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کاهش مصرف نمک در رژیم غذایی برای پیشگیری از ابتلا به بیماری کلیوی ناشی از دیابت و پیشرفت آن

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پیشینه

شواهدی قوی وجود دارد مبنی بر اینکه مصرف کنونی نمک عامل اصلی افزایش فشار خون (blood pressure; BP) بوده و کاهش مصرف آن، BP را کاهش می‌دهد، چه سطح BP در ابتدا طبیعی بوده یا افزایش یافته باشد. کنترل موثر BP در افراد مبتلا به دیابت منجر به کاهش خطر سکته مغزی، حملات قلبی و نارسایی قلبی شده و پیشرفت بیماری مزمن کلیوی (chronic kidney disease; CKD) را در این افراد کند می‌کند. این یک نسخه به‌روز شده از مروری است که نخستین‌بار در سال 2010 منتشر شد.

اهداف

ارزیابی تاثیر تغییر مصرف نمک بر BP و نشانگرهای بیماری قلبی عروقی و CKD در افراد مبتلا به دیابت.

روش‌های جست‌وجو

پایگاه ثبت مطالعات گروه کلیه و پیوند را در کاکرین تا 31 مارچ 2022 از طریق تماس با متخصص اطلاعات و با استفاده از اصطلاحات جست‌وجوی مربوط به این مرور، جست‌وجو کردیم. مطالعات موجود در پایگاه ثبت از طریق جست‌وجو در CENTRAL؛ MEDLINE؛ و EMBASE؛ خلاصه مقالات کنفرانس‌ها، پورتال جست‌وجوی پایگاه ثبت بین‌المللی کارآزمایی‌های بالینی (ICTRP) و ClinicalTrials.gov شناسایی شدند.

معیارهای انتخاب

کارآزمایی‌های تصادفی‌سازی و کنترل شده (randomised controlled trials; RCTs) را با محوریت کاهش مصرف نمک در افراد مبتلا به دیابت نوع 1 و 2 وارد کردیم. مطالعات زمانی وارد شدند که میان مصرف کم و زیاد سدیم حداقل 34 میلی‌مول/روز تفاوت وجود داشت.

گردآوری و تجزیه‌وتحلیل داده‌ها

دو نویسنده به‌طور مستقل از هم مطالعات را ارزیابی کرده و اختلاف نظرات را با بحث و تبادل نظر حل کردند. میانگین اندازه تاثیرگذاری (effect size) مداخله را در قالب تفاوت میانگین (MD) و 95% فاصله اطمینان (CI) با استفاده از مدل اثرات تصادفی (random‐effects model) محاسبه کردیم. سطح قطعیت شواهد با استفاده از رویکرد درجه‌‏بندی توصیه‏، ارزیابی، توسعه و ارزشیابی (Grading of Recommendations Assessment, Development and Evaluation; GRADE) ارزیابی شد.

نتایج اصلی

سیزده RCT (313 شرکت‌کننده)، شامل 21 مقایسه (مطالعه)، واجد شرایط ورود بودند. یک RCT (دو مطالعه) به این به‌روزرسانی مرور افزوده شد. شرکت‌کنندگان شامل 99 فرد مبتلا به دیابت نوع 1 و 214 فرد مبتلا به دیابت نوع 2 بودند. دو RCT (چهار مطالعه) شامل برخی از شرکت‌کنندگان با کاهش عملکرد کلی کلیه بودند. مطالعات باقی‌مانده گزارش کردند که شرکت‌کنندگان دچار کاهش نرخ فیلتراسیون گلومرولی (glomerular filtration rate; GFR) از مطالعه حذف شدند یا فقط شرکت‌کنندگانی را با میکروآلبومینوری (microalbuminuria) و GFR طبیعی وارد کردند. پنج مطالعه از طراحی مطالعه موازی (parallel study) و 16 مطالعه از طراحی متقاطع (cross‐over) استفاده کردند. همه مطالعات دارای خطر بالای سوگیری (bias) برای اغلب معیارها بودند. تولید تصادفی توالی (random sequence generation) و پنهان‏‌سازی تخصیص (allocation concealment)، به ترتیب، فقط در سه و دو مطالعه کافی بودند. یک مطالعه در معرض خطر پائین سوگیری برای کورسازی (blinding) شرکت‌کنندگان و ارزیابی پیامد بود، اما هیچ مطالعه‌ای در معرض خطر پائین سوگیری برای گزارش‌دهی انتخابی (selective reporting) قرار نداشت. دوازده مطالعه دارای منابع مالی غیر تجاری بودند، سه مطالعه به تضاد منافع اشاره کرده، و هشت مطالعه دوره پاک‌شدگی (washout period) کافی را میان مداخلات در مطالعات متقاطع گزارش کردند.

میانه (median) کاهش خالص در دفع سدیم ادرار 24 ساعته (24‐hour UNa) در هفت مطالعه طولانی‌مدت (طول دوره درمان چهار تا 12 هفته) معادل 76 میلی‌مول (mmol) (محدوده 51 تا 124 میلی‌مول) و در 10 مطالعه کوتاه‌مدت (طول دوره درمان پنج تا هفت روز) برابر با 187 میلی‌مول (محدوده 86 تا 337 میلی‌مول) بود. داده‌ها در چهار مطالعه فقط به صورت گرافیکی در دسترس بودند. در مطالعات طولانی‌مدت، کاهش مصرف سدیم ممکن است BP سیستولیک (systolic BP; SBP) را تا 6.15 میلی‌متر جیوه (7 مطالعه: 95% CI؛ 9.27‐ تا ‐3.03‐؛ I² = 12%)؛ BP دیاستولیک (diastolic BP; DBP) را تا 3.41 میلی‌متر جیوه (7 مطالعه: 95% CI؛ 5.56‐ تا 1.27‐؛ I² = 41%) و میانگین فشار شریانی (mean arterial pressure; MAP) را تا 4.60 میلی‌متر جیوه (4 مطالعه: 95% CI؛ 7.26‐ تا 1.94‐؛ I² = 28%) کاهش دهد. در مطالعات کوتاه‌مدت، کاهش مصرف سدیم ممکن است SBP را تا 8.43 میلی‌متر جیوه (5 مطالعه: 95% CI؛ 14.37‐ تا 2.48‐؛ I² = 88%)؛ DBP را تا 2.95 میلی‌متر جیوه (5 مطالعه: 95% CI؛ 4.96‐ تا 0.94‐؛ I² = 70%) و MAP را تا 2.37 میلی‌متر جیوه (9 مطالعه: 95% CI؛ 4.75‐ تا 0.01‐؛ I² = 65%) کاهش دهد. در اکثر آنالیزها، به ویژه میان مطالعات کوتاه‌مدت، ناهمگونی قابل‌توجهی وجود داشت. تمام آنالیزها با شواهدی با قطعیت پائین در نظر گرفته شدند.

کاهش SBP؛ DBP و MAP ممکن است میان شرکت‌کنندگان هیپرتانسیو و دارای فشار خون طبیعی یا میان افراد مبتلا به دیابت نوع 1 یا نوع 2 متفاوت نباشند. در شرکت‌کنندگان هیپرتانسیو، SBP؛ DBP و MAP ممکن است به ترتیب تا 6.45، 3.15 و 4.88 میلی‌متر جیوه کاهش یابند، در حالی که در شرکت‌کنندگان دارای فشار خون طبیعی، ممکن است به ترتیب تا 8.43، 2.95 و 2.15 میلی‌متر جیوه کاهش یابند (همه شواهد با قطعیت پائین). SBP؛ DBP و MAP ممکن است، به ترتیب، تا 7.35، 3.04 و 4.30 میلی‌متر جیوه در شرکت‌کنندگان مبتلا به دیابت نوع 2 و تا 7.35، 3.20 و 0.08 میلی‌متر جیوه در شرکت‌کنندگان مبتلا به دیابت نوع 1 کاهش یابند (همه شواهد با قطعیت پائین).

هشت مطالعه معیارهایی را برای دفع ادراری پروتئین قبل و بعد از محدودیت نمک ارائه کردند؛ چهار مورد کاهش دفع ادراری آلبومین را با محدودیت نمک گزارش دادند. آنالیزهای تجمعی هیچ تغییری را در GFR؛ (12 مطالعه: MD؛ 1.87‐ میلی‌لیتر/دقیقه/1.73 متر مربع (m²)؛ 95% CI؛ 5.05‐ تا 1.31؛ I² = 32%) یا HbA1c؛ (6 مطالعه: MD؛ 0.62‐؛ 95% CI؛ 1.49 ‐تا 0.26؛ I² = 95%) با محدودیت در مصرف نمک (شواهد با قطعیت پائین) نشان ندادند. وزن بدن در مطالعاتی که یک تا دو هفته به طول انجامیدند، کاهش یافت، اما نه در مطالعاتی که برای دوره‌های طولانی‌تری انجام شدند (شواهد با قطعیت پائین). عوارض جانبی فقط در یک مطالعه گزارش شدند؛ 11% و 21%، به ترتیب، با رژیم غذایی کم نمک و با رژیم کم نمک همراه با مصرف هیدروکلروتیازید (hydrochlorothiazide) دچار هیپوتانسیون وضعیتی شدند.

نتیجه‌گیری‌های نویسندگان

این مرور سیستماتیک کاهش قابل‌توجهی را در SBP و DBP در افراد مبتلا به دیابت با GFR طبیعی در طول دوره‌های کوتاه محدودیت مصرف نمک نشان می‌دهد، مشابه آنچه با درمان تک دارویی برای هیپرتانسیون به دست آمد. این داده‌ها از توصیه‌های بین‌المللی حمایت می‌کنند که افراد مبتلا به دیابت با یا بدون هیپرتانسیون یا دارای شواهدی از بیماری کلیوی، باید مصرف نمک را به کمتر از 5 گرم/روز (2 گرم سدیم) برسانند.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

آیا کاهش مصرف نمک به پیشگیری و درمان بیماری مزمن کلیوی در افراد مبتلا به دیابت کمک می‌کند؟

موضوع چیست؟

شواهدی قوی وجود دارد مبنی بر اینکه همه ما بیش از حد نمک می‌خوریم، که خطر ابتلا به فشار خون (BP) بالا را افزایش می‌دهد. این امر به ویژه در افراد مبتلا به دیابت مهم است زیرا دیابت خطر بروز سکته مغزی، حمله قلبی و نارسایی کلیه را افزایش می‌دهد، و هم‌چنین داشتن BP بالا این خطرات را بیشتر می‌کند. کاهش مصرف نمک می‌تواند به کاهش BP و در نتیجه کاهش خطر حملات قلبی و بدتر شدن عملکرد کلیه کمک کند.

ما چه کاری را انجام دادیم؟

تا 31 مارچ 2022، پایگاه ثبت مطالعات گروه کلیه و پیوند در کاکرین را برای یافتن کارآزمایی‌های تصادفی‌سازی و کنترل شده جست‌وجو کردیم که سطوح پائین و بالای نمک دریافتی را در افراد مبتلا به دیابت مقایسه کردند. متوسط سطح کاهش در BP سیستولیک (سطح «بالای (top)» فشار خون اندازه‌گیری شده) و در BP دیاستولیک (سطح «پائین (bottom)» فشار خون اندازه‌گیری شده) را در بیماران دیابتی، زمانی که رژیم غذایی پر نمک و کم نمک دریافت کردند، محاسبه کردیم. همچنین بررسی کردیم که میزان پروتئین موجود در ادرار (نشانه‌ای از آسیب کلیه) در بیماران مبتلا به دیابت که رژیم غذایی کم نمک دریافت کردند، کاهش یافت یا خیر.

ما به چه نتایجی رسیدیم؟

تعداد 13 مطالعه را، شامل 313 فرد مبتلا به دیابت نوع 1 یا 2، پیدا کردیم. ما دریافتیم که کاهش مصرف نمک به‌طور متوسط تا 5 گرم/روز باعث کاهش BP می‌شود، BP سیستولیک تا 7 میلی‌متر جیوه (Hg) و فشار خون دیاستولیک تا 3 میلی‌متر جیوه کاهش می‌یابند. ما دریافتیم که در چهار مطالعه از هشت مطالعه‌ای که این پیامد را گزارش کردند، مقدار پروتئین در ادرار کاهش یافت. فقط یک مطالعه عوارض جانبی ناشی از BP پائین را هنگام ایستادن با رژیم‌های غذایی کم نمک گزارش کرد که در یک چهارم از شرکت‌کنندگان گزارش شد.

نتیجه‌گیری‌‌ها

کاهش مصرف نمک در رژیم غذایی به سطوح توصیه شده 5 گرم/روز یا کمتر، مشابه با کاهش BP با یک داروی BP، برای افراد مبتلا به دیابت مفید خواهد بود.

Authors' conclusions

Implications for practice

This updated systematic review confirms previous findings that salt reduction reduces BP in people with type 1 and type 2 diabetes and can increase pharmacological interventions' efficacy in achieving strict BP control.  These findings, in conjunction with other evidence relating salt intake to BP and albuminuria in hypertensive and normotensive people as well as in people with CKD, suggest that reducing salt intake in people with diabetes to the amounts recommended in public health guidelines for the general population may improve outcomes for people with diabetes.

Implications for research

The studies included in this review were of short duration, involved large changes in dietary salt intake and required frequent measurements of urinary sodium excretion. These studies demonstrated that short‐term reductions in salt intake result in important reductions in SBP, DBP and MAP in people with diabetes with normal GFR with or without microalbuminuria. However, these short‐term studies cannot assess patient‐level outcomes, including CVD and CKD. Assessing such patient‐level outcomes requires larger and longer‐term studies of reduction in salt intake. A recent study of Chinese people with hypertension and previous strokes (Neal 2021) has demonstrated that a longer‐term reduction in sodium intake with a reduction in cardiovascular and cerebral outcomes could be achieved using salt supplements (75% sodium chloride and 25% potassium chloride) to reduce sodium intake. Similar studies could be considered in people with diabetes without reduced GFR since replacing sodium chloride with potassium chloride is potentially harmful in participants with reduced GFR. However, the opportunity to do such studies is limited now that many people with type 2 diabetes are managed with SGLT2 inhibitors, increasing sodium excretion.

Summary of findings

Open in table viewer
Summary of findings 1. Reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Patient or population: patients with diabetes with or without CKD

Setting: inpatients and outpatients
Intervention: reduced salt intake
Comparison: usual or high salt intake

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Risk with usual or high salt intake

Risk with reduced salt intake

Systolic BP: long‐term studies

Duration: up to 12 weeks

The mean systolic BP was 6.15 mm Hg lower with a reduced salt intake (9.27 lower to 3.03 lower) compared to a usual or high salt intake

288 (7)

⊕⊕⊝⊝
LOW 1 2

Systolic BP: short‐term studies

Duration: 1 week

The mean systolic BP was 8.43 mm Hg lower with a reduced salt intake (9.6 lower to 5.81 lower) compared to a usual or high salt intake

112 (5)

⊕⊕⊝⊝
LOW 1 2

Diastolic BP: long‐term studies

Duration: up to 12 weeks

The mean diastolic BP was 3.41 mm Hg lower with a reduced salt intake (5.56 lower to 1.27 lower) compared to a usual or high salt intake

288 (7)

⊕⊕⊝⊝
LOW 1 2

Diastolic BP: short‐term studies

Duration: 1 week

The mean diastolic BP was 2.95 mm Hg lower with a reduced salt intake (4.96 lower to 0.94 lower) compared to a usual or high salt intake

112 (5)

⊕⊕⊝⊝
LOW 1 2

MAP: all studies

Duration: up to 12 weeks

The mean MAP was 3.01 mm Hg lower with a reduced salt intake (4.95 lower to 1.07 lower) compared to a usual or high salt intake

421 (13)

⊕⊕⊝⊝
LOW 1 2

GFF: all studies

Duration: up to 12 weeks

The mean GFR was 1.78 mL/min/1.73 m² lower
with a reduced salt intake (4.21 lower to 0.65 higher) compared to a usual or high salt intake

392 (12)

⊕⊕⊝⊝
LOW 1 2

Body weight: all studies

Duration: up to 12 weeks

The mean body weight was 1.21 kg lower with a reduced salt intake (1.73 lower to 0.68 lower) compared to a usual or high salt intake

454 (12)

⊕⊕⊝⊝
LOW 1 2

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)

CKD: Chronic kidney disease; CI: Confidence interval; RCT: Randomised controlled trial; BP: Blood pressure; MD: Mean difference; MAP: Mean arterial pressure; GFR: Glomerular filtration rate

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Heterogeneity between studies

2 High or unclear risk of bias for allocation concealment and blinding due to study design (cross‐over studies) with small numbers of enrolled participants

Open in table viewer
Summary of findings 2. Net change in blood pressure in hypertensive and normotensive participants with a reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Net change in BP in hypertensive and normotensive participants with a reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Patient or population: patients with diabetes with or without CKD
Setting: inpatients and outpatients
Intervention: reduced salt intake
Comparison: usual or high salt intake

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Risk with usual or high salt intake

Risk with reduced salt intake

Systolic BP

Duration: up to 12 weeks

The mean systolic BP in hypertensive patients was 6.45 mm Hg lower with a reduced salt intake (11.69 lower to 3.61 lower) compared to a usual or high salt intake

108 (5)

⊕⊕⊝⊝
LOW 1 2

The mean systolic BP in normotensive patients was 8.43 mm Hg lower with a reduced salt intake (9.6 lower to 5.81 lower) compared to a usual or high salt intake

108 (5)

⊕⊕⊝⊝
LOW 1 2

Diastolic BP

Duration: up to 12 weeks

The mean diastolic BP in hypertensive patients was 3.15 mm Hg lower with a reduced salt intake (6.49 lower to 0.18 lower) compared to a usual or high salt intake

108 (5)

⊕⊕⊝⊝
LOW 1 2

The mean diastolic BP in normotensive patients was 2.95 mm Hg lower with a reduced salt intake (4.11 lower to 2 lower) compared to a usual or high salt intake

108 (5)

⊕⊕⊝⊝
LOW 1 2

MAP

Duration: up to 12 weeks

The mean MAP in hypertensive patients was 4.88 mm Hg lower with a reduced salt intake (10.39 lower to 0.63 lower) compared to a usual or high salt intake

59 (3)

⊕⊕⊝⊝
LOW 1 2

The MAP in normotensive patients was 2.15 mm Hg lower with a reduced salt intake (4.56 lower to 0.26 lower) compared to a usual or high salt intake

182 (8)

⊕⊕⊝⊝
LOW 1 2

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

BP: Blood pressure; CKD: Chronic kidney disease; CI: Confidence interval; MD: Mean difference; MAP: Mean arterial pressure

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Heterogeneity between studies

2 High or unclear risk of bias for allocation concealment and blinding due to study design (cross‐over studies) with small numbers of enrolled participants

Open in table viewer
Summary of findings 3. Net change in blood pressure in participants with type 1 or type 2 diabetes with a reduced salt diet versus usual or high salt intake for preventing diabetic kidney disease and its progression

Net change in BP in participants with type 1 and type 2 diabetes with a reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Patient or population: patients with diabetes with or without CKD
Setting: inpatients and outpatients
Intervention: reduced salt intake
Comparison: usual or high salt intake

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Risk with usual or high salt intake

Risk with reduced salt intake

Systolic BP

Duration: up to 12 weeks

The mean systolic BP in patients with type 1 diabetes was 7.35 mm Hg lower with a reduced salt intake (14.49 lower to 0.21 lower) compared to a usual or high salt intake

96 (4)

⊕⊕⊝⊝
LOW 1 2

The mean systolic BP in patients with type 2 diabetes was 7.35 mm Hg lower with a reduced salt intake (10.32 lower to 4.38 lower) compared to a usual or high salt intake

304 (8)

⊕⊕⊝⊝
LOW 1 2

Diastolic BP:

Duration: up to 12 weeks

The mean diastolic BP in patients with type 1 diabetes was 3.20 mm Hg lower with a reduced salt intake (5.16 lower to 1.23 lower) compared to a usual or high salt intake

96 (4)

⊕⊕⊝⊝
LOW 1 2

The mean diastolic BP in patients with type 2 diabetes was 3.04 mm Hg lower with a reduced salt intake (5.20 lower to 0.89 lower) compared to a usual or high salt intake

304 (8)

⊕⊕⊝⊝
LOW 1 2

MAP

Duration: up to 12 weeks

The mean MAP in patients with type 1 diabetes was 0.08 mm Hg higher with a reduced salt intake (1.92 lower to 2.08 higher) compared to a usual or high salt intake

62 (3)

⊕⊕⊝⊝
LOW 1 2

The mean MAP in patients with type 2 diabetes was 4.03 mm Hg lower with a reduced salt intake (6.54 lower to 2.05 lower) compared to a usual or high salt intake

359 (10)

⊕⊕⊝⊝
LOW 1 2

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

BP: Blood pressure; CKD: Chronic kidney disease; CI: Confidence interval; MD: Mean difference; MAP: Mean arterial pressure

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Heterogeneity between studies

2 High or unclear risk of bias for allocation concealment and blinding due to study design (cross‐over studies) with small numbers of enrolled participants

Background

Description of the condition

Approximately 75% of cardiovascular disease (CVD) in people with diabetes can be attributed to raised blood pressure (BP), and it is the largest direct cause of death due to stroke, heart attack and heart failure in people with diabetes (Adler 2000Mozaffarian 2014Sowers 2001Strain 2018). Chronic kidney disease (CKD) associated with diabetes is responsible for the largest group on dialysis programmes, with a significant burden on healthcare resources (Harvey 2003). Lowering BP reduces the progression of CKD in people with diabetes, and diabetic patients with BP less than 130/80 mm Hg have the same reduction in glomerular filtration rate (GFR) due to age as healthy individuals (Giunti 2006Schrier 2002).

Description of the intervention

In an analysis for the Global Burden of Disease Study (GBD 2017), a high salt intake was determined to be one of the main factors leading to increased death and morbidity among people worldwide due largely to CVD. Reducing salt intake reduces systolic BP (SBP) and diastolic BP (DBP) in adults and children (WHO 2012). Therefore, WHO recommends a reduction in salt intake to below 5 g/day (< 2 g/day sodium) in adults to reduce BP and the risk of CVD, stroke and coronary heart disease (WHO 2012). In agreement with the WHO, the KDIGO guidelines (KDIGO 2020) on diabetes management in CKD recommend salt intake should be below 5 g/day (< 2 g of sodium) in people with diabetes and CKD to potentiate the suppression of the renin‐angiotensin system (RAS) by angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptors blockers (ARB). RAS blockade is considered essential to delay the progression of CKD in people with diabetes. However, cardiovascular and kidney protection by RAS blockade may not be complete. Therefore, additional strategies to improve the efficacy of RAS blockade, including dietary salt restriction, may be useful in people with diabetes to potentiate RAS blockade efficacy.

How the intervention might work

Diabetic patients differ from the nondiabetic population in having an increase in total body sodium, an increase in renal tubular sodium reabsorption, and an impaired ability to excrete a sodium load. These factors suggest that reducing dietary salt intake may play an important role in the management of hypertension in the diabetic population (Houlihan Losartan 2002Houlihan Placebo 2002). The activity of the sodium‐glucose co‐transporter increases proximal tubular reabsorption of sodium, and this reduces distal sodium delivery (Woods 1987). Insulin directly increases distal tubular sodium reabsorption (DeFronzo 1981). Furthermore, increased angiotensin II in the tubular fluid activates sodium channels in the collecting duct (Nishiyama 2002). People with diabetes have a lower incidence of low renin state and a higher plasma renin activity on a high salt diet than volunteers. This lack of suppression of the RAS with a high salt diet may play a part in the development of hypertension (De'Oliveira 1997Price 1999) in people with diabetes. Lowering salt intake also reduces urinary protein excretion in several populations, and increased urinary protein excretion is an important marker of CKD and CVD in people with diabetes (Allen 1997Cianciaruso 1998He 2009aSwift 2005).

Why it is important to do this review

There is strong evidence that our current consumption of salt is a major factor in increasing BP (GBD 2017He 2009b). Despite the high cardiovascular risk and theoretical reasons for increased salt sensitivity in people with diabetes, the current knowledge of the role of salt in regulating BP and its impact on people with diabetes is limited to small studies. Therefore, we carried out a systematic review of all studies where the salt intake was altered in people with diabetes. There are no standard criteria for high and low salt diets in people with diabetes. As with previous meta‐analyses of salt reduction, this review included studies where the difference in sodium intake between periods of high and low sodium intakes was at least 34 mmol/day (He 2002He 2003Law 1991). This is an update of a review first published in 2010.

Objectives

We aimed to evaluate the effects of salt restriction on the prevention and progression of CKD in people with diabetes by studying the effects of changing salt intake on BP, urinary protein excretion and surrogate markers of CVD and CKD.

Methods

Criteria for considering studies for this review

Types of studies

For inclusion, studies needed to satisfy the following inclusion criteria. 

  • Randomised controlled trials (RCT) with random allocation to either a low or a high salt intake.

  • Sodium intake was estimated by 24‐hour urinary sodium excretion (24‐hour UNa), and studies achieved a minimum difference in 24‐hour UNa of 34 mmol (i.e. 2 g salt/day). The reduction in 24‐hour UNa was calculated as UNa (high) ‐ UNa (low) in cross‐over studies and was calculated as (UNa (high) ‐ UNa (low)) low salt group ‐ (UNa (high) ‐ UNa (low)) control group in parallel studies. For cross‐over studies, UNa (low) was the 24‐hour UNa at the end of the reduced salt period, and the UNa (high) was the 24‐hour UNa at the end of the high salt period. For parallel studies, UNa (high) and UNa (low) were the 24‐hour UNa measurements at baseline and at the end of the intervention for each group.

  • Studies where concomitant interventions, such as antihypertensive medication or other dietary modifications, were used during the study period were included providing that these interventions were constant throughout the low and high salt period.

Types of participants

We included all RCTs of adults (18 years or older) with type 1 or type 2 diabetes mellitus, irrespective of ethnicity or gender. We excluded studies of children and pregnant women.

Types of interventions

We included studies where a low salt intake was compared to a high salt intake with a minimum difference in 24‐hour UNa, as described above.

Types of outcome measures

The updated primary and secondary outcomes aimed to cover all clinically relevant and critical outcomes according to the recent KDIGO guidelines (KDIGO 2020).

Primary outcomes

  1. Net change in 24‐hour UNa

  2. Net change in 24‐hour BP (SBP, DBP, mean arterial pressure (MAP))

  3. Death (any cause)

Secondary outcomes

  1. Functional kidney measurements: urinary albumin excretion (UAE), proteinuria, serum creatinine (SCr), creatinine clearance (CrCl), estimated (e) GFR, effective renal plasma flow (ERPF)

  2. Glycated haemoglobin (HbA1c), hypoglycaemia

  3. Body weight: body weight, body mass index (BMI)

  4. CVD events: stroke, heart failure, myocardial infarction

  5. Adverse events

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of Studies up to 31 March 2022 through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources:

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of kidney‐related journals and the proceedings of major kidney conferences

  4. Searching the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected kidney and transplant journals

  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website under CKT Register of Studies.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of review articles and relevant studies.

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

Two review authors independently undertook an assessment of citations. We retrieved full articles if the initial assessment suggested that studies or reviews might include relevant data. We independently assessed abstracts and, if necessary, the full text to identify suitable studies. We resolved disagreements through discussion between the authors.

Data extraction and management

We extracted data using standard data extraction forms. We recorded relevant data, including characteristics of the study, design (parallel or cross‐over), type of study (open, single‐blind, double‐blind), method of blinding, study duration and pre‐ and post‐intervention results. Where more than one publication of a study existed, we used the publication with the most complete data.

Assessment of risk of bias in included studies

The following items were assessed independently by two authors using the risk of bias assessment tool (Higgins 2022) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study?

    • Participants and personnel (performance bias)

    • Outcome assessors (detection bias)

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at risk of bias?

Measures of treatment effect

We calculated treatment effects for each study. We calculated the mean difference (MD) for outcome measurements with 95% confidence intervals (CI). In cross‐over studies, we calculated the MD in outcomes as the difference between the end of the low salt period and the end of the high salt period. For parallel studies, we calculated the treatment effect as the difference between the two treatment groups in the change in outcomes from baseline.

Unit of analysis issues

The majority of included studies were cross‐over studies, providing separate data for each treatment period's end. We calculated the treatment effect for cross‐over studies as the MD between the results at the end of the low salt period and those at the end of the high salt period. 

Dealing with missing data

We contacted the original authors when relevant data were not reported in the publication.

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows.

  • 0% to 40%: might not be important

  • 30% to 60%: may represent moderate heterogeneity

  • 50% to 90%: may represent substantial heterogeneity

  • 75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P value from the Chi² test or a CI for I²) (Higgins 2022).

Assessment of reporting biases

We planned to use funnel plots to assess the potential existence of small study bias (Higgins 2022). However, there were too few studies included in the review to allow assessment of reporting bias. 

Data synthesis

We pooled data using generic inverse variance with both fixed‐effect and random‐effects models to ensure the robustness of the model chosen and susceptibility to outliers. Data are presented using the random effects model.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were used to explore possible sources of heterogeneity.

  • Long‐term (four to 12 weeks) versus short‐term studies (up to seven days)

  • Studies of hypertensive versus normotensive participants

  • Studies including type 1 versus type 2 diabetes participants

Heterogeneity between studies may be related to the types of participants. Heterogeneity between studies could be related to variations in the degree of sodium reduction, the different durations of the studies, differences between parallel group and cross‐over designs and the presence or absence of a washout period between interventions in cross‐over studies. 

Sensitivity analysis

We had planned to perform sensitivity analyses to explore the influence of the following factors on effect size. However, we could not undertake most of these analyses as outlined below.

  • Repeating the analysis, excluding unpublished studies

  • Repeating the analysis taking account of the risk of bias, as specified

  • Repeating the analysis, excluding any very long or large studies, to establish how much they dominate the results.

Summary of findings and assessment of the certainty of the evidence

We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2022a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008GRADE 2011). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of the within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, the precision of effect estimates and risk of publication bias (Schunemann 2022b). We presented the following outcomes in the 'Summary of findings' tables:

  • Net changes in SBP, DBP, MAP, GFR and weight with reduced dietary salt in all participants

  • Net changes in SBP, DBP and MAP with reduced dietary salt in hypertensive and normotensive participants

  • Net changes in SBP, DBP and MAP with reduced dietary salt in type 1 and type 2 diabetes participants.

We had planned to include data on death and cardiovascular outcomes in the Summary of Findings Tables, but no data were available for these outcomes from included studies.

Results

Description of studies

Results of the search

The initial search in 2010 identified 914 citations, of which 72 reports were potentially eligible. After full‐text analysis, 13 RCTs (16 reports, 254 participants) were included, and 53 studies (56 reports) were excluded.

For this 2022 update, two additional RCTs were identified, of which one was excluded (Ushigome 2019) and one was included (Kwakernaak HTZ 2014Kwakernaak Placebo 2014). Petrie 1998, which was included in the 2010 review, was reviewed and was excluded from this update as frusemide was only given to the high salt intake group and would have increased sodium excretion. Therefore, for this update, we included 13 studies (20 reports) with 313 participants were included in this review (Figure 1).


Study flow diagram

Study flow diagram

Included studies

To avoid confusion, we used the term "study" for each entry throughout this meta‐analysis because some RCTs had two or more comparisons and have been split and entered more than once for the purpose of the meta‐analyses. There were 21 separate studies from 13 RCTs with 313 included participants.

We have summarised the studies' characteristics in the review in Appendix 3.

Outcome reporting

All studies reported BP measurements and 24‐hour UNa. There was much variability in reporting of measurements of kidney function and UAE. Studies used different isotopes to measure GFR and other haemodynamic measurements. UAE was reported in ways that could not be entered into a pooled analysis: two studies reported data as geometric mean and percentage change (Houlihan Losartan 2002Houlihan Placebo 2002); two studies reported data as mean albumin excretion and as albumin:creatinine ratios (Kwakernaak HTZ 2014Kwakernaak Placebo 2014); one study reported data as a change in 24‐hour albumin excretion (Luik 2002); one study reported the mean level and range of urinary albumin (Mulhauser 1996); and two studies presented data as the median and interquartile range of albumin excretion (Vedovato Micro 2004Vedovato Normo 2004). We have summarised the outcomes reported in each study in Appendix 4.

Excluded studies

Fourteen studies in people with diabetes were excluded. Six studies were excluded because they studied multiple interventions (DNETT Japan 2010Dodson 1984Ekinci 2009Gilleran 1996Helou 2016HHK 2018) rather than altered salt intake. Three studies included some participants without diabetes, and the data for participants with or without diabetes could not be separated (LowSALT CKD 2012Suckling 2016ViRTUE‐CKD 2016). Two studies did not measure urinary sodium levels (Imanishi 1997Ushigome 2019). One study included in the initial review was excluded in this update because additional frusemide was given to the high‐salt group but not the low‐salt group (Petrie 1998). PROCEED 2018 was excluded because the difference in 24‐hour UNa between high and low sodium intakes was less than 34 mmol/L.

Risk of bias in included studies

All included studies were small and of variable methodology resulting generally in high risk of bias (Figure 2; Figure 3)


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.


Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation

Three studies were at low risk of bias for sequence generation. Low risk of bias was judged when the method of randomisation was reported as random number allocation in Luik 2002 and by computer randomisation in blocks of two (Kwakernaak HTZ 2014Kwakernaak Placebo 2014). Sixteen studies were judged to be at unclear risk of bias as they provided no details about how the methods of randomisation were performed. Two studies were judged as having a high risk of bias because the dietician randomised the patients upon enrolment (Miller 1995Miller 1997).

Allocation concealment

Two studies provided a description of allocation concealment by reporting that the randomisation code remained a secret during the entire trial and was judged to be at low risk of bias (Kwakernaak HTZ 2014Kwakernaak Placebo 2014). One study was judged to be a high risk of bias (Lopes De Faria 1997). The remaining 18 studies did not provide information about allocation concealment and were judged to have an unclear risk of bias.

Blinding

Blinding of participants and personnel (performance bias)

Only Mulhauser 1996 adequately described the methods used for double‐blinding of both the patients and investigators and was judged to be at low risk of bias.

Three studies were stated to be double‐blind trials but failed to provide any further details about how the participants or personnel were kept blind to treatments, and so were judged to be an unclear risk of bias (Dodson_X 1989Houlihan Losartan 2002Houlihan Placebo 2002).

The remaining 17 studies were unblinded, open‐label studies and judged to be at high risk of bias. In Kwakernaak HTZ 2014 and Kwakernaak Placebo 2014, the dietary component was open‐label, but the hydrochlorothiazide and placebo were double‐blind, and for this reason, the study was judged at a high risk of bias.

Blinding of outcome assessors (detection bias)

Only Mulhauser 1996 adequately described the methods used to keep all investigators, and outcome assessors blind until the last patient had completed the study and was judged to be at low risk of bias.

Miller 1995 reported the investigators remained blind to the diets, but no further details were provided about how this was carried out, so this study was judged as at unclear risk of bias.

The remaining 19 studies were either unblinded (De'Oliveira 1997Dodson_P 1989Imanishi Micro 2001Imanishi Normo 2001Lopes De Faria 1997Luik 2002) or stated to be double‐blind studies but provided no information regarding the blinding of outcome assessors (Dodson_X 1989Houlihan Losartan 2002Houlihan Placebo 2002Miller 1997Trevisan Micro 1998Trevisan Normo 1998Vedovato Micro 2004Vedovato Normo 2004Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998). In Kwakernaak HTZ 2014 and Kwakernaak Placebo 2014, the dietary component was open‐label, but the hydrochlorothiazide and placebo were double‐blind, and for this reason, the study was judged at high risk of bias.
 

Incomplete outcome data

In two studies, all participants were accounted for from the start to the end of the study, with only two participants withdrawing per study (attrition rate = 4%). Intention‐to‐treat (ITT) analysis was performed for the original participant samples, including those two withdrawals (ITT; N = 45), so the studies were judged to be low risk of bias (Kwakernaak HTZ 2014Kwakernaak Placebo 2014).

In three studies, all participants were accounted for from the start to the end of the study. No participants dropped out. However, it was unclear whether ITT analysis was performed; therefore, the studies were judged to be at unclear risk of bias (Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998).

In the remaining 16 studies, either withdrawals or data were not complete; study attrition was not clearly reported, or an ITT analysis was not reported or performed, and therefore the studies were judged to be at high risk of bias.

Selective reporting

All 21 studies were judged to be at high risk of bias. In all studies, the outcomes planned in the methods were reported in the results. However, none of the studies had published protocols or trial registrations to provide evidence to show that reporting bias was not present. In four studies, the protocol was provided as supplementary materials. either online or in appendices. However, all were published at the same time as the article, which was considered insufficient, so they were judged to be at high risk of bias (Imanishi Micro 2001Imanishi Normo 2001Kwakernaak HTZ 2014Kwakernaak Placebo 2014).

Other potential sources of bias

Funding declaration

Seventeen studies declared their funding sources. Twelve were not industry funding and were judged to be at low risk of bias. Five declared funding from the pharmaceutical industry and were judged to be at high risk of bias (Dodson_P 1989Dodson_X 1989Houlihan Losartan 2002Houlihan Placebo 2002Mulhauser 1996). The remaining four studies failed to declare any sources of funding and were judged to be at unclear risk of bias (Lopes De Faria 1997Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998).

Conflicts of interest

Only three studies reported conflicts of interest, and all three declared no competing interests (Kwakernaak HTZ 2014Kwakernaak Placebo 2014Lopes De Faria 1997). Two studies were judged to be at high risk of bias (Houlihan Losartan 2002Houlihan Placebo 2002). The remaining 16 studies did not report any details about whether they had conflicts or not and were judged to be at unclear risk of bias.

Other information

Eight studies were judged to be at low risk of other potential biases because they either did not require a washout period (parallel design) or a sufficient washout period of seven days or more was applied (De'Oliveira 1997Dodson_P 1989Houlihan Losartan 2002Houlihan Placebo 2002Lopes De Faria 1997Luik 2002Miller 1997Mulhauser 1996).

In one cross‐over study, insufficient details were reported on whether a washout period was applied between treatment arms and was therefore judged to have an unclear risk of bias (Dodson_X 1989).

In the remaining 12 studies, no washout period was applied between cross‐over phases resulting in possible carryover effects, and therefore they were judged to be at high risk of bias (Imanishi Micro 2001Imanishi Normo 2001Kwakernaak HTZ 2014Kwakernaak Placebo 2014Miller 1995Trevisan Micro 1998Trevisan Normo 1998Vedovato Micro 2004Vedovato Normo 2004Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998).

No other potential sources of bias were identified.

Effects of interventions

See: Summary of findings 1 Reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression; Summary of findings 2 Net change in blood pressure in hypertensive and normotensive participants with a reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression; Summary of findings 3 Net change in blood pressure in participants with type 1 or type 2 diabetes with a reduced salt diet versus usual or high salt intake for preventing diabetic kidney disease and its progression

As studies were not of sufficient duration to test the efficacy of salt reduction on outcome measurements such as heart attacks, end‐stage kidney disease (ESKD) or death, changes in salt intake on BP and surrogate markers of CKD in participants were considered in evaluating the evidence for this review.

Urinary sodium excretion

In 17 studies (Appendix 5), the median 24‐hour UNa on the usual or high salt intake was 203 mmol (4.7 g sodium/day) with a range of 159 to 361 mmol/24 hours (3.7 to 8.3 g sodium/day). The median 24‐hour UNa on a low salt diet was 73 mmol (1.7 g sodium/day) with a range of 14 to 164 mmol (0.6 to 7.1 g sodium/day). The median net change in 24‐hour UNa was 123 mmol/24 hours (5.4 g sodium/day) with a range of 51 to 337 mmol (2.2 to 14.7 g sodium/day). Four studies (Imanishi Micro 2001Imanishi Normo 2001Vedovato Micro 2004Vedovato Normo 2004) were excluded from these calculations as they only provided graphical data of urinary sodium concentrations.

In the seven long‐term studies (Dodson_P 1989Dodson_X 1989Houlihan Losartan 2002Houlihan Placebo 2002Kwakernaak HTZ 2014Kwakernaak Placebo 2014Mulhauser 1996), the median 24‐hour UNa on the high salt diet was 202 mmol, with a range of 188 to 224 mmol and on the low salt diet was 123 mmol, ranging from 80 to 164 mmol. The median net change in 24‐hour UNa was 76 mmol, ranging from 51 to 124 mmol.

In short‐term studies, data were available from 10 studies (De'Oliveira 1997Lopes De Faria 1997Luik 2002Miller 1995Miller 1997Trevisan Micro 1998Trevisan Normo 1998Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998). Median 24‐hour UNa on the usual or high salt diet was 224 mmol, with a range of 159 to 361 mmol and on the low salt diet was 32 mmol, with a range of 14 to 99 mmol. The median net change in 24‐hour UNa was 187 mmol, with a range of 86 to 337 mmol.

In 10 studies, which included participants with hypertension (De'Oliveira 1997Dodson_P 1989Dodson_X 1989Houlihan Losartan 2002Houlihan Placebo 2002Kwakernaak HTZ 2014Kwakernaak Placebo 2014Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998), the median net change in 24‐hour UNa was 89 mmol, with a range of 51 to 181 mmol. In seven studies (Lopes De Faria 1997Luik 2002Miller 1995Miller 1997Mulhauser 1996Trevisan Micro 1998Trevisan Normo 1998) which included participants with normal BP levels, the median net change in 24‐hour UNa was 211 mmol with a range of 107 to 337 mmol.

In seven studies of participants with type 1 diabetes, the median net change in 24‐hour UNa was 211 mmol with a range of 107 to 337 mmol (Lopes De Faria 1997Luik 2002Miller 1995Miller 1997Mulhauser 1996Trevisan Micro 1998Trevisan Normo 1998). In 10 studies of participants with type 2 diabetes, the median net change in 24‐hour UNa was 89 mmol with a range of 51 to 181 mmol (De'Oliveira 1997Dodson_P 1989Dodson_X 1989Houlihan Losartan 2002Houlihan Placebo 2002Kwakernaak HTZ 2014Kwakernaak Placebo 2014Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998).

Effects of different sodium intakes on blood pressure

All studies that could be included in the meta‐analyses reported measurements of BP as SBP and DBP or MAP (defined as DBP + (SBP‐DBP)/3).

Systolic blood pressure

Data from 12 studies were available for analysis of SBP. Combining data on longer‐term (up to 12 weeks) with short‐term use (one week) of low sodium intake demonstrated that a low sodium intake diet may reduce SBP by 7.36 mm Hg (Analysis 1.1 (12 studies): MD ‐7.36 mm Hg, 95% CI ‐10.75 to ‐3.98; I² = 74%). In longer studies, low sodium intake may reduce SBP by 6.15 mm Hg (Analysis 1.1.1 (7 studies): MD ‐6.12 mm Hg, 95% CI ‐9.27 to ‐3.03; I² = 12%) while in one‐week studies, low sodium intake may reduce SBP by 8.43 mm Hg (Analysis 1.1.2 (5 studies): MD ‐8.43 mm Hg, 95% CI ‐14.37 to ‐2.48; I² = 88%). There was considerable heterogeneity in the analysis of one‐week studies (I² = 88%) but not in the analysis of longer studies (I² = 12%).

The reduction in SBP with a low sodium diet may not differ between studies of participants with (Analysis 1.6.2) or without albuminuria (Analysis 1.6.1) at study enrolment.

Diastolic blood pressure

Data from 12 studies were available for analysis of DBP (Analysis 1.3). Combining longer‐term and short‐term use of low sodium intake demonstrated that a low sodium intake diet may reduce DBP by 3.17 mm Hg (Analysis 1.3 (12 studies): MD ‐3.17 mm Hg, 95% CI ‐4.58 to ‐1.76; I² = 54%). In longer studies, low sodium intake may reduce DBP by 3.41 mm Hg (Analysis 1.3.1 (7 studies): MD ‐3.41 mm Hg, 95% CI ‐5.56 to ‐1.27; I² = 41%) while in one‐week studies, low sodium intake also may reduce DBP by 2.95 mm Hg (Analysis 1.3.2 (5 studies): MD ‐2.95 mm Hg, 95% CI ‐4.96 to ‐0.94; I² = 70%). There was substantial heterogeneity in the analysis of one‐week studies (I² = 70%), but this was lower in the analysis of longer studies (I² = 41%).

The reduction in DBP with a low sodium diet may not differ between studies of participants with (Analysis 1.7.2) or without albuminuria (Analysis 1.7.1) at study enrolment.

Mean arterial pressure

Data from 13 studies were available for analysis of MAP. Both long‐term and short‐term use of low sodium intake may reduce MAP by 3.01 mm Hg (Analysis 1.5 (13 studies): MD ‐3.01 mm Hg, 95% CI ‐4.95 to ‐1.07; I² = 63%). In longer studies, low sodium intake may reduce MAP by 4.60 mm Hg (Analysis 1.5.1 (4 studies): MD ‐4.60 mm Hg, 95% CI ‐7.26 to ‐1.94; I² = 28%). In one‐week studies, low sodium intake may reduce MAP by 2.37 mm Hg (Analysis 1.5.2 (9 studies): MD ‐2.37 mm Hg, 95% CI ‐4.75 to ‐0.01; I² = 65%). There was substantial heterogeneity in the analysis of one‐week studies (I = 65%), but this was not seen in the analysis of longer studies (I² = 28%).

The reduction in MAP with a low sodium intake may be greater in studies of participants with albuminuria at study enrolment (Analysis 1.8.2 (7 studies): MD ‐5.40 mm Hg, 95% CI ‐7.72 to ‐3.08) compared with those without albuminuria (Analysis 1.8.1 (3 studies): MD ‐0.11 mm Hg, 95% CI ‐2.27 to 2.05) at study enrolment.

Certainty of the evidence

The certainty of the evidence is summarised in summary of findings Table 1. All results were considered to be at low certainty evidence because of the small numbers of included participants, heterogeneity between study results and increased risk of bias.

Effects of different sodium intakes on blood pressure in hypertensive and normotensive participants

Hypertensive participants

Five studies evaluated the effects of salt restriction on SBP and DBP in hypertensive participants (Dodson_P 1989Dodson_X 1989Houlihan Losartan 2002Houlihan Placebo 2002Mulhauser 1996), and three studies evaluated MAP (De'Oliveira 1997Houlihan Losartan 2002Houlihan Placebo 2002).

In hypertensive participants, salt restriction may reduce SBP by 6.45 mm Hg (Analysis 2.1.1 (5 studies): MD ‐6.45 mm Hg, 95% CI ‐11.47 to ‐1.42; I² = 41%), DBP by 3.15 mm Hg (Analysis 2.2.1 (5 studies): MD ‐3.15 mm Hg, 95% CI ‐6.49 to ‐0.18; I ² = 60%), and MAP by 4.88 mm Hg (Analysis 2.3.1 (3 studies): MD ‐4.88 mm Hg, 95% CI ‐10.39 to ‐0.63; I² = 54%). There was moderate heterogeneity in the analyses.

Normotensive participants

Five studies evaluated the effects of salt restriction in normotensive participants (Imanishi Micro 2001Imanishi Normo 2001Luik 2002Trevisan Micro 1998Trevisan Normo 1998), and eight studies evaluated MAP (Lopes De Faria 1997Miller 1995Miller 1997Vedovato Micro 2004Vedovato Normo 2004Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998).

In normotensive participants, salt restriction may reduce SBP by 8.43 mm Hg (Analysis 2.1.2 (5 studies): MD ‐8.43 mm Hg, 95% CI ‐14.37 to ‐2.48; I² = 88%), reduce DBP by 2.95 mm Hg (Analysis 2.2.2 (5 studies): MD ‐2.95 mm Hg, 95% CI ‐4.96 to ‐0.94; I² = 70%), and MAP by 2.15 mm Hg (Analysis 2.3.2 (8 studies): MD ‐2.15 mm Hg, 95% CI ‐4.56 to ‐0.26; I² = 68%). There was substantial heterogeneity in the analyses.

Certainty of the evidence

The certainty of the evidence is summarised in summary of findings Table 2. All results were considered to be of low certainty evidence because of the small numbers of included participants, heterogeneity between study results and increased risk of bias.

Effects of different sodium intakes on blood pressure in type 1 and type 2 diabetes

Type 1 diabetes

Four studies evaluated the effects of salt restriction on SBP and DBP in participants with type 1 diabetes (Luik 2002Mulhauser 1996Trevisan Micro 1998Trevisan Normo 1998), and three studies reported the effects on MAP (Lopes De Faria 1997Miller 1995Miller 1997).

Salt restriction may reduce SBP by 7.35 mm Hg (Analysis 3.1.1 (4 studies): MD ‐7.35 mm Hg, 95% CI ‐14.49 to ‐0.21; I² = 91%) and DBP by 3.20 mm Hg (Analysis 3.2.1 (4 studies): MD ‐3.20 mm Hg, 95% CI ‐5.16 to ‐1.23; I² = 62%), but may make little or no difference to MAP (Analysis 3.3.1 (3 studies): MD 0.08 mm Hg, 95% CI ‐4.95 to 2.08; I² = 8%).

Type 2 diabetes

Eight studies evaluated the effects of salt restriction on SBP and DBP in participants with type 2 diabetes (Dodson_P 1989Dodson_X 1989Houlihan Losartan 2002Houlihan Placebo 2002Imanishi Micro 2001Imanishi Normo 2001 Kwakernaak HTZ 2014Kwakernaak Placebo 2014), and 10 studies evaluated MAP (De'Oliveira 1997Houlihan Losartan 2002Houlihan Placebo 2002Kwakernaak HTZ 2014Kwakernaak Placebo 2014Vedovato Micro 2004Vedovato Normo 2004Yoshioka Adva Alb 1998Yoshioka Micro 1998Yoshioka Normo 1998).

Salt restriction may reduce SBP by 7.35 mm Hg (Analysis 3.1,2 (8 studies): MD ‐7.35 mm Hg, 95% CI ‐10.32 to ‐4.38; I² = 22%), DBP by 3.04 mm Hg (Analysis 3.2.2 (8 studies): MD ‐3.04 mm Hg, 95% CI ‐5.20 to ‐0.89; I² = 57%), and MAP by 4.30 mm Hg (Analysis 3.3.2 (10 studies): MD ‐4.30 mm Hg, 95% CI ‐6.54 to ‐2.05; I = 56%). There was substantial heterogeneity in the analyses.

Certainty of the evidence

The certainty of the evidence is summarised in summary of findings Table 3. All results were considered to be of low certainty evidence because of the small numbers of included participants, heterogeneity between study results and increased risk of bias.

Concomitant interventions with renin‐angiotensin system blockers

Salt restriction has been demonstrated to reduce BP when the RAS is blocked (MacGregor 1987). Three of seven studies in the long‐term studies included participants treated with RAS blockers (Houlihan Losartan 2002Kwakernaak HTZ 2014Kwakernaak Placebo 2014). Therefore we recalculated pooled data, excluding data from these studies. Pooled estimates of the changes in the remaining four studies showed reductions in SBP of 5.55 mm Hg (Analysis 1.2.1 (4 studies): MD ‐5.55 mm Hg, 95% CI ‐11.73 to ‐0.62) and in DBP of 2.26 mm Hg (Analysis 1.4.1 (4 studies): MD ‐2.26m Hg, 95% CI ‐6.54 to 2.02) with 95% CIs that overlapped those of Analysis 1.1 and Analysis 1.3 (which included the studies using ACEi or ARBs), suggesting that RAS blockade may not result in further reductions in SBP and DBP in this small group of studies.

Effects of altering salt intake on measurements of kidney function

Pooled analysis of seven studies showed that salt restriction may reduce CrCl by 6.05 mL/min (Analysis 1.9 (7 studies): MD ‐6.05 mL/min, 95% CI ‐10.00 to ‐2.10; I² = 0%). However, pooled analysis of 12 studies of eGFR found that there may make little or no difference in eGFR in these studies (Analysis 1.10 (12 studies): MD ‐1.87 mL/min/1.73 m², 95% CI ‐5.05 to 1.31; I² = 32%).

Eight studies reported change in ERPF. Salt restriction may not alter ERPF in longer studies (Analysis 1.11.1 (8 studies): MD ‐0.73 mL/min, 95% CI ‐2.83 to 1.37; I² = 0%) or short‐term studies (Analysis 1.11.2 (5 studies): MD ‐0.14 mL/min, 95% CI ‐68.26 to 67.98; I² = 82%).

Effects of altering salt intake on urinary albumin and protein excretion

Eight studies presented data on changes in urinary albumin or urinary protein excretion during salt restriction (Houlihan Losartan 2002Houlihan Placebo 2002Kwakernaak HTZ 2014Kwakernaak Placebo 2014Luik 2002Mulhauser 1996Vedovato Micro 2004Vedovato Normo 2004. The data for individual studies are shown in Appendix 6. These studies reported the data in ways which were not suitable for meta‐analysis, so pooled analyses were not performed. One study of type 2 diabetics (Vedovato Micro 2004) reported salt restriction may reduce UAE in patients with microalbuminuria, while two other studies reported no change in UAE in type 1 diabetics with (Mulhauser 1996) or without (Luik 2002) microalbuminuria. Salt restriction may reduce UAE in type 2 diabetics receiving RAS blockade (Houlihan Losartan 2002Kwakernaak HTZ 2014Kwakernaak Placebo 2014) but may not reduce UAE in those not receiving RAS blockade (Houlihan Placebo 2002).

Effects of altering salt intake on HbA1c

Six studies reported the results of HbA1c at the beginning and end of the study (Dodson_P 1989Houlihan Losartan 2002Houlihan Placebo 2002Lopes De Faria 1997Luik 2002Mulhauser 1996).

Pooled analysis showed no difference in HbA1c during salt restriction, suggesting that there were no alterations in diabetic control during the studies (Analysis 1.12 (6 studies): MD ‐0.62, 95% CI ‐1.49 to 0.26; I² = 95%). There was significant heterogeneity between studies; however, the exclusion of one small study (Lopes De Faria 1997) (which showed a small decrease of 3% in HbA1c) removed the heterogeneity between studies.

Effects of altering salt intake on body weight

Twelve studies reported data on body weight (Dodson_P 1989Dodson_X 1989Kwakernaak HTZ 2014Kwakernaak Placebo 2014Lopes De Faria 1997Luik 2002Miller 1997Mulhauser 1996Trevisan Micro 1998Trevisan Normo 1998Vedovato Micro 2004Vedovato Normo 2004).

Salt restriction lowered body weight by ‐1.21 kg (Analysis 1.13 (12 studies): MD ‐1.21 kg, 95% CI ‐1.73 to ‐0.68; I² = 76%). This effect was primarily due to changes in short‐term studies, with minimal weight change with salt restriction in longer studies (Analysis 1.13.1 (5 studies): MD ‐0.35 kg, 95% CI ‐1.63 to 0.94; I² = 0%) compared with short‐term studies (Analysis 1.13.2 (7 studies): MD ‐1.30 kg, 95% CI ‐1.89 to ‐0.72; I² = 86%) suggesting that these changes are likely to be due to a reduction in extracellular volume.

Adverse effects

Only two studies reported adverse effects (Kwakernaak HTZ 2014Kwakernaak Placebo 2014). These studies reported orthostatic hypotension was identified in 11% of participants receiving a reduced sodium diet compared with 4% receiving a normal sodium diet. It occurred most frequently (21%) in those receiving a low salt diet together with hydrochlorothiazide.

Fixed effects versus random effects model

To ensure robustness, we performed analyses using both the fixed effect and random effects models.

In all studies (Analysis 1.1 to Analysis 1.5), reductions in SBP, DBP and MAP with salt restrictions were similar using both analyses. Compared with the initial version of this review, the addition of Kwakernaak HTZ 2014 and Kwakernaak Placebo 2014 to the subgroup analysis resulted in the net change in DBP in longer studies no longer differing between the fixed effects (MD ‐3.71 mm Hg, 95% CI ‐5.29 to ‐2.14) and random effects models (MD ‐3.41 mm Hg, 95% CI ‐5.56 to ‐1.27) with both models showing a reduction in DBP with salt restriction.

In studies of hypertensive and normotensive participants, salt restriction reduced SBP, DBP and MAP in both groups (Analysis 2.1Analysis 2.2Analysis 2.3). Among the subgroup of hypertensive participants, the net change in DBP did not differ between fixed (MD ‐3.78 mm Hg, 95% CI ‐5.73 to ‐1.84) and random effects models (MD ‐3.15 mm Hg, 95% CI ‐6.49 to 0.18) but the 95% CIs crossed 1 with the random effects model. There was no difference between subgroups with either analysis.

In studies of type 1 and type 2 diabetics, changes in SBP, DBP and MAP with salt restriction were similar between fixed and random effects analyses (Analysis 3.1Analysis 3.2Analysis 3.3).

Investigation of sources of heterogeneity

We assessed heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). We investigated levels of heterogeneity considered to be substantial (50% to 90%) or considerable (75% to 100%). For the outcomes of SBP, DBP and MAP, there was considerable heterogeneity among short‐term studies (SBP: 88%; DBP: 70%; MAP: 65%), but this variation was not seen in long‐term studies (SBP: 12%; DBP: 41%; MAP: 28%). While variations in MDs between studies within short‐term studies did not appear to be related to either the reduction in urinary sodium achieved or to the minimum urine sodium recorded (Appendix 7), the range of net change in UNa recorded in short‐term studies (86 to 337 mmol) was much greater than that seen in long‐term studies (51 to 124 mmol) suggesting that differences in study design contributed to heterogeneity between studies.

We also examined whether there were differences in the degree of heterogeneity among cross‐over studies in which there was or was not a washout period between the first and second parts of the cross‐over. For SBP (Analysis 1.14) but not for MAP (Analysis 1.15), there was less heterogeneity among cross‐over studies with washout compared with those without washout. However, the results for SBP largely mirrored those seen overall for SBP among long‐term and short‐term studies (Analysis 1.1). For MAP, there remained heterogeneity of 69% among cross‐over studies with washout (Analysis 1.15.1) and 66% among studies without washout (Analysis 1.15.2). Overall, we were not able to identify specific sources for heterogeneity between studies. However, most studies were at high risk of bias for most criteria (Figure 2).

Sensitivity analyses

We planned to perform sensitivity analyses to explore the influence of the following factors on effect size.

  • Repeating the analysis excluding unpublished studies: This was not done as we did not identify any unpublished studies.

  • Repeating the analysis taking account of the risk of bias, as specified: This was not done as studies were at unclear or high risk of bias for most criteria (Figure 2Figure 4Figure 5)

  • Repeating the analysis excluding any long duration or large studies to establish how much they dominate the results: We re‐analysed the results after excluding three studies with long durations and more than 30 participants (Dodson_P 1989Kwakernaak HTZ 2014Kwakernaak Placebo 2014). The results for SBP for long‐term studies with these three studies excluded (MD ‐5.57 mm Hg, 95% CI ‐9.51 to ‐1.62) did not differ from the overall results (MD ‐6.12 m Hg, 95% CI ‐9.02 to ‐3.22). The MD for DBP in long‐term studies (MD ‐5.02 mm Hg, 95% CI ‐9.38 to ‐0.65) was slightly higher than for the overall results (MD ‐3.71 mm Hg, 95% CI ‐5.29 to ‐2.14), but the CIs overlapped. Therefore we did not identify that the exclusion of these three studies made major changes to the results.


Forest plot of comparison: 1 Net change with altering salt diet, outcome: 1.1 Systolic BP.

Forest plot of comparison: 1 Net change with altering salt diet, outcome: 1.1 Systolic BP.


Forest plot of comparison: 1 Net change with altering salt diet, outcome: 1.5 MAP.

Forest plot of comparison: 1 Net change with altering salt diet, outcome: 1.5 MAP.

Discussion

Summary of main results

This systematic review identified 21 studies (313 participants) from 13 RCTs, which evaluated the efficacy of reducing salt intake on BP and kidney function in participants with type 1 or type 2 diabetes. This update added two additional studies (Kwakernaak HTZ 2014Kwakernaak Placebo 2014). All studies were of short duration, and no studies addressed the outcomes of cardiovascular events (stroke, heart failure, myocardial infarction).

  • The median net reduction in all studies in 24‐hour UNa during the low sodium intake was 123 mmol/24 hours (5.4 g sodium/day) with a range of 51 to 337 mmol (2.2 to 14.7 g sodium/day). The median net reduction in seven long‐term studies (treatment duration four to 12 weeks) was 76 mmol, ranging from 51 to 124 mmol. The median net reduction in 10 short‐term studies (treatment duration five to seven days) was 187 mmol, with a range of 86 to 337 mmol. Data were only available graphically in four studies.

  • Sodium restriction may reduce SBP by 7.36 mm Hg, DBP by 3.17 mm Hg and MAP by 3.01 mm Hg in all participants (low certainty evidence).

  • No differences were identified between hypertensive and normotensive participants or between participants with type 1 or type 2 diabetes (low certainty evidence).

  • During salt restriction, SBP and DBP may be reduced by similar amounts in studies, including participants with or without microalbuminuria at study enrolment. However, the reduction in MAP may be greater in participants with microalbuminuria at study enrolment compared with those without microalbuminuria.

  • UAE was formally assessed in only eight studies. During salt restriction, UAE fell in four studies (Appendix 6).

  • There may be a small reduction in body weight during salt restriction, but this was largely seen in studies of one to two weeks rather than in longer studies (low certainty evidence).

  • There may be no differences in HbA1c during salt restriction (low certainty evidence).

  • There may be no changes to GFR or ERPF though CrCl may be reduced by 6 mL/min during salt restriction (low certainty evidence).

  • Adverse effects were only reported in two of 21 studies. Two studies reported that orthostatic hypotension was identified more frequently in participants receiving a reduced sodium diet with or without hydrochlorothiazide compared with those receiving a normal sodium diet (Kwakernaak HTZ 2014Kwakernaak Placebo 2014).

Overall completeness and applicability of evidence

The available data from this systematic review of RCTs of salt restriction indicate that lowering sodium intake may reduce BP in participants with type 1 and type 2 diabetes, with and without hypertension and with normal or slightly abnormal kidney function (G1, A1 or A2 on the KDIGO classification) (KDIGO 2020). No studies were identified in this patient group which evaluated salt restriction in participants with greater degrees of reduced kidney function. Two additional studies were added in this update (Kwakernaak HTZ 2014Kwakernaak Placebo 2014), but these data did not change the conclusions of the initial version of the review. The duration of the studies (maximum duration three months) and the small size of the studies (maximum number of 45 participants) did not allow any assessment of important patient‐centred outcomes, including death and CVD. The majority of studies were cross‐over studies, with only one or two weeks in each phase of the study. Seventeen studies provided information on the sodium intakes in each group, with four studies providing graphical information only. Twelve studies provided information on SBP and DBP, while nine provided information only on MAP. Data on kidney function were more limited, with only 12 studies providing information on eGFR and an additional three studies providing information on CrCl. Overall, eGFR was maintained unchanged during the study periods. Limited data were available to assess the effect of salt reduction on UAE. UAE is important in monitoring the progression of kidney disease in participants with diabetes and is an independent predictor of CVD (Hillege 2002). We found only eight studies in this meta‐analysis where UAE and/or protein excretion was measured, and it was not possible to perform pooled analysis due to variations in the way data were reported. Four of the eight studies demonstrated a reduction in UAE with salt restriction. Most studies were performed before 2000, and participants did not routinely receive RAS inhibitors. RAS inhibition with either ACEi or ARBs is now recommended for all diabetic patients with albuminuria since RAS blockade slows the deterioration in kidney function (KDIGO 2020). Since high salt intake reduces the efficacy of these agents on BP (MacGregor 1987), guidelines recommend that salt intake be reduced to 5 g/day (sodium intake < 2 g or < 90 mmol/day) (KDIGO 2020). While such reductions in salt intake may be achievable in the short term, it is hard to maintain long‐term reductions without intensive input from dietitians and easily interpretable information about the salt content of commonly used foods.

Quality of the evidence

There are important limitations to this review. The number of studies on the effects of salt reduction in diabetics was limited, and the majority of available studies were of short duration with few included participants. The results show considerable heterogeneity, particularly among studies lasting only one to two weeks. The small number of studies limits the ability to explore potential sources of this heterogeneity. It is likely that differing methodologies and degrees and duration of salt restriction affect heterogeneity. Studies varied from five days to 12 weeks, and longer studies had more modest changes in salt intake. Several short studies restricted levels of salt intake to as low as 0.6 g/day, followed by loading of up to 20 g/day of salt. Acute, large changes in dietary salt intake such as this will stimulate the RAS and increase sympathetic activity. This will have an impact on the effects on BP and renal haemodynamics. This is demonstrated by the lack of any difference in SBP or DBP between shorter and longer studies, despite a change in median salt intake of almost double that seen in the longer studies. While MDs in MAP did differ slightly between long‐term and short‐term studies, the CIs overlapped.

Outcome measurements were mostly restricted to measurements of BP and surrogate markers of kidney function. We did not find any available data on outcome measurements such as time to ESKD, CVD and death. 24‐hour UNa is a surrogate method of estimating salt intake, but since approximately 90% of the salt we eat is excreted through the kidneys, 24‐hour UNa provides an accurate assessment of sodium intake. Compared with all other methods, e.g. dietary record or recall, measuring 24‐hour UNa excretion is the most accurate and accepted method for assessing dietary salt intake.

GRADE assessment of the included outcomes showed that the certainty of the evidence was low for all outcomes when all studies were included (summary of findings Table 1), when studies evaluated participants with or without hypertension (summary of findings Table 2) and when studies evaluated participants with type 1 and type 2 diabetes (summary of findings Table 3). Studies were downgraded for risk of bias issues (allocation concealment and blinding), for heterogeneity between studies and for imprecision based on small numbers of enrolled participants.

Potential biases in the review process

The search strategy was comprehensive and covers all important and relevant databases. We do not believe we have missed any potentially relevant studies. Of the studies identified, we have endeavoured to obtain all data by contacting the authors, but we were unsuccessful in obtaining additional data. Therefore, there is a small potential for bias in the available outcome data. Data collection was undertaken using a piloted data extraction form. Data analysis and assessment of the quality of studies were all performed in duplicate with a third party for disagreement resolution. We do not believe any other biases could have been introduced.

Agreements and disagreements with other studies or reviews

A recently published systematic review of RCTs has evaluated the effect of reducing salt intake on BP in people with type 2 diabetes (Ren 2021). This review included eight RCTs (10 studies) in adults, who underwent a period of salt restriction of at least one week, the sodium intake was calculated from 24‐hour UNa measurements, and the differences in SBP and DBP between low and usual sodium diets were reported or could be calculated. Six studies (Dodson_P 1989Houlihan Losartan 2002Houlihan Placebo 2002Imanishi Micro 2001Imanishi Normo 2001Kwakernaak Placebo 2014) were also included in this Cochrane review. The authors found that salt restriction reduced SBP and DBP by 5.6 mm Hg and 1.7 mm Hg, respectively, compared with reductions of 7.2 mm Hg and 3 mm Hg found in our Cochrane review. Recent systematic reviews of RCTs in people with CKD and not on dialysis found that reducing salt intake lowers SBP and DBP by similar amounts to those seen in our review(Garafalo 2018McMahon 2021). In systematic reviews of studies in people with normal kidney function, reducing sodium intake consistently reduces BP levels with greater reductions in hypertension participants (Graudal 2020He 2003). In this review, we found that urinary protein excretion was reduced in four of the eight studies in which this outcome was reported. This outcome was not reported in Ren 2021, which reviewed studies of participants with type 2 diabetes. Systematic reviews in people with CKD (Garafalo 2018McMahon 2021) have found that reduced salt intake reduces urinary protein excretion by about 30%.

Study flow diagram

Figures and Tables -
Figure 1

Study flow diagram

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Net change with altering salt diet, outcome: 1.1 Systolic BP.

Figures and Tables -
Figure 4

Forest plot of comparison: 1 Net change with altering salt diet, outcome: 1.1 Systolic BP.

Forest plot of comparison: 1 Net change with altering salt diet, outcome: 1.5 MAP.

Figures and Tables -
Figure 5

Forest plot of comparison: 1 Net change with altering salt diet, outcome: 1.5 MAP.

Comparison 1: Net change with altering salt diet, Outcome 1: Systolic BP

Figures and Tables -
Analysis 1.1

Comparison 1: Net change with altering salt diet, Outcome 1: Systolic BP

Comparison 1: Net change with altering salt diet, Outcome 2: Systolic BP (excluding studies using RAS)

Figures and Tables -
Analysis 1.2

Comparison 1: Net change with altering salt diet, Outcome 2: Systolic BP (excluding studies using RAS)

Comparison 1: Net change with altering salt diet, Outcome 3: Diastolic BP

Figures and Tables -
Analysis 1.3

Comparison 1: Net change with altering salt diet, Outcome 3: Diastolic BP

Comparison 1: Net change with altering salt diet, Outcome 4: Diastolic BP (excluding studies using RAS)

Figures and Tables -
Analysis 1.4

Comparison 1: Net change with altering salt diet, Outcome 4: Diastolic BP (excluding studies using RAS)

Comparison 1: Net change with altering salt diet, Outcome 5: MAP

Figures and Tables -
Analysis 1.5

Comparison 1: Net change with altering salt diet, Outcome 5: MAP

Comparison 1: Net change with altering salt diet, Outcome 6: Systolic BP according to presence/absence of albuminuria at enrolment

Figures and Tables -
Analysis 1.6

Comparison 1: Net change with altering salt diet, Outcome 6: Systolic BP according to presence/absence of albuminuria at enrolment

Comparison 1: Net change with altering salt diet, Outcome 7: Diastolic BP according to presence/absence of albuminuria at enrolment

Figures and Tables -
Analysis 1.7

Comparison 1: Net change with altering salt diet, Outcome 7: Diastolic BP according to presence/absence of albuminuria at enrolment

Comparison 1: Net change with altering salt diet, Outcome 8: MAP according to the presence/absence of albuminuria at enrolment

Figures and Tables -
Analysis 1.8

Comparison 1: Net change with altering salt diet, Outcome 8: MAP according to the presence/absence of albuminuria at enrolment

Comparison 1: Net change with altering salt diet, Outcome 9: Creatinine clearance

Figures and Tables -
Analysis 1.9

Comparison 1: Net change with altering salt diet, Outcome 9: Creatinine clearance

Comparison 1: Net change with altering salt diet, Outcome 10: Glomerular filtration rate

Figures and Tables -
Analysis 1.10

Comparison 1: Net change with altering salt diet, Outcome 10: Glomerular filtration rate

Comparison 1: Net change with altering salt diet, Outcome 11: Effective renal plasma flow

Figures and Tables -
Analysis 1.11

Comparison 1: Net change with altering salt diet, Outcome 11: Effective renal plasma flow

Comparison 1: Net change with altering salt diet, Outcome 12: HbA1c

Figures and Tables -
Analysis 1.12

Comparison 1: Net change with altering salt diet, Outcome 12: HbA1c

Comparison 1: Net change with altering salt diet, Outcome 13: Body weight

Figures and Tables -
Analysis 1.13

Comparison 1: Net change with altering salt diet, Outcome 13: Body weight

Comparison 1: Net change with altering salt diet, Outcome 14: Systolic BP in cross‐over studies with or without washout between interventions

Figures and Tables -
Analysis 1.14

Comparison 1: Net change with altering salt diet, Outcome 14: Systolic BP in cross‐over studies with or without washout between interventions

Comparison 1: Net change with altering salt diet, Outcome 15: MAP in cross‐over studies with or without washout between study periods

Figures and Tables -
Analysis 1.15

Comparison 1: Net change with altering salt diet, Outcome 15: MAP in cross‐over studies with or without washout between study periods

Comparison 2: Net change in BP in hypertensive and normotensive participants, Outcome 1: Systolic BP

Figures and Tables -
Analysis 2.1

Comparison 2: Net change in BP in hypertensive and normotensive participants, Outcome 1: Systolic BP

Comparison 2: Net change in BP in hypertensive and normotensive participants, Outcome 2: Diastolic BP

Figures and Tables -
Analysis 2.2

Comparison 2: Net change in BP in hypertensive and normotensive participants, Outcome 2: Diastolic BP

Comparison 2: Net change in BP in hypertensive and normotensive participants, Outcome 3: MAP

Figures and Tables -
Analysis 2.3

Comparison 2: Net change in BP in hypertensive and normotensive participants, Outcome 3: MAP

Comparison 3: Net change in BP in type 1 and type 2 diabetes, Outcome 1: Systolic BP

Figures and Tables -
Analysis 3.1

Comparison 3: Net change in BP in type 1 and type 2 diabetes, Outcome 1: Systolic BP

Comparison 3: Net change in BP in type 1 and type 2 diabetes, Outcome 2: Diastolic BP

Figures and Tables -
Analysis 3.2

Comparison 3: Net change in BP in type 1 and type 2 diabetes, Outcome 2: Diastolic BP

Comparison 3: Net change in BP in type 1 and type 2 diabetes, Outcome 3: MAP

Figures and Tables -
Analysis 3.3

Comparison 3: Net change in BP in type 1 and type 2 diabetes, Outcome 3: MAP

Comparison 3: Net change in BP in type 1 and type 2 diabetes, Outcome 4: HbA1c

Figures and Tables -
Analysis 3.4

Comparison 3: Net change in BP in type 1 and type 2 diabetes, Outcome 4: HbA1c

Comparison 4: Adverse events, Outcome 1: Orthostatic hypotension

Figures and Tables -
Analysis 4.1

Comparison 4: Adverse events, Outcome 1: Orthostatic hypotension

Summary of findings 1. Reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Patient or population: patients with diabetes with or without CKD

Setting: inpatients and outpatients
Intervention: reduced salt intake
Comparison: usual or high salt intake

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Risk with usual or high salt intake

Risk with reduced salt intake

Systolic BP: long‐term studies

Duration: up to 12 weeks

The mean systolic BP was 6.15 mm Hg lower with a reduced salt intake (9.27 lower to 3.03 lower) compared to a usual or high salt intake

288 (7)

⊕⊕⊝⊝
LOW 1 2

Systolic BP: short‐term studies

Duration: 1 week

The mean systolic BP was 8.43 mm Hg lower with a reduced salt intake (9.6 lower to 5.81 lower) compared to a usual or high salt intake

112 (5)

⊕⊕⊝⊝
LOW 1 2

Diastolic BP: long‐term studies

Duration: up to 12 weeks

The mean diastolic BP was 3.41 mm Hg lower with a reduced salt intake (5.56 lower to 1.27 lower) compared to a usual or high salt intake

288 (7)

⊕⊕⊝⊝
LOW 1 2

Diastolic BP: short‐term studies

Duration: 1 week

The mean diastolic BP was 2.95 mm Hg lower with a reduced salt intake (4.96 lower to 0.94 lower) compared to a usual or high salt intake

112 (5)

⊕⊕⊝⊝
LOW 1 2

MAP: all studies

Duration: up to 12 weeks

The mean MAP was 3.01 mm Hg lower with a reduced salt intake (4.95 lower to 1.07 lower) compared to a usual or high salt intake

421 (13)

⊕⊕⊝⊝
LOW 1 2

GFF: all studies

Duration: up to 12 weeks

The mean GFR was 1.78 mL/min/1.73 m² lower
with a reduced salt intake (4.21 lower to 0.65 higher) compared to a usual or high salt intake

392 (12)

⊕⊕⊝⊝
LOW 1 2

Body weight: all studies

Duration: up to 12 weeks

The mean body weight was 1.21 kg lower with a reduced salt intake (1.73 lower to 0.68 lower) compared to a usual or high salt intake

454 (12)

⊕⊕⊝⊝
LOW 1 2

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)

CKD: Chronic kidney disease; CI: Confidence interval; RCT: Randomised controlled trial; BP: Blood pressure; MD: Mean difference; MAP: Mean arterial pressure; GFR: Glomerular filtration rate

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Heterogeneity between studies

2 High or unclear risk of bias for allocation concealment and blinding due to study design (cross‐over studies) with small numbers of enrolled participants

Figures and Tables -
Summary of findings 1. Reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression
Summary of findings 2. Net change in blood pressure in hypertensive and normotensive participants with a reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Net change in BP in hypertensive and normotensive participants with a reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Patient or population: patients with diabetes with or without CKD
Setting: inpatients and outpatients
Intervention: reduced salt intake
Comparison: usual or high salt intake

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Risk with usual or high salt intake

Risk with reduced salt intake

Systolic BP

Duration: up to 12 weeks

The mean systolic BP in hypertensive patients was 6.45 mm Hg lower with a reduced salt intake (11.69 lower to 3.61 lower) compared to a usual or high salt intake

108 (5)

⊕⊕⊝⊝
LOW 1 2

The mean systolic BP in normotensive patients was 8.43 mm Hg lower with a reduced salt intake (9.6 lower to 5.81 lower) compared to a usual or high salt intake

108 (5)

⊕⊕⊝⊝
LOW 1 2

Diastolic BP

Duration: up to 12 weeks

The mean diastolic BP in hypertensive patients was 3.15 mm Hg lower with a reduced salt intake (6.49 lower to 0.18 lower) compared to a usual or high salt intake

108 (5)

⊕⊕⊝⊝
LOW 1 2

The mean diastolic BP in normotensive patients was 2.95 mm Hg lower with a reduced salt intake (4.11 lower to 2 lower) compared to a usual or high salt intake

108 (5)

⊕⊕⊝⊝
LOW 1 2

MAP

Duration: up to 12 weeks

The mean MAP in hypertensive patients was 4.88 mm Hg lower with a reduced salt intake (10.39 lower to 0.63 lower) compared to a usual or high salt intake

59 (3)

⊕⊕⊝⊝
LOW 1 2

The MAP in normotensive patients was 2.15 mm Hg lower with a reduced salt intake (4.56 lower to 0.26 lower) compared to a usual or high salt intake

182 (8)

⊕⊕⊝⊝
LOW 1 2

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

BP: Blood pressure; CKD: Chronic kidney disease; CI: Confidence interval; MD: Mean difference; MAP: Mean arterial pressure

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Heterogeneity between studies

2 High or unclear risk of bias for allocation concealment and blinding due to study design (cross‐over studies) with small numbers of enrolled participants

Figures and Tables -
Summary of findings 2. Net change in blood pressure in hypertensive and normotensive participants with a reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression
Summary of findings 3. Net change in blood pressure in participants with type 1 or type 2 diabetes with a reduced salt diet versus usual or high salt intake for preventing diabetic kidney disease and its progression

Net change in BP in participants with type 1 and type 2 diabetes with a reduced salt intake versus usual or high salt intake for preventing diabetic kidney disease and its progression

Patient or population: patients with diabetes with or without CKD
Setting: inpatients and outpatients
Intervention: reduced salt intake
Comparison: usual or high salt intake

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Risk with usual or high salt intake

Risk with reduced salt intake

Systolic BP

Duration: up to 12 weeks

The mean systolic BP in patients with type 1 diabetes was 7.35 mm Hg lower with a reduced salt intake (14.49 lower to 0.21 lower) compared to a usual or high salt intake

96 (4)

⊕⊕⊝⊝
LOW 1 2

The mean systolic BP in patients with type 2 diabetes was 7.35 mm Hg lower with a reduced salt intake (10.32 lower to 4.38 lower) compared to a usual or high salt intake

304 (8)

⊕⊕⊝⊝
LOW 1 2

Diastolic BP:

Duration: up to 12 weeks

The mean diastolic BP in patients with type 1 diabetes was 3.20 mm Hg lower with a reduced salt intake (5.16 lower to 1.23 lower) compared to a usual or high salt intake

96 (4)

⊕⊕⊝⊝
LOW 1 2

The mean diastolic BP in patients with type 2 diabetes was 3.04 mm Hg lower with a reduced salt intake (5.20 lower to 0.89 lower) compared to a usual or high salt intake

304 (8)

⊕⊕⊝⊝
LOW 1 2

MAP

Duration: up to 12 weeks

The mean MAP in patients with type 1 diabetes was 0.08 mm Hg higher with a reduced salt intake (1.92 lower to 2.08 higher) compared to a usual or high salt intake

62 (3)

⊕⊕⊝⊝
LOW 1 2

The mean MAP in patients with type 2 diabetes was 4.03 mm Hg lower with a reduced salt intake (6.54 lower to 2.05 lower) compared to a usual or high salt intake

359 (10)

⊕⊕⊝⊝
LOW 1 2

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

BP: Blood pressure; CKD: Chronic kidney disease; CI: Confidence interval; MD: Mean difference; MAP: Mean arterial pressure

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Heterogeneity between studies

2 High or unclear risk of bias for allocation concealment and blinding due to study design (cross‐over studies) with small numbers of enrolled participants

Figures and Tables -
Summary of findings 3. Net change in blood pressure in participants with type 1 or type 2 diabetes with a reduced salt diet versus usual or high salt intake for preventing diabetic kidney disease and its progression
Comparison 1. Net change with altering salt diet

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Systolic BP Show forest plot

12

Mean Difference (IV, Random, 95% CI)

‐7.36 [‐10.75, ‐3.98]

1.1.1 Long‐term studies

7

Mean Difference (IV, Random, 95% CI)

‐6.15 [‐9.27, ‐3.03]

1.1.2 Short‐term studies

5

Mean Difference (IV, Random, 95% CI)

‐8.43 [‐14.37, ‐2.48]

1.2 Systolic BP (excluding studies using RAS) Show forest plot

9

Mean Difference (IV, Random, 95% CI)

‐7.44 [‐11.83, ‐3.04]

1.2.1 Long‐term studies

4

Mean Difference (IV, Random, 95% CI)

‐5.55 [‐11.73, 0.62]

1.2.2 Short‐term studies

5

Mean Difference (IV, Random, 95% CI)

‐8.43 [‐14.37, ‐2.48]

1.3 Diastolic BP Show forest plot

12

Mean Difference (IV, Random, 95% CI)

‐3.17 [‐4.58, ‐1.76]

1.3.1 Long‐term studies

7

Mean Difference (IV, Random, 95% CI)

‐3.41 [‐5.56, ‐1.27]

1.3.2 Short‐term studies

5

Mean Difference (IV, Random, 95% CI)

‐2.95 [‐4.96, ‐0.94]

1.4 Diastolic BP (excluding studies using RAS) Show forest plot

9

Mean Difference (IV, Random, 95% CI)

‐2.76 [‐4.53, ‐0.99]

1.4.1 Long‐term studies

4

Mean Difference (IV, Random, 95% CI)

‐2.26 [‐6.54, 2.02]

1.4.2 Short‐term studies

5

Mean Difference (IV, Random, 95% CI)

‐2.95 [‐4.96, ‐0.94]

1.5 MAP Show forest plot

13

Mean Difference (IV, Random, 95% CI)

‐3.01 [‐4.95, ‐1.07]

1.5.1 Long‐term studies

4

Mean Difference (IV, Random, 95% CI)

‐4.60 [‐7.26, ‐1.94]

1.5.2 Short‐term studies

9

Mean Difference (IV, Random, 95% CI)

‐2.37 [‐4.75, 0.01]

1.6 Systolic BP according to presence/absence of albuminuria at enrolment Show forest plot

12

Mean Difference (IV, Random, 95% CI)

‐6.63 [‐10.19, ‐3.08]

1.6.1 No albuminuria

5

Mean Difference (IV, Random, 95% CI)

‐8.08 [‐15.42, ‐0.73]

1.6.2 Albuminuria

7

Mean Difference (IV, Random, 95% CI)

‐5.85 [‐8.76, ‐2.95]

1.7 Diastolic BP according to presence/absence of albuminuria at enrolment Show forest plot

12

Mean Difference (IV, Random, 95% CI)

‐3.54 [‐4.92, ‐2.16]

1.7.1 No albuminuria

5

Mean Difference (IV, Random, 95% CI)

‐3.58 [‐5.75, ‐1.42]

1.7.2 Albuminuria

7

Mean Difference (IV, Random, 95% CI)

‐3.48 [‐5.45, ‐1.52]

1.8 MAP according to the presence/absence of albuminuria at enrolment Show forest plot

10

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.8.1 No albuminuria

3

Mean Difference (IV, Random, 95% CI)

‐0.11 [‐2.27, 2.05]

1.8.2 Albuminuria

7

Mean Difference (IV, Random, 95% CI)

‐5.40 [‐7.72, ‐3.08]

1.9 Creatinine clearance Show forest plot

7

Mean Difference (IV, Random, 95% CI)

‐6.05 [‐10.00, ‐2.10]

1.9.1 Long‐term studies

3

Mean Difference (IV, Random, 95% CI)

‐6.66 [‐18.55, 5.23]

1.9.2 Short‐term studies

4

Mean Difference (IV, Random, 95% CI)

‐7.23 [‐12.88, ‐1.58]

1.10 Glomerular filtration rate Show forest plot

12

Mean Difference (IV, Random, 95% CI)

‐1.87 [‐5.05, 1.31]

1.10.1 Long‐term studies

5

Mean Difference (IV, Random, 95% CI)

‐2.07 [‐5.29, 1.15]

1.10.2 Short‐term studies

7

Mean Difference (IV, Random, 95% CI)

‐3.26 [‐9.93, 3.42]

1.11 Effective renal plasma flow Show forest plot

8

Mean Difference (IV, Random, 95% CI)

‐6.74 [‐17.08, 3.59]

1.11.1 Long‐term studies

3

Mean Difference (IV, Random, 95% CI)

‐0.73 [‐2.83, 1.37]

1.11.2 Short‐term studies

5

Mean Difference (IV, Random, 95% CI)

‐0.14 [‐68.26, 67.98]

1.12 HbA1c Show forest plot

6

Mean Difference (IV, Random, 95% CI)

‐0.62 [‐1.49, 0.26]

1.12.1 Long‐term studies

4

Mean Difference (IV, Random, 95% CI)

‐0.05 [‐0.35, 0.25]

1.12.2 Short‐term studies

2

Mean Difference (IV, Random, 95% CI)

‐1.44 [‐4.47, 1.60]

1.13 Body weight Show forest plot

12

Mean Difference (IV, Random, 95% CI)

‐1.21 [‐1.73, ‐0.68]

1.13.1 Long‐term studies

5

Mean Difference (IV, Random, 95% CI)

‐0.35 [‐1.63, 0.94]

1.13.2 Short‐term studies

7

Mean Difference (IV, Random, 95% CI)

‐1.30 [‐1.89, ‐0.72]

1.14 Systolic BP in cross‐over studies with or without washout between interventions Show forest plot

10

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.14.1 Studies with washout

5

Mean Difference (IV, Random, 95% CI)

‐4.33 [‐7.32, ‐1.33]

1.14.2 Studies without washout

5

Mean Difference (IV, Random, 95% CI)

‐9.92 [‐15.67, ‐4.16]

1.15 MAP in cross‐over studies with or without washout between study periods Show forest plot

12

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.15.1 Studies with washout

6

Mean Difference (IV, Random, 95% CI)

‐2.52 [‐5.50, 0.46]

1.15.2 Studies without washout

6

Mean Difference (IV, Random, 95% CI)

‐3.32 [‐6.28, ‐0.36]

Figures and Tables -
Comparison 1. Net change with altering salt diet
Comparison 2. Net change in BP in hypertensive and normotensive participants

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Systolic BP Show forest plot

10

Mean Difference (IV, Random, 95% CI)

‐7.65 [‐11.69, ‐3.61]

2.1.1 Hypertensive

5

Mean Difference (IV, Random, 95% CI)

‐6.45 [‐11.47, ‐1.42]

2.1.2 Normotensive

5

Mean Difference (IV, Random, 95% CI)

‐8.43 [‐14.37, ‐2.48]

2.2 Diastolic BP Show forest plot

10

Mean Difference (IV, Random, 95% CI)

‐3.08 [‐4.74, ‐1.43]

2.2.1 Hypertensive

5

Mean Difference (IV, Random, 95% CI)

‐3.15 [‐6.49, 0.18]

2.2.2 Normotensive

5

Mean Difference (IV, Random, 95% CI)

‐2.95 [‐4.96, ‐0.94]

2.3 MAP Show forest plot

11

Mean Difference (IV, Random, 95% CI)

‐2.74 [‐4.97, ‐0.51]

2.3.1 Hypertensive

3

Mean Difference (IV, Random, 95% CI)

‐4.88 [‐10.39, 0.63]

2.3.2 Normotensive

8

Mean Difference (IV, Random, 95% CI)

‐2.15 [‐4.56, 0.26]

Figures and Tables -
Comparison 2. Net change in BP in hypertensive and normotensive participants
Comparison 3. Net change in BP in type 1 and type 2 diabetes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Systolic BP Show forest plot

12

Mean Difference (IV, Random, 95% CI)

‐7.36 [‐10.75, ‐3.98]

3.1.1 Type 1 diabetes

4

Mean Difference (IV, Random, 95% CI)

‐7.35 [‐14.49, ‐0.21]

3.1.2 Type 2 diabetes

8

Mean Difference (IV, Random, 95% CI)

‐7.35 [‐10.32, ‐4.38]

3.2 Diastolic BP Show forest plot

12

Mean Difference (IV, Random, 95% CI)

‐3.17 [‐4.58, ‐1.76]

3.2.1 Type 1 diabetes

4

Mean Difference (IV, Random, 95% CI)

‐3.20 [‐5.16, ‐1.23]

3.2.2 Type 2 diabetes

8

Mean Difference (IV, Random, 95% CI)

‐3.04 [‐5.20, ‐0.89]

3.3 MAP Show forest plot

13

Mean Difference (IV, Random, 95% CI)

‐3.01 [‐4.95, ‐1.07]

3.3.1 Type 1 diabetes

3

Mean Difference (IV, Random, 95% CI)

0.08 [‐1.92, 2.08]

3.3.2 Type 2 diabetes

10

Mean Difference (IV, Random, 95% CI)

‐4.30 [‐6.54, ‐2.05]

3.4 HbA1c Show forest plot

6

Mean Difference (IV, Random, 95% CI)

‐0.62 [‐1.49, 0.26]

3.4.1 Type 1 diabetes

3

Mean Difference (IV, Random, 95% CI)

‐0.94 [‐2.38, 0.51]

3.4.2 Type 2 diabetes

3

Mean Difference (IV, Random, 95% CI)

‐0.12 [‐0.58, 0.34]

Figures and Tables -
Comparison 3. Net change in BP in type 1 and type 2 diabetes
Comparison 4. Adverse events

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Orthostatic hypotension Show forest plot

2

180

Risk Ratio (M‐H, Random, 95% CI)

2.50 [0.81, 7.68]

Figures and Tables -
Comparison 4. Adverse events