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\begin{document}

\title{Effects of the 52\% low-sodium salt applied to CM-DASH diet in
hypertensive patients with type 2 diabetes:A Randomized Controlled
Trial}



\author[1]{Lisha Mu}%
\author[1]{Huakun Rao}%
\author[2]{Pingping Yu}%
\author[3]{Huini Xu}%
\author[3]{Hao Wang}%
\author[1]{Dan Chen}%
\author[1]{Jie Tang}%
\author[1]{Tao Gong}%
\author[1]{Jing Li}%
\author[2]{Ying Mei}%
\author[1]{Lihong Mu}%
\affil[1]{Chongqing Medical University}%
\affil[2]{Chongqing Medical University Affiliated Second Hospital}%
\affil[3]{Chongqing Nan'an District People's Hospital}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background and Aims: The DASH diet have been proven to be effective in
lowering blood pressure (BP), but it is rarely used in people with type
2 diabetes (T2D), especially in the Chinese population. We aimed to
evaluate the effects of 52\% low- sodium salt applied to CM-DASH diet in
patients with hypertension and T2D. Methods and Results: This trial is a
single-blind, randomized controlled study conducted from December 2019
to November 2020 at Chongqing, China. 61 participants were randomly
allocated to intervention group or control group for 8 weeks.2
participants were lost, and 59 patients were finally included in the
analysis. The systolic blood pressure (SBP) and diastolic blood pressure
(DBP) of intervention group and control group were significantly
decreased compared with baseline, but there was no difference between
groups. The 24-hour urine Na+ and Cl- of the two groups decreased
significantly after intervention, but the increase of 24-hour urine K+
and the decrease of Na+/ K+ ratio were only observed in the intervention
group. Furthermore,the urine urinary albumin creatinine ratio (UACR) and
serum creatinine of two groups also decreased from baseline.
Conclusions: Following the CM-DASH diet in hypertensive patients with
T2D has beneficial effects in improving SBP and DBP. and the application
of 52\% low-sodium salt has a significant effect in reducing sodium
intake and increasing potassium intake.%
\end{abstract}%



\sloppy


\textbf{1. Introduction}

Hypertension and T2D has become a global public health concern in the
21st century.Both diseases lead to severe complications such as chronic
kidney diseases\textsuperscript{{[}1{]}}and
cardiovascular\textsuperscript{{[}2{]}},which increase the risk of death
over a long period of time. Both of them related to lifestyles such as
physical exercise\textsuperscript{{[}3{]}},alcohol
consumption\textsuperscript{{[}4{]}} , and dietary
habits\textsuperscript{{[}5,6{]}}. Studies have found that about 50\% of
T2D patients have hypertension, and 20\% of hypertensive patients have
T2D\textsuperscript{{[}7{]}}. Hypertension coexists with T2D, which
increases the risk of cardiovascular-related events and makes BP
management more complicated and difficult\textsuperscript{{[}8{]}}. Drug
use alone makes BP control hard to achieve, so lifestyle intervention
(such as dietary intervention and exercise) is more needed.

The DASH diet was proposed by National Heart, Lung, and Blood Institute
(NHLBI) in 1977 to control the BP of hypertensive patients. The DASH
eating plan encourages the consumption of potassium-rich vegetables and
fruits, including whole grains, poultry, fish, and nuts, and reduces
sodium and saturated fat intake\textsuperscript{{[}9{]}}. There is
strong evidence that the DASH dietary pattern can lower
BP\textsuperscript{{[}10,11{]}}, including patients with T2D and
hypertension\textsuperscript{{[}12,13{]}}.However, as the DASH diet was
designed for white ethnicity, it is difficult for Chinese people to
follow the original DASH diet. In addition, Chinese people generally
prefer salty foods.It is estimated that Chinese people consume an
average of 12g of salt per day\textsuperscript{{[}14{]}},but DASH diet
requires a daily consumption of 2300 mg of sodium (equivalent to 5.8 g
of sodium chloride) or less\textsuperscript{{[}10{]}}, which also makes
it difficult for the DASH diet to be used in Chinese population. Among
many salt reduction strategies, consuming low-sodium salt is a feasible
and low-cost method. Numerous studies have shown that low-sodium salt
can lower BP by reducing sodium and adding
potassium\textsuperscript{{[}15,16{]}},but it has not been used in the
DASH diet so far.

Therefore, in this randomized controlled trial, we developed a modified
DASH diet for the use of Chinese people, and we want to know the
hypotensive effect of 52\% low-sodium salt applied to CM-DASH diet in
patients with hypertension and T2D.

\textbf{2. Materials and Methods}

2.1. Participants

\begin{equation}
n=2\delta^{2}*f(\alpha,\beta)/(\ u_{1}-u_{2})^{2}\nonumber \\
 \end{equation}

Inclusion criteria: (1) aged [?] 35 and [?] 75~years; (2) no plan to move
out of the community in the next three months; (3) agree to consume the
salt and DASH meals we provide during the trial; (4) clinically
diagnosed patients with hypertension and T2D,and the SBP is between
130-180mmHg, DBP is between 80-110mmHg (without antihypertensive
drugs).Exclusion criteria:(1)serious complications of hypertension or
T2D; (2) hypercortisolism or aldosteronism; (3) acute disease, such as
upper respiratory infection, fever and diarrhea; (4) patients or family
members has abnormal kidney function or use potassium-retaining
diuretics; (5) patients or family members have abnormal liver function;
(6) pregnant or others who are not suitable to consume low-sodium salt.

The Ethics Committee of CQMU (Chongqing Medical University) has approved
the experiments, including any relevant details(20/03/2020) which means
that all experiments were performed in accordance with relevant
guidelines and regulations,and all participants provided written
informed consent before enrollment in the trial.

2.2. Study design

We used a randomized controlled parallel-design. After completing the
baseline questionnaire and physical checkup, participants were randomly
assigned to intervention group (CM-DASH diet +52\% low-sodium salt) or
control group (CM-DASH diet +common salt) for 8 weeks with a random
number table,and participants do not know which group they are assigned
to. The present study is divided into 3 phases(2 weeks of CM-DASH diet
adaptation + 2 weeks of CM-DASH diet feeding + 4 weeks of CM-DASH diet
behavior intervention), and two dietary intervention methods have been
adopted. In phase 1 and phase 3, we designed a 7-day menu of Chinese
food that met the nutrient criteria of the DASH diet. At the same time,
we also provide salt (52\% low sodium salt or common salt), and the
participants cooked at home according to the menu we provided .In phase
2, patients are required to consume the CM-DASH diet provided by us at a
uniform location. All participants were told not to change their
previous exercise habits and drug use during the intervention.

Participants were followed up in the hospital once a week to collect
information on OBP, salt and drug use. In addition, for trial safety,
patients were examined at baseline, 4 weeks after the intervention and
the end of the trial.

2.3. CM-DASH

We have developed a modified DASH diet that we called CM-DASH. CM-DASH
is tailor-made according to Chinese dietary habits, with the same
nutritional content as the original DASH diet, and is generally better
accepted by Chinese people.The general requirements of food selection
are as follows: rice is the staple food mixed with coarse grains;white
meat (chicken and fish) accounts for the majority of meat;low-fat milk
is used; more green leafy vegetables and fruits with low sugar;moderate
intake of nuts;daily cooking oil(plant oil) \textless{} 30g and salt
\textless{} 5g. Compared to the original DASH diet, the modified diet
contains less total fat,saturated fatty acids and calories.The CM-DASH
diet for one person is shown in Table 1.

2.4. Salt

In this study, 52\% low sodium salt of ''Gu Da Chu'' was developed by
Shanghai Institute of Ecological Health Sciences. Name: solid compound
condiment, standard of execution: Q/BAAM0009S, food production license
number: SC10334042205441, and the main ingredients include potassium
chloride (31\%), sodium chloride (52\%). Common salt of ''Jing Xin'' was
developed by Chongqing salt industry group Co., Ltd. Name: purified
salt, product standard: NY/T1040, and the content of sodium chloride
content\textgreater{}99\%. In Phase 1 and Phase 3, we used 52\%
low-sodium salt or common salt to completely replace the salt in the
participants' homes,and we also provided a quantitative pot and a
quantitative spoon to allow participants to control the amount of salt
used in the family(\textless{}5g per person per day). In addition, we
use an electronic scale(Precision:0.1g) to weigh the salt consumption
every week , and estimate the daily salt consumption of each person
according to the family population.

2.5. Blood pressure measurement

Participants were followed up in the hospital once a week to collect
information on OBP. OBP was measured by trained professionals, and 3
measurements was required to be completed between 8-9 am, interval of
about 2~min,and the average of the last two BP measurements was used for
analysis. The BP measuring instrument adopt validated automated
upper-arm cuff devices that operate through the oscillometric technique
(Manufacturer:Omron,Dalian,Co.,Ltd. Product name:``Omron'' electronic
sphygmomanometer. Model: HEM-7130).

2.6. Laboratory Measurements

Laboratory measurements included 24-hour urinary electrolytes, blood
electrolytes, blood lipids, liver function, renal function, urinary
creatinine and urinary albumin. All indexes were tested in the Second
Affiliated Hospital of CQMU, and we reported the results to patients in
a timely manner.

2.7. Statistical analysis

Statistical analysis was carried out using SPSS 24.0 (IBM, Armonk, NY,
USA). Quantitative normal distribution data was described by mean and
standard deviation, and T test was used to compare the difference
between the intervention group and the control group. Qualitative data
is described by frequency, and the Pearson's chi-square test is used to
compare the differences between groups. Non-positive distribution data
are expressed in median and quartiles, and Friedman's Rank Test was
used. Repeated measures analysis of variance (RMANOVA) was used to
analyze the changes of physical examination indexes during the
intervention.The Generalized Estimating Equation (GEE) was used to
compare the changes in blood pressure during each week, and Bonferroni
method was used for comparison between groups. P values \textless{}0.05
were considered statistically significant.

\textbf{3. Results}

3.1. Baseline Characteristics

In this study, 61 were included in the intervention, 2 participants
withdrew from the trial due to personal reasons, and finally 59
completed the intervention and were included analysis. (Figure 1) The
baseline features of hypertensive patients with T2D are shown in Table
2. There were no differences between the intervention and control groups
regarding demographic features, lifestyle characteristics
,anthropometric indices, 24-hour urine sodium and potassium values and
OBP values. In addition, the use of antihypertensive drugs was not
different between groups.

3.2. Urine test result

Analysis of RMANOVA for repeated measures indicated that 24-hour urine
Na+(Intervention: -49.29mmol/24h,\emph{P} \textless{}0.001;
Control:-27.62mmol/24h, \emph{P} =0.015; between
groups:21.67mmol/24h,\emph{P} =0.123)and 24-hour urine Cl-(Intervention:
-35.50mmol/24h, \emph{P} =0.002; Control:-26mmol/24h,\emph{P} =0.017;
between groups:9.51 mmol/24h,\emph{P} =0.514)decreased significantly in
both groups after 4-week dietary intervention.However, 24-hour urine
Na+(+25.88mmol/24h, \emph{P}=0.006)and 24-hour urine Cl -- (+26.11
mmol/24h, \emph{P} =0.005 )in the intervention group increased again
from the 4th week. The increase of 24-hour urinary K+( \emph{P} =0.020)
and the decrease of Na+ / K+ ratio (\emph{P} \textless{}0.001)were
observed in the intervention group, but not in the control
group(\emph{P} \textgreater{}0.05). In addition, the UACR (\emph{P}
=0.017) of two groups decreased from baseline(Table 3).

3.3. Serum test result

Compared with baseline, the changes of Na\textsuperscript{+},
K\textsuperscript{+}, Cl\textsuperscript{-} and Ca\textsuperscript{2+}in
serum electrolytes concentration were observed in the intervention group
and the control group, and the change trend was the same as that of
24-hour urine electrolytes. There was no significant change in
AST(Alanine aminotransferase), ALT(Aspartate aminotransferase), UA(Uric
acid) and Creatinine during the study .However, serum lactate and
creatinine were significantly lower than baseline(Table 4).

3.4. BP Measurements During the Study

The results of GEE showed that after one week of intervention, the SBP
of the intervention group and the control group (intervention
group:-12.17 mmHg, 95\% CI: -19.72 \textasciitilde{} -4.62,
\emph{P}\textless{}0.001; control group:-7.16 mmHg, 95 \%CI: -13.53
\textasciitilde{} -0.78, \emph{P} =0.012) was significantly lower than
the baseline. The DBP of the two groups also decreased significantly
from baseline after one week of intervention (intervention group:
-7.25mmHg, 95\%CI: -0.61 \textasciitilde{} -3.89,
\emph{P}\textless{}0.001; control group: -5.29mmHg 95\%CI: -8.55
\textasciitilde{} -2.04, \emph{P} \textless{}0.001). At the end of the
intervention, the SBP of the intervention group decreased by an average
of 14.32 mmHg from the baseline (95\%CI: -21.80 \textasciitilde{}
-6.83,\emph{P} \textless{}0.001), and the DBP was decreased by an
average of 6.32 mmHg from the baseline (95\%CI: -9.55 \textasciitilde{}
-3.08,\emph{P} \textless{}0.001), the SBP of the control group decreased
by an average of 10.98 mmHg from the baseline (95\%CI: -18.26
\textasciitilde{} -3.71, \emph{P} \textless{}0.001), and the DBP was
decreased by an average of 5.24 mmHg from the baseline (95\%CI: -9.23
\textasciitilde{} -1.25, \emph{P} =0.001). However, from baseline to the
end of the intervention, the changes in SBP and DBP were not
statistically significant between the intervention group and the control
group (SBP: -0.28mmHg, 95\%CI: -6.42 \textasciitilde{} 5.86,
\emph{P}=0.929; DBP: -3.32 mmHg, 95\%CI: -7.21 \textasciitilde{} 0.56,
\emph{P}=0.093) (Table 5. Table 6).

3.5. Safety

No serious adverse events occurred during the intervention. Other
adverse events included: 1~weeks after intervention, 2 patients
developed fatigue and dizziness. At the third week of intervention,2
patients developed mild diarrhea.

\textbf{4. Discussion}

Large number of studies has repeatedly demonstrated that consumption of
the DASH diet could decrease BP in
hypertensives\textsuperscript{{[}10,11{]}},but it has been less commonly
used in hypertensive patients with T2D. In the study by Azadbakht et
al.\textsuperscript{{[}13{]}}, after 8 weeks of DASH diet intervention
among patients with T2D, the intervention group had a significant BP
reduction compared with the control group. Paula et
al.\textsuperscript{{[}12{]}}also had a similar conclusion, but in the
study of Hashemi et al.\textsuperscript{{[}17{]}}, there was no
significant difference in the reduction of BP between the DASH diet and
the control diet. To the best of our knowledge, this is the first study
evaluating the effects of DASH eating pattern on BP among Chinese
patients with hypertension and T2D.

We modified the original DASH diet according to the dietary habits of
Chinese people, and formed CM-DASH diet. Participants had high
compliance during the intervention, and no one dropped out because of
diet,which indicated that CM-DASH diet was meets the dietary preferences
of Chinese people.Our study revealed that hypertensive patients with T2D
who followed a CM-DASH diet during an 8-week period had a major
reduction in SBP and DBP. From baseline to 8 weeks later, the mean SBP
had decreased by 14.32 mmHg in intervention group,10.98mmHg in control
group and ,the mean DBP had decreased by 6.32 mmHg in intervention
group,5.24 in control group.The largest reduction in BP was observed in
SBP at the end of week 4, approximately 18 mmHg in the intervention
group, 12mmHg in the control group.

Sodium reduction was considered to be a factor underlying the
hypotensive effect observed in this study. The baseline mean salt
consumption of participants in this study was 8.94g per day, but with
the CM-DASH diet, the mean salt intake of participants was reduced by
approximately 4g per day. As the golden criteria to determine the intake
of sodium, 24-hour urine electrolyte electrolytes has been widely used
in scientific research\textsuperscript{{[}18{]}}.Our results shows that
after the intervention of CM-DASH diet, the 24-hour urine
Na\textsuperscript{+} of the intervention group and the control group
both decreased significantly, which indicated that CM-DASH diet had a
marked effect on reducing the sodium intake of the participants. Studies
have shown that high dietary sodium intake can lead to high BP by
inhibiting the activity of Na \textsuperscript{+} - K\textsuperscript{+}
- ATPase pumps in cell membrane\textsuperscript{{[}19{]}}, damaging
vascular endothelial function\textsuperscript{{[}20{]}}and activating
RAAS (Renin-Angiotension-Aldosterone System)\textsuperscript{{[}21{]}}.
There is substantial evidence that reducing sodium intake lowers BP in
persons with hypertension. We also found similar hypotensive effects in
patients with hypertension and diabetes.

Contrary to the effect of sodium on BP, potassium can lower BP by
stimulating Na \textsuperscript{+} - K \textsuperscript{+} - ATPase
pumps and the opening of potassium channels in vascular smooth muscle
cells and adverse nerve receptors\textsuperscript{{[}22{]}}.The DASH
diet also recommends reducing dietary sodium and consuming more
potassium-rich fruits and vegetables\textsuperscript{{[}9{]}}, but it is
hard to achieve the desired effect by supplementing potassium with food.
Studies have shown that increasing potassium intake by consuming low
sodium salt is an effective and economical
way\textsuperscript{{[}23{]}}. We used low-sodium salt with a sodium
chloride content of 52\% and a potassium chloride content of 31\% in the
intervention group, while the control group used common salt with a
sodium chloride content of \textgreater{}99\%. Our results showed that
there were significant changes in 24-hour urinary
K\textsuperscript{+}and Na\textsuperscript{+} / K\textsuperscript{+}
ratio in the intervention group, but not in the control group. Although
there is no significant difference in BP drop between the intervention
group and the control group, we observed that the decrease of SBP in the
intervention group appeared earlier and more significantly than that in
the control group. In view of previous
studies\textsuperscript{{[}24,25{]}} suggest that the high level of
potassium in the DASH diet is important for its hypotensive effects,we
still consider that the application of low-sodium salt in the DASH diet
may have more beneficial effects on BP reduction in hypertensive
patients with T2DM, and a significant difference may be found by
increasing the intervention time and expanding the sample size.

It was considered that the high potassium content of the low-sodium salt
could result in hyperkalemia and safety monitoring was conducted. During
the study period,

no serious adverse events occurred, and the safety of the participants
was monitored and confirmed throughout the study period. Serum test
results showed that there was a slight increase in potassium during the
intervention period, but it was still within the normal range. In
addition, there is no significant difference in the changes of AST, ALT,
UA, Urea. However, urine UACR and serum creatinine showed a significant
decrease compared with baseline in two groups , which may be related to
the reduced sodium intake in the CM-DASH diet. Studies have reported
that excessive salt intake is associated not only with high BP but also
target organ damage\textsuperscript{{[}26{]}}.There is an association
between high salt intake and UACR independent of BP, and oxidative
stress is a modifying factor between them\textsuperscript{{[}27{]}}.The
research of Feng J. He et al. showed that with the salt reduction, the
urine albumin and UACR also decreased
significantly\textsuperscript{{[}28{]}}. In view of these results, we
believe that short-term CM-DASH diet and sodium reduction feeding trials
may have beneficial effects on the improvement of renal function.

Most evidence for the DASH diet comes from short-term feeding
studies\textsuperscript{{[}10,29{]}} or dietary behavioral intervention
studies\textsuperscript{{[}30{]}},but both methods were used in this
study. Interestingly, although the dietary and salt requirements for
participants during the dietary behavior intervention were the same as
those during the feeding trial, we still observed a small increase in BP
in phase 3, which was also confirmed by the changes in urine
Na\textsuperscript{+} and K\textsuperscript{+} in 24 hours. Cooking
meals that meet dash nutritional requirements at home is affected by
many interference factors, which makes it difficult for participants to
strictly comply with our recommendations. On the other hand, CM-DASH
diet menu contains coarse grains, low-fat milk and nuts, which is
difficult for Chinese people to consume on a regular basis. It will take
longer to change the eating habits of Chinese people that have lasted
for thousands of years. In the future, we should strengthen health
education on diet to change the dietary behavior of Chinese people with
hypertension and T2D.

In conclusion, The results of the present study demonstrated that 52\%
low-sodium salt applied to the CM-DASH diet is an effective nutritional
strategy for the control and management of BP in Chinese people with
hypertension and T2D.

\textbf{Acknowledgements}

\textbf{Author Contributions:} H.M , Y.M and S.M contributed to the
conception and design of the study. S.M, H.R, P.Y, H.X, H.W, D.C, J.T,
T.G and J.L were responsible for data acquisition, analysis, and
interpretation. H.M, S.M, H.R, P.Y contributed to the discussion and
reviewed/edited the manuscript, and all authors reviewed the manuscript.

\textbf{Funding:} This research was supported by Science and Technology
Bureau of Chongqing(STBC), China, project No: cstc2019jscx-msxmX0267,
but STBC did not participate in the design, implementation, data
collection, analysis and article writing process of the study.

\textbf{Competing interests:} The authors declare no competing
interests.

\textbf{Trial registration:} ChiCTR2000029017. Registered on
11/01/2020-Prospective registration, \emph{http://www.chictr.org.cn/}



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\textbf{Figure legends}

Table 1. A Chinese modified daily DASH diet for one person

Table 2. Baseline Characteristics of hypertensive patients with type 2
diabetes

Table 3. Changes of Urine Test Results During the Study

Table 4. Changes of Serum Test Results During the Study

Table 5. Changes in SBP From Baseline During the Study

Table 6. Changes in DBP From Baseline During the Study

Figure 1. Flow diagram of trial participants

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