EUCLID (ACE-inhibitor in DM)

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The EUCLID Study Group writers. "Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria". The Lancet. 1997. 349(9068):1787-1792.
PubMedFull text

Clinical Question

In patients with T1DM, BP systolic <155 mmHg, diastolic 75-90 mmHg and either normoalbuminuria or microalbuminuria, does lisinopril slow the progression of renal disease as compared to placebo?

Bottom Line

In patients with T1DM, BP systolic <155 mmHg, diastolic 75-90 mmHg and either normoalbuminuria or microalbuminuria, lisinopril slows the progression of renal disease as compared to placebo. The greatest benefit was observed in patients with microalbuminuria at baseline. Lisinopril did not increase the risk of hypoglycemia or impaired glycemic control.

Major Points

Diabetes mellitus is the most common cause of end-stage renal disease (ESRD).[1] Hypertension and proteinuria are recognized risk factors for progression of diabetic nephropathy.[2][3]

A meta-analysis published in 1993 showed that the angiotensin-converting enzyme (ACE) inhibitors had beneficial effects on proteinuria and GFR which were independent of its antihypertensive mechanism.[4] At the time of the trial, ACE inhibitors have been shown to slow the progression of renal disease in patients with macroalbuminuria.[5] However, there were less data on patients with normoalbuminuria or macroalbuminuria available. Therefore it was unclear what is the degree of albuminuria at which ACE-i should be commenced.

The EURODIAB controlled trial of lisinopril in insulin dependent diabetes (EUCLID) randomized 530 patients with type 1 diabetes mellitus (T1DM), BP systolic <155 mmHg, diastolic 75-90 mmHg with predominantly normoalbuminuria (83.8%) or microalbuminuria (15%) to receive the ACE inhibitor lisinopril or placebo. The outcome of interest is progression of kidney disease as measured by the rate of change in urinary albumin excretion rate (AER). The trial showed that the AER in lisinopril group was 2.2 μg/min lower than placebo (treatment difference 18.8%; 95% CI 2·0-32·7; P=0·03) at 2-years. The greatest benefit was seen in patients with microalbuminuria at baseline. The treatment difference in AER was 38·5 μg/min (P=0·001) at 2 years. In comparison the treatment difference was 0·23 μg/min (p=0·6) in patients with normoalbuminuria at baseline. Lisinopril did not increase the risk of hypoglycemia or impaired glycemic control.

A systematic review published in 2005 (updated in 2012) included the EUCLID trial and another 25 studies with a total of 61,264 participants. In adults ≥18 years with type 1 or type 2 diabetes without kidney disease and albuminuria, ACE inhibitors reduced the risk of new onset microalbuminuria, macroalbuminuria or both as compared to placebo (8 studies, 11,906 patients: RR 0.71; 95% CI 0.56-0.89). The benefits were similar in patients with and without hypertension. ACE-i also reduced the risk of death (6 studies, 11,350 participants: RR 0.84; 95% CI 0.73-0.97).[6]

Guidelines

ADA Standards of Medical Care in Diabetes (2015, adapted)[7]

  • An ACE inhibitor or angiotensin receptor blocker (ARB) is not recommended for primary prevention of diabetic kidney disease in patients with diabetes with normal BP and normal UACR (<30 mg/g). (Level of evidence: B)
  • Either an ACE inhibitor or ARB is suggested for the treatment of the nonpregnant patient with modestly elevated urinary albumin excretion (30–299 mg/day) (Level of evidence: C) and is recommended for those with urinary albumin excretion >300 mg/day. (Level of evidence: A)
  • When ACE inhibitors, ARBs, or diuretics are used, monitor serum creatinine and potassium levels for the development of increased creatinine or changes in potassium. (Level of evidence: E)

Design

  • Randomized, double-blind, placebo-controlled, parallel-design
  • N=530
    • Lisinopril: n=265 (244 in intention-to-treat)
    • Placebo: n=265 (246 in intention-to-treat)
  • Setting: 18 centers in Europe
  • Enrollment:
  • Mean follow-up: 2 years
  • Analysis: intention-to-treat
  • Primary outcome: rate of change in urinary albumin excretion rate (AER)
    • This was derived from a summary measures approach. The mean of the 2 AERs from each visit was plotted, and a regression line drawn between these points was drawn. The slope of this line is equivalent to the rate of change in AER.

Population

Inclusion Criteria

  • Either sex, females eligible only if postmenopausal or using contraception
  • Age: 20-59 years
  • Type 1 diabetes mellitus, defined as diagnosis before age 36 and requirement for continuous insulin therapy within 1 year after diagnosis
  • Systolic BP <155 mmHg; diastolic BP 75-90 mmHg

Exclusion Criteria

  • renal-artery stenosis
  • abnormal renal function:
    • plasma creatinine >150 μmol/L (>1·8 mg/dL) in the previous 6 months
    • persistent proteinuria (Albustix positive or AER>250 μg/min)
    • persistent haematuria (on dipstick) on 3 occasions within the previous 12 months
  • cardiac-valve obstruction, accelerated hypertension; myocardial infarction 3 months before enrollment, coronary bypass surgery, stroke, heart failure
  • postural hypotension, medication that affects BP
  • previous idiosyncratic reaction to ACE-i
  • seropositivity for hepatitis B or HIV

Baseline Characteristics

From the lisinopril group

  • Demographics: age: 33 (27-40) years; 58.5% males
  • Median duration of diabetes: 13 (8-19) years
  • Median HbA1c: 6.9 (5,6-8.2) %
  • Median BMI: 24.3 (22.8-26) kg/m2
  • Median BP: systolic 122 (116-130) mmHg; diastolic 79 (76-84) mmHg
  • AER: 8 (4.4-14.8) μg/min
  • Patients with: normoalbuminuria 80%; microalbuminuria 17%; macroalbuminuria 2%

Interventions

Patients were randomized to receive lisinopril or placebo with stratification by centre and albuminuric status (normoalbuminuria or microalbuminuria)

  • lisinopril was started at 10 mg per day and increased to 20 mg to achieve a target diastolic BP of <75 mmHg
  • patients were examined at 1, 3, 6, 12, 18, and 24 months post-randomization
  • compliance was assessed by tablet counts at each visit

Outcomes

Comparisons are lisinopril vs. placebo unless stated otherwise

Primary Outcomes

rate of change in urinary AER
AER was 2.2 μg/min lower in the lisinopril group as compared to placebo (treatment difference 18.8%; 95% CI 2·0-32·7; P=0·03)

Other Outcomes

Progression of AER to ≥ 20 μg/min
Comparison is placebo vs. lisinopril
8% vs. 6% (rate ratio of progression 1.3; 95% CI 0·64–2·70; P=0·5)

Subgroup Analysis

for the primary outcome

Albuminuria

  • normoalbuminuric at baseline: AER was 1.0 μg/min lower in lisinopril group (treatment difference 12.7%; 95% CI -2.9 to 26; P=0·1)
  • microalbuminuric at baseline: AER was 34.2 μg/min lower in lisinopril group (treatment difference 49.7%; 95% CI -14.5 to 77.9; P=0·1)
  • P-value for interaction=0.04

Gender

  • Males: treatment difference was 0·40 μg/min (p=0·6)
  • Females: treatment difference was 6.52 μg/min (p=0·01)
  • P-value for interaction=0.04. However, females had higher AERs than males at baseline. After adjusting for baseline AER, the P-value for interaction was 0.1

There were no significant interactions with centre, glycaemic control at baseline, duration of diabetes, and initial BP.

for mean AER at final visit

Albuminuria

  • normoalbuminuric at baseline: treatment difference was 0.23 μg/min (P=0·6)
  • microalbuminuric at baseline: treatment difference was 38.5 μg/min (P=0·001)

Adverse Events

mean diastolic BP
74 vs. 77 mmHg (P=0·0001)
Hypoglycemia
12 vs. 10 incidents (no treatment difference)
mean HbA1c
similar in both groups (values not reported)
Cough
24 vs. 7 episodes (P-value not reported)
Serious adverse events
56 vs. 52 events (P-value not reported)
Minor adverse events
266 vs. 211 events (P-value not reported)

Criticisms

  • The systolic BP criteria for inclusion was <155 mmHg. This includes patients with systolic BP between 140-155 mmHg which are considered hypertensive. Reduction of albuminuria might have occurred due to antihypertensive effect.[8]
  • GFR was not measured in this study.[9]
  • Data on BP at randomization according to baseline AER and systolic BP response to treatment were not reported.[10]
  • The antiproteinuric effect of lisinopril seen may have been strongly influenced by the effect of ACE inhibition in microalbuminuric patients, but not normoalbuminuric patients.[10]
  • The incidence of microalbuminuria in this trial was less than expected.

Funding

Grant, lisinopril and placebo tablets provided by Zeneca Pharmaceuticals. Micral and Nephur test sticks were provided by Boehringer Mannheim.

Further Reading

  1. U.S. Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2012.
  2. Hasslacher C, Ritz E, Terpstra J, Gallasch G, Kunowski G, Rall C. Natural history of nephropathy in type I diabetes. Relationship to metabolic control and blood pressure. Hypertension 1985;7(6 Pt 2):74-8
  3. CE. Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment. Scandinavian Journal of Clinical & Laboratory Investigation 1976;36(4):383-8.
  4. BL Kasiske, RSN Kalil, JZ Ma, M Liao, WF Keane. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med, 1993;118:129–138
  5. EJ Lewis, LG Hunsicker, RP Bain, RD Rohde. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med, 1993;329:1456–1462
  6. Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GFM. Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD004136. DOI:10.1002/14651858.CD004136.pub3
  7. American Diabetes Association. 9. Microvascular Complications and Foot Care. Diabetes Care. 2015 Jan 1;38(Supplement 1):S58–66.
  8. Sawicki PT. Lisinopril and albumin excretion in diabetes. Lancet. 1997 Aug 30;350(9078):662; author reply 663-4.
  9. Tripathi K. EUCLID study. Lancet. 1997 Oct 11;350(9084):1102-3.
  10. 10.0 10.1 Williams B. Lisinopril and albumin excretion in diabetes. Lancet. 1997 Aug 30;350(9078):662; author reply 663-4.