Antihypertensive agents for preventing diabetic kidney disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the benefits and harms of different antihypertensive agents (ACE inhibitors, angiotensin receptor antagonists, calcium channel blockers, beta blockers, diuretics) for preventing the onset of kidney disease in diabetic patients.
To evaluate if combination therapy with different antihypertensive agents is better than treatment with a single agent.
To evaluate the variation of effects of interventions according to:
‐ Diabetes type 1 or 2
‐ Duration of diabetes at initiation of antihypertensive treatment (time of trial entry)
‐ Presence/absence of hypertension
‐ Use of statins
Background
Diabetic kidney disease (also called diabetic nephropathy) occurs in 30‐40% of type 1 diabetic patients 20‐25 years after the onset of diabetes, and in about 25% of type 2 diabetic patients within 20 years (Ritz 1999). Approximately 20‐40% of patients with diabetic kidney disease progress to end‐stage renal failure (ESRF) while the rest may die from associated coronary artery disease or other cardiovascular causes before the onset of ESRF (Gall 1993).
It is commonly assumed that type 1 and type 2 diabetics have similar pathogenetic and clinical features of renal damage, as outlined by Mogensen 1997. The recognised phases are:
1. Renal hypertrophy and hyperfiltration which generally runs over a decade;
2. "Incipient" diabetic kidney disease (defined as the excretion of 30‐300 mg albumin/day confirmed with three, timed consecutive measurements, also called microalbuminuria) presenting 7‐13 years after the onset of disease;
3. Established (also called "overt") kidney disease (excretion of> 300 mg albumin/day, also called macroalbuminuria, with clinical evidence of hypertension and increasing proteinuria).
This later condition eventually leads to ESRF, commonly 7‐10 years after the onset of persistent proteinuria. The time course for this process may be influenced by glycaemic control, control of hypertension and reduction in proteinuria.
Cardiovascular disease is the major cause of death worldwide for patients with ESRF, and its frequency is further increased in diabetics. Hypertension, hyperlipidaemia, obesity and smoking are all additional cardiovascular risk factors for the diabetic patient. Hypertension and proteinuria contribute to a progressive deterioration of kidney function in patients with diabetic kidney disease (Mogensen 1976; Hasslacher 1985) and most antihypertensive agents are used for both the treatment of hypertension and in an effort to slow the progression of kidney damage. The use of these agents to either prevent or delay the progression of kidney disease, has been widely advocated and tested in clinical studies (EUCLID 1997; Schrier 2002). There are relevant cost implications for treating diabetic complications, particularly kidney disease with its related dialysis treatment once ESRF has been reached. Screening and intervention programmes are likely to have life‐saving effects and lead to considerable economic savings (Borch‐Johnsen 1993; Clark 2000; Faller 2002).
The major antihypertensive agents; angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, calcium channel blockers, beta blockers and diuretics, have been tried, either alone or in combination. While it is fairly well established that the use of antihypertensive agents in this group of patients is beneficial to delay the progression of the disease, it is unclear if they are also beneficial in preventing the onset of diabetic kidney disease, and if they should be used as an early treatment in diabetic patients. If any benefit is present, it is not clear whether any one of these agents are more effective than another, or if combined treatments are better than monotherapy. Finally, it is unclear whether the type of diabetes is a possible effect modifier and when, during the course of diabetes, should antihypertensive treatment be initiated to prevent kidney disease (Kasiske 1993).
The aim of this review is to assess the benefits and harms of antihypertensive agents for preventing diabetic kidney disease.
Objectives
To evaluate the benefits and harms of different antihypertensive agents (ACE inhibitors, angiotensin receptor antagonists, calcium channel blockers, beta blockers, diuretics) for preventing the onset of kidney disease in diabetic patients.
To evaluate if combination therapy with different antihypertensive agents is better than treatment with a single agent.
To evaluate the variation of effects of interventions according to:
‐ Diabetes type 1 or 2
‐ Duration of diabetes at initiation of antihypertensive treatment (time of trial entry)
‐ Presence/absence of hypertension
‐ Use of statins
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) and quasi‐RCTs which evaluate the effect of any antihypertensive agent administered to diabetic patients without kidney disease will be included.
Types of participants
INCLUSION CRITERIA:
Any type 1 or type 2 diabetic patient without kidney disease (defined as an albumin excretion rate of less than 30 mg/day on a timed specimen confirmed with three serial measurements) irrespective of blood pressure status.
EXCLUSION CRITERIA:
Studies in non‐diabetic patients shall be excluded.
Types of interventions
Any antihypertensive agent (compared to placebo, no treatment, another antihypertensive agent either singly or in combination), irrespective of class, administered at any dose and for a duration of at least six months.
Types of outcome measures
‐ Death (any cause)
‐ Death (cardiovascular)
‐ Number of patients who develop microalbuminuria
‐ Albuminuria (mg/24 h or ug/min), macroalbuminuria (mg/24 h or ug/min) or proteinuria (mg/24 h) at end of treatment or change between beginning and end of treatment
‐ Urinary Albumin Creatinine Ratio (mg albumin/mmol creatinine)
‐ Blood pressure (mmHg) (systolic, diastolic, mean arterial pressure (MAP)) at end of treatment or change between the beginning and end of treatment
‐ Serum creatinine (mg/dl; umol/l) at end of treatment or change in serum creatinine between beginning and end of treatment
‐ Doubling of serum creatinine at end of treatment
‐ Creatinine clearance or GFR (any measure) at end of treatment or change in creatinine clearance/GFR (any measure) between beginning and end of treatment
‐ Change in GFR /year (ml/min/year)
‐ Change in renal plasma flow (ml/min) from the beginning to the end of treatment
‐ Presence/absence of cardiovascular impairment (myocardial infarction, left ventricular dilatation, left ventricular hypertrophy)
‐ Side effects of individual drugs
‐ ACE inhibitors and angiotensin receptor antagonists (cough, headache, hyperkalaemia)
‐ Calcium channel blockers (headache, dryness of mouth, nausea, increased appetite, weight gain, arrhythmia)
‐ Beta blockers (tiredness, trouble in sleeping, decreased sexual ability)
‐ Diuretics (electrolyte disturbances, dryness of mouth, nausea, vomiting, arrhythmia)
‐ Glycaemic control (HbA1c %)
‐ BMI (kg/m²)
‐ Lipid profile
Search methods for identification of studies
Relevant trials will be obtained from the following sources:‐
1. Cochrane Renal Group Specialised Register of Randomised Controlled Trials
2. Cochrane Central Register of Controlled Trials (CENTRAL) ‐ latest issue for any "New" records not yet incorporated in the Specialised Register
#1 ANTIHYPERTENSIVE AGENTS explode all trees (MeSH)
#2 (antihypertensive* and (agent* or drug))
#3 chlorothiazide
#4 chlorthalidone
#5 hydralazine
#6 hydrochlorothiazide
#7 indapamide
#8 minoxidil
#9 ANGIOTENSIN CONVERTING ENZYME INHIBITORS explode all trees (MeSH)
#10 captopril
#11 enalapril
#12 cilazapril
#13 enalaprilat
#14 fosinopril
#15 lisinopril
#16 perindopril
#17 ramipril
#18 saralasin
#19 teprotide
#20 Losartan explode all trees (MeSH)
#21 losartan
#22 imidazole*
#23 irbesartan
#24 candesartan
#25 eprosartan
#26 valsartan
#27 olmesartan
#28 telmisartan
#29 ace near inhibitor*
#30 (angiotensin near (receptor next antagonist*)
#31 CALCIUM CHANNEL BLOCKERS explode all trees (MeSH)
#32 amlodipine
#33 diltiazem
#34 felodipine
#35 nicardipine
#36 nifedipine
#37 nimodipine
#38 nisoldipine
#39 nitrendipine
#40 verapamil
#41 ADRENERGIC BETA‐ANTAGONISTS explode all trees (MeSH)
#42 alprenolol
#43 atenolol
#44 metoprolol
#45 nadolol
#46 oxprenolol
#47 pindolol
#48 propranolol
#49 ADRENERGIC ALPHA‐ANTAGONISTS explode all trees (MeSH)
#50 labetalol
#51 prazosin
#52 beta block*
#53 DIURETICS explode all trees (MeSH)
#54 spironolactone
#55 triamterene
#56 bumetanide
#57 chlorthalidone
#58 furosemide
#59 indapamide
#60 chlorothiazide
#61 hydrochlorothiazide
#62 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61
#63 exp DIABETES MELLITUS explode all trees (MeSH)
#64 DIABETIC NEPHROPATHIES explode all trees (MeSH)
#65 diabetic nephropath*
#66 diabetic glomerulo*
#67 ((diabetic or diabetes) and (kidney disease* or renal disease*)
#68 #63 or #64 or #65 or #66 or #67
#69 #62 and #68
3. MEDLINE and Pre‐MEDLINE 1966 ‐ present ‐ to ensure all trials have been identified.
The following MEDLINE subject‐specific search strategy will be used (modified as appropriate for other databases):
MEDLINE search strategy (1966 to most recent) and Pre‐MEDLINE search strategy:
1 exp antihypertensive agents/
2 (antihypertensive$ adj (agent$ or drug)).tw.
3 chlorothiazide.tw.
4 chlorthalidone.tw.
5 hydralazine.tw.
6 hydrochlorothiazide.tw.
7 indapamide.tw.
8 minoxidil.tw.
9 exp angiotensin converting enzyme inhibitors/
10 captopril.tw.
11 enalapril.tw.
12 cilazapril.tw.
13 enalaprilat.tw.
14 fosinopril.tw.
15 lisinopril.tw.
16 perindopril.tw.
17 ramipril.tw.
18 saralasin.tw.
19 teprotide.tw.
20 exp losartan/
21 losartan.tw.
22 imidazole$.tw.
23 irbesartan.tw.
24 candesartan.tw.
25 eprosartan.tw.
26 valsartan.tw.
27 olmesartan.tw.
28 telmisartan.tw.
29 (ace adj2 inhibitor$).tw.
30 (angiotensin adj2 receptor antagonist$).tw.
31 exp calcium channel blockers/
32 amlodipine.tw.
33 diltiazem.tw.
34 felodipine.tw.
35 nicardipine.tw.
36 nifedipine.tw.
37 nimodipine.tw.
38 nisoldipine.tw.
39 nitrendipine.tw.
40 verapamil.tw.
41 exp adrenergic beta‐antagonists/
42 alprenolol.tw.
43 atenolol.tw.
44 metoprolol.tw.
45 nadolol.tw.
46 oxprenolol.tw.
47 pindolol.tw.
48 propranolol.tw.
49 exp adrenergic alpha‐antagonists/
50 labetalol.tw.
51 prazosin.tw.
52 beta block$.tw.
53 exp diuretics/
54 spironolactone.tw.
55 triamterene.tw.
56 bumetanide.tw.
57 chlorthalidone.tw.
58 furosemide.tw.
59 indapamide.tw.
60 chlorothiazide.tw.
61 hydrochlorothiazide.tw.
62 or/1‐61
63 exp diabetes mellitus/
64 diabetic nephropathies/
65 diabetic nephropath$.tw.
66 diabetic glomerulo$.tw.
67 ((diabetic or diabetes) and (kidney disease$ or renal disease$)).tw.
68 or/63‐67
69 62 and 68
This will be combined with the Cochrane highly sensitive search strategy for identifying RCTs in MEDLINE (Dickersin 1994), and a similar strategy for EMBASE (Lefebvre 1996). Please see Cochrane Renal Group Module for details of these strategies.
4. EMBASE 1980 ‐ present ‐ to ensure all trials have been identified.
5. Reference lists of nephrology textbooks, review articles and relevant trials.
6. Conference proceedings from nephrology meetings.
7. Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous trials.
Data collection and analysis
The review will be undertaken by four reviewers (GFMS, MC, FPS, JC). The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by (GFMS) and (MC), who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially.
Reviewers (GFMS) and (MC) will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria. Data extraction will be carried out independently by the same reviewers using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one trial exists, only the publication with the most complete data will be included. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved in consultation with (JC).
STUDY QUALITY
The quality of studies to be included will be assessed independently by (GFMS) and (MC) without blinding to authorship or journal using the checklist developed for the Cochrane Renal Group. Discrepancies will be resolved by discussion with (JC). The quality items to be assessed are allocation concealment, intention‐to‐treat analysis, completeness to follow‐up and blinding of investigators, participants, outcome assessors and data analysis.
QUALITY CHECKLIST
1. Allocation Concealment
A. Adequate ‐ Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
B. Unclear ‐ Randomisation stated but no information on method used is available
C. Inadequate ‐ Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group
2. Blinding
Investigators: Yes/No/not stated
Participants: Yes/No/not stated
Outcome assessor: Yes/No/not stated
Data analysis: Yes/No/not stated
The above are considered not blinded if the treatment group can be identified in >20% of participants because of the side effects of treatment
3. Intention‐to‐treat analysis
Yes ‐ Specifically reported by authors that intention‐to‐treat analysis was undertaken and this was confirmed on study assessment.
Yes ‐ Not stated but confirmed upon study assessment
No ‐ Not reported and lack of intention‐to‐treat analysis confirmed on study assessment (patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation).
No ‐ Stated but not confirmed upon study assessment
Not stated
4. Completeness to follow‐up
Per cent of participants excluded
STATISTICAL ASSESSMENT
For dichotomous outcomes results will be expressed as relative risk (RR) with 95% confidence intervals (CI). Data will be pooled using the random effects model but the fixed effects model will also be analysed to ensure robustness of the model chosen and susceptibility to outliers. Where continuous scales of measurement are used to assess the effects of treatment (microalbuminuria, blood pressure), the weighted mean difference (WMD) will be used, or the standardised mean difference (SMD) if different scales have been used. Heterogeneity will be analysed using a Chi squared test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance.
Heterogeneity among participants could be related to age, renal pathology and glycaemic control. Heterogeneity in treatments could be related to dose and duration of therapy which patients are receiving.
If sufficient RCTs are identified, an attempt will be made to examine for publication bias using a funnel plot (Egger 1997).
When different treatment options have not been compared directly within available RCTs, conclusions on relative efficacy will be based on indirect comparisons of different interventions (Bucher 1997; Song 2000).
