EAL

DM: Prevention and Treatment of CVD (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the antihypertensive, antiproteinuric, and renal hemodynamic effects of combination therapy with a low-sodium diet and the ANG-II receptor antagonist, Losartan, in subjects with hypertension, elevated albumin excretion rate (AER), and type 2 diabetes.

Inclusion Criteria:

type 2 diabetes
seated systolic blood pressure > 130 mm/Hg and/or seated diastolic blood pressure > 85 mmHg
albuminuria of 10-200 micrograms/min
ages 30-75
HbA1c <11%
absence of serious systemic illness
absence of history of substance abuse
habitual 24-h urinary sodium excretion > 100 mmol/24 h

Exclusion Criteria:

seated systolic blood pressure > 165 mm/Hg or diastolic blood pressure >100 mm/Hg
serum potassium > 5.5 mmol/l
plasma creatinine > 200 micromol/l
long-term use of non-steroidal anti-inflammatory drugs
history of more than 3 urinary tract infections per year
BMI > 35
cardiac failure, nitrate therapy, or intolerance of ACE inhibitors

Description of Study Protocol:

Recruitment : recruited from Austin and Repatriation Medical center diabetes clinic

Design: Randomized Crossover Trial

patients randomized into either Losartan group or placebo group
2-week run-in period non medication or placebo, then each group was randomly divided into two sub-groups for 2 weeks: low-sodium intake or regular-sodium intake
4-week washout period, followed by a second run-in period and a second 2-week period where subjects consumed the diet alternate to that consumed previously

Blinding used (if applicable): randomization was conducted in a double-blind way

Intervention (if applicable)

50 mg Losartan v. placebo
diet
- regular-sodium diet = subject's usual diet
- low-sodium diet: patients received advice from a clinical nutritionist and received no-salt-added bread; all other foods were bought and prepared by the subjects
terms used to refer to groups and phases of study
- Losartan_LS:losartan group, low-sodium diet phase
- Losartan_RS :losartan group, regular-sodium diet phase
- placebo_LS :placebo group, low-sodium phase
- placebo_RS:placebo group, regular-sodium phase
no crossover in medication assignment; during second 4-week phase there was a crossover in dietary assignment

Statistical Analysis

data presented as means±SEM with 95% CI
skewed parameters were analyzed after logarithmic transformation; shown as geometric mean multiplied/divided by the tolerance factor
data measured at multiple time points were analyzed by a single factor ANOVA with repeated measures, followed by Fisher's least significant difference test for multiple comparisons
differences between two groups were analyzed using either Student's paired or unparied t test or the chi-square analysis for proportions, where appropriate

Data Collection Summary:

Timing of Measurements

measured at baseline, 2, and 4 weeks: body weight, albumin-to-creatinine ratio on 24-h urine collection, plasma glucose, electrolytes, plasma renin activity, ANG-II, and aldosterone
measured at baseline and weekly during each phase: urinary electrolytes, urea, and creatinine
measured at weeks 2 and 4 of each phase: 24-h ambulatory blood pressure, GFR, and effective renal plasma flow

Dependent Variables

urinary sodium excretion
plasma renin activity (PRA)
plasma ANG-II
plasma aldosterone
blood pressure
glomerular filtration rate (GFR)
effective renal plasma flow (ERPF)

Independent Variables

50 mg Losartan v. placebo

Control Variables

Description of Actual Data Sample:

Initial N: 20; 19 males, 1 female

Attrition(final N): 20

Age: 60.6 y ±3.7 for Losartan group; NS from placebo group

Ethnicity: not specified

Other relevant demographics: duration of diabetes: range 1-38 years; 24-h urine sodium at baseline: 230±36 mmol/day for Losartan group; NS from placebo group.

Anthropometrics :BMI 30.4 ±2.1 for Losartan group; NS from placebo group

Location: Australia

Summary of Results:

Baseline characteristics: NS differences in mean arterial blood pressure, urinary sodium excretion, AER, HbA1c, or pharmacotherapy between the Losartan and placebo groups.

Sodium Restriction:

NS difference for sodium restriction, based on 24-h urinary sodium excretion, between the Losartan_LS and placebo_LS groups.
Weight was significantly lower for the LosartanLS and placeboLS phases when compared to weights during the regular-sodium phases for each group.

Biochemical and Renin-Angiotensin system parameters in losartan and placebo groups

	Losartan			Placebo
	Week 0	Week 4	ANOVA	Week 0	Week 4	ANOVA
Urinary sodium excretion, mmol/day
RS diet	255±33	208±20	NS	208±15	204±27	NS
LS diet	225±24	85±14	<0.0001	205±29	80±22	0.0007
PRA, ng·ml^-1·h^-1
RS diet	0.47 (1.28)	1.09 (1.52)	0.0004	0.49 (1.31)	0.51 (1.27)	NS
LS diet	1.31 (163)	3.07 (1.63)	<0.0001	0.57 (1.3)	0.92 (1.3)	0.01
Plasma aldosterone (pmol/l)
RS diet	188.1±33.3	190.8±38.7	NS	200.7±43.2	233.452.5	NS
LS diet	209±32.3	345.3±51.5	0.0009	173.9±36.8	192±34.5	<0.0001
Plasma ANG-II, pg/ml
RS diet	4.51(1.24)	10.04 (1.41)	0.001	6.84 (1.29)	5.82 (1.25)	NS
LS diet	5.65 (1.29)	24.71 (1.53)	0.0002	6.65 (1.37)	10.8 (1.16)	0.02

Hemodynamic and renal parameters during Losartan_RS and Losartan _LS

Variables	Losartan_RS,week 4 - week 2	Losartan_LS, week 4 - week 2	change in Losartan_LS-change in Losartan_RS	P
24-h mean arterial pressure, mmHg	-0.4±1.5	-7.7±1.7	-7.3(-11.3 to -3.3)	0.003
Glomerular Filtration Rate, ml·min^-1·1.73m^-2	-2.3±2.1	-5.0±1.7	-2.7(-8.1 to 2.6)	0.28
MAG-3 effective renal plasma flow, ml·min^-1·1.73m^-2	-5.6±9.9	-6.3±9.3	-0.7(-26 to 25)	0.95
Glomerular capillary pressure, mmHG	-1.4±1.7	-9.0±1.7	-7.6(-11.8 to -3.5)	0.0002

Other Findings

The antihypertensive effect of losartan was doubled by the addition of a low-sodium diet.

In the losartan group the albumin-to-creatinine ratio did not decrease significantly from baseline until a low-sodium diet was added.

Author Conclusion:

In patients taking losartan, the magnitude of blood pressure that occured after 2 weeks of low-sodium diet was equivalent to the effects of adding a second antihypertensive agent and led to an approximate doubling of the antihypertensive effect of the drug.

In this study, a significant decrease in both blood pressure and albuminuria was observed only when a low-sodium diet was added to losartan therapy.

A low-sodium diet optimizes the renoprotective effects fo the ANG-receptor blocker, losartan. The authors propose that that a low-sodium diet be used in subjects with type 2 diabetes wo are receiving monotherapy with an ANG receptor antagonist when further blood pressure reductions is desired. A low-sodium diet should be considered an appropriate alternative to additional pharmacological antihypertensive agents, including combination therapy with a diuretic.

Funding Source:

Reviewer Comments:

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	N/A
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes