al. A dose-response analysis of candesartan-hydrochlorothiazide combination therapy in patients with hypertension. Blood Press 2009; 18: 149–56

    PubMed  Article  CAS  Google Scholar 

  19. Ohma KP, Milon H, Valnes K. Efficacy and tolerability of a combination tablet of candesartan cilexetil and hydrochlorothiazide in insufficiently controlled primary hypertension: comparison with a combination of losartan and hydrochlorothiazide. Blood Press 2000; 9: 214–20

    PubMed  Article  CAS  Google Scholar 

  20. Meredith PA, Murray LS, McInnes GT. Comparison of the efficacy of candesartan and losartan: a meta-analysis of trials in the treatment of hypertension. J Hum Hypertens 2009; doi: 10.1038/jhh.2009.99

  21. Belcher G, Lunde H, Elmfeldt D, et al. The combination tablet of candesartan cilexetil 16mg and hydrochlorothiazide 12.5mg has a tolerability profile similar to that of placebo [abstract]. J Hypertens 2000; 18: S94

    Google Scholar 

  22. Bramlage P, Hasford J. Blood pressure reduction, persistence and costs in the evaluation of antihypertensive drug treatment: a review. Cardiovasc Diabetol 2009; 8: 18

    PubMed  Article  Google Scholar 

  23. Mengden T, Vetter H, Tousset E, et al. Management of patients with uncontrolled arterial hypertension: the role of electronic compliance monitoring, 24-h ambulatory blood pressure monitoring and candesartan/HCTZ. BMC Cardiovasc Disord 2006; 6: 36

    PubMed  Article  Google Scholar 

  24. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369: 201–7

    PubMed  Article  CAS  Google Scholar 

  25. Yusuf S,Ostergren JB, Gerstein HC, et al. Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation 2005; 112: 48–53

    Article  Google Scholar 

  26. Zanchetti A, Elmfeldt D. Findings and implications of the Study on COgnition and Prognosis in the Elderly (SCOPE): a review. Blood Press 2006; 15: 71–9

    PubMed  Article  Google Scholar 

  27. Lindholm LH, Persson M, Alaupovic P, et al. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). J Hypertens 2003; 21: 1563–74

    PubMed  Article  CAS  Google Scholar 

  28. Carlsen JE, Kober L, Torp-Pedersen C, et al. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ 1990; 300: 975–8

    PubMed  Article  CAS  Google Scholar 

  29. Carter BL, Einhorn PT, Brands M, et al. Thiazide-induced dysglycemia: call for research from a working group from the National Heart, Lung, and Blood Institute. Hypertension 2008; 52: 30–6

    PubMed  Article  CAS  Google Scholar 

  30. Zorad S, Dou JT, Benicky J, et al. Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma. Eur J Pharmacol 2006; 552: 112–22

    PubMed  Article  CAS  Google Scholar 

  31. UKPDS. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13

    Article  Google Scholar 

  32. UKPDS. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53

    Article  Google Scholar 

  33. UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–65

    Article  Google Scholar 

  34. Schmieder RE, Schrader J, Zidek W, et al. Low-grade albuminuria and cardiovascular risk: what is the evidence? Clin Res Cardiol 2007; 96: 247–57

    PubMed  Article  CAS  Google Scholar 

  35. Schmieder RE, Martin S, Lang GE, et al. Angiotensin blockade to reduce microvascular damage in diabetes mellitus. Dtsch Arztebl Int 2009; 106: 556–62

    PubMed  Google Scholar 

  36. Jackson CE, Solomon SD, Gerstein HC, et al. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet 2009; 374: 543–50

    PubMed  Article  CAS  Google Scholar 

  37. Schrader J, Luders S, Kulschewski A, et al. Microalbuminuria and tubular proteinuria as risk predictors of cardiovascular morbidity and mortality in essential hypertension: final results of a prospective long-term study (MARPLE Study). J Hypertens 2006; 24: 541–8

    PubMed  Article  CAS  Google Scholar 

  38. Trenkwalder P, Lehtovirta M, Dahl K. Long-term treatment with candesartan cilexetil does not affect glucose homeostasis or serum lipid profile in mild hypertensives with type II diabetes. J Hum Hypertens 1997; 11Suppl. 2: S81–3

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This non-interventional study was conducted by Takeda Pharma GmbH, Aachen, Germany. We would like to thank the participating physicians, their assistants and all participating patients observed during the study. Our special gratitude goes to the Clinical Research Organization (CRO) factum-Gesellschaft für Statistik, wissenschaftliche Information und Kommunikation mbH, Offenbach, Germany, for data processing and conduction of the statistical analyses.

Reinhard Ketelhut designed the study and revised the manuscript for important intellectual content. Peter Bramlage explored the data, requested statistical analyses from the CRO (responsible statistician Michael Vornkahl) and wrote the first draft of the manuscript. Both authors reviewed and approved the final manuscript.

Reinhard Ketelhut has given lectures on behalf of Takeda. Peter Bramlage has acted as a consultant to, received honoraria from, and conducted research for Takeda.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Reinhard Ketelhut.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ketelhut, R., Bramlage, P. Candesartan Cilexetil/Hydrochlorothiazide Treatment in High-Risk Patients with Type 2 Diabetes Mellitus and Microalbuminuria. Clin. Drug Investig. 30, 301–311 (2010). https://doi.org/10.1007/BF03256905

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256905

Keywords

  • Blood Pressure Reduction
  • Candesartan
  • HCTZ
  • Thiazide Diuretic
  • Candesartan Cilexetil