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Prevention of Transition From Incipient to Overt Nephropathy With Telmisartan in Patients With Type 2 Diabetes

¹ Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
² Department of Medicine, Division of Metabolism and Biosystemic Science, Asahikawa Medical College, Hokkaido, Japan
³ Division of Nephrology and Hypertension, Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
⁴ Department of Endocrinology, Diabetes, and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan
⁵ Division of Nephrology, Tohoku University Graduate Medical School, Miyagi, Japan
⁶ Department of Medicine, Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
⁷ Department of Medicine, Medical School, Juntendo University, Tokyo, Japan
⁸ Division of Biostatistics, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
⁹ Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical School, Saitama, Japan

Address correspondence and reprint requests to Professor Hirofumi Makino, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, Japan. E-mail: makino{at}md.okayama-u.ac.jp

Abbreviations: ARB, angiotensin receptor blocker • DBP, diastolic blood pressure • SBP, systolic blood pressure • UACR, urinary albumin-to-creatinine ratio

	INTRODUCTION

TOP INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS-- CONCLUSIONS-- References

 
To date, evidence for long-term renoprotection with angiotensin receptor blockers (ARBs) has come almost exclusively from Caucasian patients (1–3), despite Japanese people being at high risk of diabetic nephropathy and very susceptible to end-stage renal disease (4–6). We conducted the INNOVATION Study (Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy) to evaluate the efficacy of an ARB in preventing transition from microalbuminuria to overt nephropathy in Japanese patients (7). This study is the first large-scale clinical study to investigate prevention of overt diabetic nephropathy using an ARB in normotensive and hypertensive Japanese patients with type 2 diabetes.

	RESEARCH DESIGN AND METHODS—

TOP INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS-- CONCLUSIONS-- References

 
The randomized, multicenter, double-blind, placebo-controlled trial was performed in patients aged from 30 to 74 years with type 2 diabetes and urinary albumin-to-creatinine ratio (UACR) 100–300 mg/g and serum creatinine <1.5 mg/dl (men) and <1.3 mg/dl (women). Exclusion criteria included type 1 diabetes, age of diabetes onset <30 years, seated systolic blood pressure (SBP)/diastolic blood pressure (DBP) 180/100 mmHg, and definable chronic kidney disease other than diabetic nephropathy. A total of 527 patients out of 1,855 screened were randomized to 80 or 40 mg telmisartan or placebo; the starting dose was 20 mg, titrated to 40 mg after 2 weeks or to 80 mg after a further 2 weeks. Minimum treatment period was 1 year for each patient. Primary efficacy end point was the transition rate from incipient to overt nephropathy (UACR >300 mg/g and increase 30% from baseline at two consecutive 4-week visits). Secondary end point was microalbuminuria remission (UACR <30 mg/g). Frequency and severity of adverse events were also assessed. The Kaplan-Meier method was used to determine transition rates to overt nephropathy; log-rank test was used for pairwise comparison between treatment groups. Effect of blood pressure reduction on transition rate was estimated using Cox's proportional hazard model. The protocol conformed to the principles of the Declaration of Helsinki and was approved by the institutional review boards at the 142 study centers (7). Patients provided written informed consent before enrollment.

	RESULTS—

TOP INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS-- CONCLUSIONS-- References

 
Of the 527 randomized patients (mean age 61.7 years), 13 were excluded from primary analysis because of suspected type 1 diabetes or UACR measurements being missing during treatment. Mean duration of follow-up was 1.3 ± 0.5 years (maximum 2.3 years). Transition rates to overt nephropathy were 80 mg telmisartan (n = 168) 16.7%, 40 mg telmisartan (n = 172) 22.6%, and placebo (n = 174) 49.9% (both telmisartan doses vs. placebo, P < 0.0001) (Fig. 1A). In addition, 163 normotensive patients were included in the study. Transition rates in normotensive patients were 80 mg telmisartan (n = 51) 11.0%, 40 mg telmisartan (n = 58) 21.0%, and placebo (n = 54) 44.2% (both telmisartan doses vs. placebo, P < 0.01) (Fig. 1B). After adjustment for changes in SBP, telmisartan still decreased the transition rate to overt nephropathy. Telmisartan (80 and 40 mg) reduced mean UACR at final observation by 58.8 and 37.9 mg/g, respectively, and placebo increased UACR by 40.9 mg/g (both telmisartan doses vs. placebo, P < 0.0001). Microalbuminuria remission at final observation occurred in 21.2% with 80 mg telmisartan, 12.8% with 40 mg telmisartan, and 1.2% with placebo (both telmisartan doses vs. placebo, P < 0.001). One or more adverse event was recorded in >90% of patients in each treatment group; most events were mild or moderate in intensity. Regarding the decrease of blood pressure, SBP/DBP fell from 138/78 mmHg to 128/72 mmHg with 80 mg telmisartan, from 137/78 mmHg to 128/72 mmHg with 40 mg telmisartan, and from 137/77 mmHg to 132/74 mmHg with placebo (each blood pressure change at 1 year from baseline P < 0.01).

View larger version (13K): [in this window] [in a new window]   Figure 1— Kaplan-Meier curves for transition from incipient to overt nephropathy in patients treated once daily with 80 mg telmisartan (T80), 40 mg telmisartan (T40), and placebo.

	CONCLUSIONS—

TOP INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS-- CONCLUSIONS-- References

Overall, telmisartan reduced transition from incipient to overt nephropathy and induced remission of albuminuria in Japanese type 2 diabetic patients.

	Footnotes

 
Published ahead of print at http://care.diabetesjournals.org on 26 March 2007. DOI: 10.2337/dc06-1998. Clinical trial reg. no. NCT00153088, clinicaltrials.gov.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication November 21, 2006. Accepted for publication March 5, 2007.

	References

TOP INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS-- CONCLUSIONS-- References

 

1. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, for the RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869, 2001[Abstract/Free Full Text]
   
2. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, for the Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860, 2001[Abstract/Free Full Text]
   
3. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878, 2001[Abstract/Free Full Text]
   
4. Hollenberg NK: Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan. Curr Hypertens Rep 3:177, 2001[Medline]
   
5. US Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Available from http://www.usrds.org/adr_2005.htm
   
6. Nakai S, Shinzato T, Nagura Y, Masakane I, Kitaoka T, Shinoda T, Yamazaki C, Sakai R, Ohmori H, Morita O, Iseki K, Kikuchi K, Kubo K, Suzuki K, Tabei K, Fushimi K, Miwa N, Wada A, Yanai M, Akiba T: Patient Registration Committee, Japanese Society for Dialysis Therapy, Tokyo: an overview of regular dialysis treatment in Japan (as of December 31, 2001). Ther Apher Dial 8:3–32, 2004[Medline]
   
7. Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y, Kawamori R, Takeuchi M, Katayama S, for the Incipient to Overt; Angiotensin II–Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy Study Group: The telmisartan renoprotective study from incipient nephropathy to overt nephropathy: rationale, study design, treatment plan and baseline characteristics of the incipient to overt: angiotensin II receptor blocker, telmisartan, investigation on type 2 diabetic nephropathy (INNOVATION) study. J Int Med Res 33:677–686, 2005[Medline]
   
8. Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, regression of chronic renal diseases. Lancet 357:1601–1608, 2001[Medline]
   

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This Article Extract Full Text (PDF) All Versions of this Article: dc06-1998v1 30/6/1577    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Makino, H. Search for Related Content PubMed PubMed Citation Articles by Makino, H. Social Bookmarking                What's this?