Angiotensin receptor blockers for the reduction of proteinuria in diabetic patients with overt nephropathy: results from the AMADEO study

Figures & data

Figure 1 Schematic showing the current understanding of important players and pathways contributing to diabetic nephropathy/diabetic kidney disease. Point of action for telmisartan with dual ARB plus selective PPAR-γ agonist properties is highlighted. Positive indicates action favoring DKD and negative indicates protection against DKD.

Table 1 Recent clinical trials leading up to the AMADEO study

Trial/year	Patient population	N	Treatment arms	Primary endpoint	Final outcome
HOPE^Citation19 2001	High-risk patients without known diabetes	5720	Ramipril/placebo	New onset overt nephropathy	22% Reduction in new onset overt nephropathy (RR 0.66; 95% CI 0.51–0.85; p < 0.001).
IDNT^Citation20 2001	Hypertension with diabetic nephropathy	1715	Irbesartan/amlodipine/placebo	Composite of development of ESRD, doubling Cr.	Irbesartan significantly reduced primary composite end point by 20% compared to placebo (p < 0.02) and by 23% compared to amlodipine (p < 0.006).
IRMA2^Citation22 2001	Type 2 diabetes with MA	590	Irbesartan/placebo	Time to onset of diabetic nephropathy	Irbesartan reduced risk of primary end point (HR 0.30; 95% CI 0.14–0.61; p < 0.001 for 300 mg irbesartan; HR 0.61; 95% CI 0.34–0.99; p < 0.08 for 150 mg irbesartan.
RENAAL^Citation23,Citation24 2001	Type 2 diabetes with nephropathy	1513	Losartan/placebo	Composite of doubling of Cr, development of ESRD.	Losartan significantly reduced the composite end point by 16% (p < 0.02), but not death.
MARVAL^Citation25 2002	Type 2 diabetes with MA	332	Valsartan/amlodipine	% change in UAER from BL to 24 Wks.	UAER at 24 wk was reduced by 44% with valsartan and 8% with amlodipine (p < 0.001); valsartan significantly reversed MA to normal albuminuria
BENEDICT^Citation26,Citation27 2004	Type 2 diabetes and HTN but with normoalbuminuria	1204	Trandalopril/verapamil/placebo	Development of persistent MA	For developing end point AF = 0.39 for trandalopril + verapamil vs placebo. AF = 0.44 for trandalopril vs placebo and AF = 0.83 with verapamil vs placebo.
DETAIL^Citation29 2004	Type 2 diabetes with early nephropathy	250	Telmisartan/enalapril	Change in the GFR (determined by measuring the plasma clearance of iohexol)	Change in the GFR was −17.9 mL/min/1.73 m^2 of body-surface area with telmisartan, as compared with −14.9 mL/min/1.73 m^2 with enalapril, for a treatment difference of −3.0 mL/min/1.73 m^2 (95 % CI −7.6–1.6 mL/min/1.73 m^2).
TRENDY^Citation30 2007	Type 2 diabetes, HTN, GFR > 80 mL/min, and normo- or microalbuminuria.	96	Telmisartan/ramipril	Increase in renal plasma flow (RPF)	Telmisartan increased RPF from 652.0 ± 27.0 to 696.1 ± 31.0 mL/min (p = 0.047), whereas ramipril produced no significant changes in RPF. (r = 0.47, p < 0.001).
INNOVATION^Citation32 2007	Type 2 diabetes and UACR 100–300mg/g, Cr <1.5 mg/dl (men) and <1.3 mg/dl (women).	527	Telmisartan (80/40 mg)/placebo	Transition rate incipient to overt Nephropathy, UACR > 300 mg/g, and increase ≥ 30% from baseline at 2 consecutive 4-week visits.	Transition rates to overt nephropathy were 16.7% with 80 mg telmisartan (n = 168), 22.6% with 40 mg telmisartan (n = 172), and 49.9% with placebo (n = 174) (both telmisartan doses/placebo, p < 0.0001).
VIVALDI^Citation31 2008	HTN SBP/DBP > 130/80 mmHg patients with type 2 diabetes, proteinuria (≥900 mg/24 h) and Cr (≤3.0 mg/dL)	885	Telmisartan/valsartan	Change from BL of 24 h proteinuria.	Comparable reduction in 24 h urinary protein excretion rates. Geometric mean reduction (95% confidence interval) telmisartan, 33% (27%–39%); valsartan, 33% (27%–38%).
ONTARGET^Citation28 2008	55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage	8542	Telmisartan/ramipril/telmisartan + ramipril	Composite of dialysis, doubling of CR, and death	Composite primary outcome was similar for telmisartan (1147 [13.4%]) and ramipril (1150 [13.5%]; HR 1.00, 95% CI 0.92−1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01−1.18, p = 0.037).

Abbreviations: BL, baseline; CI, confidence interval; RR, relative risk; HR, hazard ratio; Cr, serum creatinine; CV, cardiovascular; HF, heart failure; CAD, coronary artery disease; MA, microalbuminuria; ESRD, end stage renal disease; RPF, renal plasma flow; MI, myocardial infarction; N, number of patients enrolled; UAER, urine albumin excretion; wk, weeks; GFR, glomerular filteration rate; NIDDM, non-insulin-dependent diabetes mellitus; HOPE, Heart Outcomes Prevention Evaluation study; IRMA, IRbesartan in patients with type 2 diabetes with MicroAlbuminuria study; IDNT, Irbesartan Diabetic Nephropathy Trial; LIFE, Losartan Intervention For Endpoint reduction in hypertension Study; MARVAL, MicroAlbuminuria Reduction with VALsartan trial; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist; Losartan; BENEDICT, Bergamo Nephrologic Diabetes Complications Trial; TRENDY, Telmisartan versus Ramipril in renal Endothelial Dysfunction; INNOVATION, INcipieNt to OVert: Angiotensin II receptor blocker, Telmisartan, Investigation On type 2 diabetic Nephropathy; VIVALDI, inVestIgate the efficacy of telmIsartan versus VALsartan in hypertensive type 2 DIabetic patients with overt nephropathy; ONTARGET, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial.

Table 2 Pharmacokinetics of ARBs^37,38,39

Drug	Bioavailability (%)	Half-life (hours)	Lipophilicity (log P)a	Protein binding (%)	AT1 receptor affinity
Losartan	33	2 (6–9)	−2.45	98.7	20 nmol/L
Valsartan	25	9	−0.95	95	1.3 nmol/L
Irbesartan	70	11–15	+1.48	90	2.7 nmol/L
Telmisartan	43	24	+1.48	>99	3.7 nmol/L
Eprosartan	15	5–7	–	98	1.4–3.9 nmol/L

^a The logarithm of the ratio of the concentrations of the un-ionized solute in the solvents is called log P (partition coefficient).

Figure 2 Inherent PPAR-γ agonist activity of various ARBs. Importantly, full PPAR-γ agonists, ie, thiazolidinediones typically have agonist activity in the 150 to 200 range. Drawn from data of.³⁶

Figure 3 Primary endpoint from AMADEO trial. Patients in the two treatment groups (telmisartan vs losartan) started with the same mean UPC of 2000 mg/g creatinine. Note that the telmisartan arm had significantly lower mean UPC at every time-point over the course of the next year when compared to losartan treated patients. Drawn from data of.²

Table 3A Primary endpoint of AMADEO trial²

Primary endpoint	Telmisartan	Losartan	P value
Urine protein: creatinine	0.71	0.80	0.0284

Table 3B Secondary endpoint of AMADEO trial²

Secondary endpoint	Telmisartan 80 mg	Losartan 100 mg	P value
Serum creatinine	15% (12% to 18%)	15% (12% to 18%)	0.895
eGFR	−6.49 (−7.56 to 5.42)	−6.50 (−7.56% to −5.43)	0.9913
Serum aldosterone	−23 (−29% to 18%)	−17% (−23% to −11%)	0.0746
CRP	−6 (−15% to 4%)	1% (−9% to 13%)	0.277

Abbreviations: CRP, C-reative protein; eGFR, estimated glomerular filtration rate.

YusufSSleightPPogueJEffects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study InvestigatorsN Engl J Med2000342314515310639539

 PubMed Web of Science ®Google Scholar

RodbyRRohdeRLewisEThe Irbesartan Type II Diabetic Nephropathy TrialNephrol Dial Transplant20001548749710727543

 PubMed Web of Science ®Google Scholar

ParvingHLehnertHArnerPIrbesartan 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 diabetesN Engl J Med20013451287087811565519

 PubMed Web of Science ®Google Scholar

BrennerBCooperMZeeuwDRENAAL Study Investigators. Losartan in patients with type 2 diabetes and proteinuria: Observations from the RENAAL StudyN Engl J Med20013451286186911565518

 PubMed Web of Science ®Google Scholar

De ZeeuwDRemuzziGParvingHProteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAALKidney Int20046562309232015149345

 PubMed Web of Science ®Google Scholar

VibertiGWheeldonNMMicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effectCirculation200210667267812163426

 PubMed Web of Science ®Google Scholar

RuggenentiPFassiAIlievaANephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetesN Engl J Med2004351191941195115516697

 PubMed Web of Science ®Google Scholar

RemuzziGMaciaMRuggenentiPPrevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT studyJ Am Soc Nephrol2006174 Suppl 2S90S9716565256

 PubMed Web of Science ®Google Scholar

BarnettAHBainSCBouterPDiabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathyN Engl J Med2004351191952196115516696

 PubMed Web of Science ®Google Scholar

SchmiederRDellesCMimranAImpact of telmisartan versus ramipril on renal endothelial function in patients with hypertension and type 2 diabetesDiabetes Care2007301351135617337492

 PubMed Web of Science ®Google Scholar

MakinoHHanedaMBabazonoTThe 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) StudyJ Int Med Res20053367768616372586

 PubMed Web of Science ®Google Scholar

GalleJSchwedhelmEPinnettiSVIVALDI investigators. Antiproteinuric effects of angiotensin receptor blockers: telmisartan versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathyNephrol Dial Transplant200823103174318318450829

 PubMed Web of Science ®Google Scholar

MannJFSchmiederREMcQueenMRenal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomized, double-blind, controlled trialLancet2008372963854755318707986

 PubMed Web of Science ®Google Scholar

WienenWHauelNVan MeelJPharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist, BIBR 277Br J Pharmacol199311012452528220885

 PubMed Web of Science ®Google Scholar

WolfgangWEntzerothMStangierJA review on telmisartan: a novel, long-acting angiotensin II-receptorCardiovasc Drug Rev2006182127154

 Google Scholar

KakutaHSudohKSasamataMTelmisartan has the strongest binding affinity to angiotensin II type 1 receptor: comparison with other angiotensin II type 1 receptor blockersInt J Clin Pharmacol Re20052514146

 Web of Science ®Google Scholar

BensonSCPershadsinghHHoCIdentification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activityHypertension200443993100215007034

 PubMed Web of Science ®Google Scholar

BakrisGBurgessEWeirMTelmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathyKidney Int200874336436918496508

 PubMed Web of Science ®Google Scholar