Efficacy and Safety of Combination Therapy With and in Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis

Efficacy and safety of Combination Therapy with Sodium-glucose
Transporter 2 Inhibitors and Renin-Angiotensin System Blockers
in Patients with Type 2 Diabetes: A Systematic Review and Meta-
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Analysis
Beichen Tian, Yuanjun Deng, Yang Cai, Min Han*, Gang Xu*
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong

University of Science and Technology, Wuhan, China
* These authors contributed equally to this work.

Correspondence to: Min Han; E-mail: minhan@tjh.tjmu.edu.cn; Gang Xu; E-mail:
xugang@tjh.tjmu.edu.cn
© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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GRAPHICAL ABSTRACT

ABSTRACT
Background. This study was designed to evaluate the efficiency and safety of
combination therapy with SGLT2 inhibitors and RAS blockers, such as ACEI/ARB, in
patients with T2DM.
Methods. We searched PubMed, EMBASE, Web of Science and Cochrane Library
from their inception to May 2020. Two authors independently performed study
selection, risk of bias assessment and data extraction. The quality and risk of bias were
assessed by the Cochrane Risk of Bias Tool. Statistical heterogeneity was qualified by
the I-squared statistics.
Results. Seven studies including 1757 patients were analyzed. Compared with
ACEI/ARB alone, combination therapy with SGLT2 inhibitors and ACEI/ARB
produced reduction in SBP (WMD -3.84mmHg), DBP (WMD -1.06mmHg), 24h
ambulatory SBP (WMD -4.59mmHg), 24h ambulatory DBP (WMD -2.08mmHg),
UACR(WMD -29.70%) , eGFR (WMD -3.46 mL/min per 1·73 m²), HbA1c (SMD -
0.48), FPG (SMD -0.28), uric acid (SMD -0.35), and body weight (SMD -0.29). The
risk of hypoglycemia with combination therapy was higher than the control group (RR
1.37). As for the risk of total AEs, genital infection and urinary tract infection, no
significant difference was revealed.
Conclusion. Compared with ACEI/ARB alone, the combination therapy with SGLT2
inhibitors and ACEI/ARB in T2DM was effective and well-tolerated, and could achieve
additional effects, including better control of blood pressure, improvement of renal
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outcomes, alleviation of long-term renal function, and decrease of blood glucose and
body weight. The combination therapy showed an increased risk of hypoglycemia.
Keywords: ACEI/ARB, meta-analysis, SGLT2 inhibitors, T2DM
Abbreviations: SGLT2 inhibitors = sodium-glucose transporter 2(SGLT2) inhibitors,

RAS = renin-angiotensin system; ACEI = angiotensin-converting enzyme inhibitors,

ARB = angiotensin receptor blockers, T2DM = type 2 diabetes mellitus, SBP = systolic
blood pressure; DBP = diastolic blood pressure; UACR= urine albumin-to-creatinine
ratio; FPG = fasting plasma glucose; AEs = adverse events; WMD = weighted mean
difference; SMD = standardized mean difference; RR = risk ratio
KEY LEARNING POINTS

What is already know about this subject?
The present drugs for diabetic patients that can improve renal prognosis are only
ACEI/ARB and SGLT2 inhibitors. When monotherapy cannot control symptoms, we
need to find a new treatment.
What this study adds?
We therefore explored the effects of combination therapy with SGLT2 inhibitors and
ACEI/ARB to study whether the combination therapy could complement each other
and achieve more significant effects.
What impact this may have on practice or policy?
This study may provide a new treatment idea for diabetic patients with hypertension or
kidney disease.
1. INTRODUCTION
Diabetes mellitus is one of the most common metabolic disorders all over the world 1.
In the past thirty years, the prevalence of diabetic patients has multiplied by four times,
90% of whom suffer from type 2 diabetes mellitus (T2DM) 2. T2DM is a multifactorial
disorder, which associates with genetic and environmental factors. The feature of
T2DM is metabolic disorders of carbohydrate, lipid, and protein, caused by β‑cell lesion,
insulin resistance, or chronic inflammation 3.
Over two-thirds of patients with T2DM develop hypertension 4. In the diabetic

population, hypertension increases the occurrence of micro- and macrovascular
complications, which bring about the enhanced risk of cardiovascular disease 4-6. The
first-choice therapeutic regiment for patients combined T2DM with hypertension is the
renin-angiotensin system (RAS) blockers, such as angiotensin-converting enzyme
inhibitors (ACEI) and angiotensin receptor blockers (ARB) 6-8. Sometimes
monotherapy of ACEI/ARB cannot control blood pressure adequately, patients will
receive combination therapy with at least two drugs 9.
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Another common complication of diabetes is diabetic kidney disease (DKD) 10. The
characteristic of DKD is the accumulation of extracellular matrix, hypertrophy and
fibrosis in renal glomerular cells and tubular cells 11. The treatment of DKD currently
depends on blood glucose reduction and blood pressure control by blocking the RAS to
slow its progression 12,13. ACEI/ARB is also the first-choice of DKD patients. Despite

receiving ACEI/ARB treatment, many patients still progress to end-stage renal failure
14.
A novel sort of antidiabetic drug, called sodium-glucose transporter 2 (SGLT-2)

inhibitors, was endorsed by the U.S. Food and Drug Administration (FDA) in March
2013 15. Evidence suggested that SGLT-2 inhibitors reduce cardiovascular risk and
improve renal outcomes 16-18. SGLT-2 expressed in the proximal tubule of the kidney
adjusts the initial glucose uptake and bears responsibility for about 90% of glucose
reabsorption 19,20. SGLT-2 inhibitors block the reabsorption of glucose and sodium,
resulting in diuretic and natriuretic effects, thereby lowering glucose levels 21-23.
Because of the increased urinary glucose and sodium excretion, SGLT-2 inhibitors can
also decrease blood pressure, lower body weight, and produce helpful metabolic and
cardio-renal effects 24.
When ACEI/ARB cannot control symptoms, we need to find a new treatment to

improve this situation, the question is whether ACEI/ARB and SGLT-2 inhibitors can
be combined to treat T2DM patients. To evaluate the efficacy and safety of combination
therapy with SGLT-2 inhibitors and ACEI/ARB compared with ACEI/ARB only, we
carried out this systematic review and meta-analysis of randomized controlled trials
(RCTs).
2. MATERIALS AND METHODS

2.1 Search strategy
We searched PubMed, EMBASE, Web of Science and Cochrane Library to identify
eligible randomized controlled trials, from their inception to May 2020. Medical
Subject Headings (Mesh) and entry terms were utilized in the search of each database.
Our search strategy used the following terms: “sodium-glucose transporter-2
inhibitors”, “angiotensin-converting enzyme inhibitor”, “angiotensin receptor blocker”
and “type 2 diabetes”. Details are reported in Supplementary Appendix 1. The
registration number for this meta-analysis is CRD42020191282.
2.2 Study selection

Two authors independently searched all databases to identify the relevant studies. After
removing the duplicated studies, they screened all titles and abstracts, and the remaining
studies were full-text assessed to determine the eligible studies. Studies were included
if they met the following criteria: (1) randomized controlled trial in humans; (2) patients
with type 2 diabetes (age≥18years); (3) all patients on a stable dose of an ACEI or ARB,
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and on this basis treatment with SGLT-2 inhibitor compared with placebo; (4) at least
one of the following outcomes: systolic blood pressure (SBP); diastolic blood pressure
(DBP); 24h ambulatory SBP; 24h ambulatory DBP; urine albumin-to-creatinine ratio
(UACR); evaluated GFR (eGFR); HbA1c; fasting plasma glucose (FPG); uric acid;
body weight; adverse events (AEs). The exclusion criteria were: (1) non-randomized
controlled trial; (2) patients with type 1 diabetes or other special types of diabetes; (3)

patients with a history of diabetic ketoacidosis; (4) patients with a urinary tract infection
or genital infection.
2.3 Risk of bias assessment

The quality and risk of bias of each included study were assessed by the Cochrane Risk
of Bias Tool, including random sequence generation, allocation concealment, blinding,
incomplete outcome data, selective reporting, and other bias. Each term was classified
as low, unclear, or high risk of bias.
2.4 Data extraction

Data were extracted from the included studies by two independent authors using a
prespecified protocol. If the outcome data were not available, we sent the email to the
corresponding authors for further information and used the formula to convert described
in the Cochrane Handbook when necessary. If only the statistical figure was given
without numerical data, we extracted the data in the figure using image extraction
software. Basic information from each study included author, year of publication,
sample size, intervention group, control group, duration of follow-up, age, gender,
T2DM duration, level of Hb1Ac and eGFR. Primary outcomes of interest included SBP,
DBP, 24h ambulatory SBP, 24h ambulatory DBP, UACR, eGFR, HbA1c, FPG, uric
acid and body weight. AEs were also assessed, including total AEs, hypoglycemia,
genital infection, and urinary tract infection.
2.5 Statistical analysis

For continuous variables, we calculated weighted mean difference (WMD) or
standardized mean difference (SMD) with 95% confidence interval (95% CI) to assess
the effects and the risk ratio (RR) with 95% CI for dichotomous variables. Statistical
heterogeneity was qualified by the I-squared statistics. When the I-squared value was
from 0% to 50%, each study showed a low level of heterogeneity and the fixed-effect
model was performed for the analysis. When the I-squared value was above 50%, each
study showed a high level of heterogeneity and we used the random-effect model to
assess the effect. All statistical analyses were conducted with STATA version 16.0
(Stata Corp, International Urology and Nephrology).
2.6 Quality of evidence

We assessed the quality of evidence on each outcome using the Grading of
Recommendations Assessment, Development and Evaluation (GRADEpro) tool
(https://gdt.gradepro.org). We rated the quality as four levels: high, moderate, low, and
very low. The risk of bias, inconsistency, indirectness, imprecision, publication bias
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may reduce the quality of evidence.
3. RESULTS
3.1 Summaries of included studies
The study search and screening process are depicted in Figure 1. The initial search in

the four databases identified a total of 1014 records, of which 242 duplicates were
removed. 772 studies were screened by titles and abstracts and 26 articles remained
were full-text assessed in detail. Finally, 7 randomized controlled trials 25-31 were
included in the systematic review and meta-analysis.
The basic characteristics of the included studies are shown in Table 1. For SGLT-2
inhibitors, two studies used canagliflozin, four studies used dapagliflozin and one study
used empagliflozin. The study Townsend 2016 contained two intervention groups,
canagliflozin 100mg and canagliflozin 300mg, so we combined these two groups to
form a new intervention group according to the Cochrane handbook. Two studies had
a follow-up duration of 6 weeks, four studies 12 weeks, and one study 24 weeks.
The quality of each study was assessed using the Cochrane Risk of Bias Tool. The
results are shown in Figure 2.
3.2 Primary Outcomes

3.2.1 Blood pressure
The results of six studies indicated that SGLT-2 inhibitors plus ACEI/ARB group (780
patients) can effectively reduce SBP than the ACEI/ARB group (719 patients) (WMD
-3.84mmHg, 95%CI -5.40, -2.28, I2=15.7%, Figure 3A). Four studies with 615 patients
in the intervention group and 552 patients in the control group were used in comparing
the effect on the level of DBP. The intervention group can produce reductions in DBP
(WMD -1.06mmHg, 95%CI -2.10, -0.02, I2=47.2%, Figure 3B).
The result of four studies showed the SGLT-2 inhibitors plus ACEI/ARB group (606
patients) can remarkably reduce the level of 24h ambulatory SBP (WMD -4.59mmHg,
95%CI -6.54, -2.63, I2=0.0%, Figure 3C) versus ACEI/ARB group (533 patients).
Compared with control group (382 patients), treatment with SGLT-2 inhibitors plus
ACEI/ARB (448 patients) was associated with significant decreases in 24h ambulatory
DBP in three studies (WMD -2.08mmHg, 95%CI -3.29, -0.87, I2=0.0%, Figure 3D).
3.2.2 Proteinuria
Abnormal UACR reflects the patient’s proteinuria. The results indicated that the
intervention group (233 patients) can effectively reduce the level of UACR than the
control group (230 patients) in three studies (WMD -29.70%, 95%CI -42.48, -16.92,
I2=0.0%, Figure 3E).
3.2.3 Renal function

Four studies showed, treatment with SGLT-2 inhibitors plus ACEI/ARB (249 patients)
also determined a decrease in eGFR (WMD -3.46 mL/min per 1·73 m², 95%CI -4.85, -
2.07, I2=12.0%, Figure 3F), compared with ACEI/ARB group (248 patients).
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3.2.4 Blood glucose
Five studies were comparing the effect on HbA1c. The combination therapy (706
patients) produced significant reductions in change from baseline of HbA1c (SMD -
0.48, 95%CI -0.68, -0.28, I2=66.6%, Figure 4A) versus the control group (690 patients).
Compared with the control group (641 patients), treatment with SGLT-2 inhibitors plus

ACEI/ARB (712 patients) was associated with a decrease in FPG in four studies(SMD
-0.28, 95%CI -0.44, -0.11, I2=54.2%, Figure 4B).
3.2.5 Uric acid

Five studies compared the effect on the level of uric acid. The results suggested that
SGLT-2 inhibitors plus ACEI/ARB group (711 patients) can reduce uric acid than the
ACEI/ARB group (705 patients) (SMD -0.35, 95%CI -0.57, -0.13, I2=70.3%, Figure
4C).
3.2.6 Body weight

Seven studies with 868 patients in the intervention group and 808 patients in the control
group compared the effect on body weight. The result revealed that the intervention
group lowers the body weight (SMD -0.29, 95%CI -0.50, -0.08, I2=72.8%, Figure 4D),
in contrast with the control group.
3.3 Safety Outcomes

All of the seven studies reported the AEs in SGLT-2 inhibitors plus ACEI/ARB group
and ACEI/ARB group. Compared with the control group, combination therapy
increases the risk of any hypoglycemia (RR 1.37, 95%CI 1.03, 1.82, I2=0.0%, Figure
5B). As for the incidence of total AEs (RR 1.08, 95%CI 0.96, 1.22, I2=0.0%, Figure
5A), genital infection(RR 1.88, 95%CI 0.90, 3.95, I2=0.0%, Figure 5C), and urinary
tract infection(RR 2.04, 95%CI 0.92, 4.50, I2=0.0%, Figure 5D), no significant
difference was revealed in the intervention group and control group.
3.4 Quality of evidence

The quality of evidence is shown in a summary of findings table in Table 2.
3.5 Publication bias

We assessed the publication bias by funnel plots for outcomes with the number of
studies more than 5 in Figure S1 (Supplementary Material 2). The result showed that
publication bias existed in body weight and AEs. Therefore, we performed the trim-and-
fill method for these two outcomes in Figure S2 (Supplementary Material 2). The results
did not change, indicating that this effect of publication bias was negligible. For outcomes
with the number of studies less than 5, the plots are difficult to interpret and any
evidence for publication bias is weak.
3.6 Sensitivity analyses and meta-regression

To explored sources of heterogeneity for outcomes with I2 > 50%, we conducted
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sensitivity analyses and meta-regression in Figure S3 and Table S1 (Supplementary
Material 2). Sensitivity analyses suggested that the omission of any study would not
significantly modify the results of these outcomes. Meta-regression was performed to
account for heterogeneity using follow-up (weeks), sample size, age, HbA1c on the
baseline, eGFR on the baseline. The high heterogeneity of uric acid may be associated
with the level of HbA1c on the baseline. Other results did not show significant values.

4. DISCUSSION
The incidence of DKD and hypertension in T2DM patients is increasing. Previous DKD
treatments were mainly antihypertensive, glucose-lowering, lipid-regulation
treatments13. After years of hard work, current clinical studies have confirmed that the
drugs that can improve renal prognosis are only ACEI/ARB and SGLT2 inhibitors 24,32.
These two drugs have similar effects on the reduction of capsular pressure through
different mechanisms, thereby reducing proteinuria and slowing down the progression
of DKD 6,20. Therefore, we explored the effects of combination therapy with SGLT2
inhibitors and ACEI/ARB to study whether the combination therapy could complement
each other and achieve more significant effects.
In this systematic review and meta-analysis, we evaluated the efficiency and safety of
the combination therapy with SGLT2 inhibitors and ACEI/ARB in type2 diabetes
mellitus by analyzing seven randomized, placebo-controlled, double-blind trials. Our
meta-analysis showed that SGLT2 inhibitors and ACEI/ARB therapy significantly
reduced blood pressure, lowered the albuminuria and decreased renal function, while it
is also associated with decreases in blood glucose, uric acid and body weight, when
compared to ACEI/ARB alone. Regarding safety, the combination therapy has led to a
higher incidence of hypoglycemia and infection, including genital infection and urinary
tract infection.
Several RCTs 33-35 indicated that SGLT-2 inhibitors monotherapy was associated with
significant and clinically meaningful reductions in blood pressure. Similarly, the
combination therapy with SGLT2 inhibitor and ACEI/ARB made more reductions in
SBP and 24h ambulatory SBP compared with ACEI/ARB alone. 24h ambulatory blood
pressure is regarded as an incredibly reliable basis for hypertension assessment. These
results confirm the clinical benefits of combination therapy. Both ACEI and ARB block
the RAS through different mechanisms to produce antihypertensive and antiproteinuric
effects 32. Research showed that dapagliflozin alleviated the RAS activation through
down-regulating kidney expression of type 2 angiotensin II receptor in an animal model
36. Therefore, the antihypertensive effect of the combination therapy may be due to the
enhanced blocking effect on RAS of ACEI/ARB by SGLT2 inhibitors. In addition, the

antihypertensive effect may be also connected with enhancing glucosuria, natriuresis,
and osmotic diuresis of SGLT2 inhibitors 37.
Evidence showed beneficial effects on renal outcomes of SGLT-2 inhibitors
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monotherapy, independent of other effects 38-41. Our study also reported a protective
effect on the kidney of combination therapy. SGLT-2 inhibitors contract the afferent
arterioles through tubuloglomerular feedback, and reduce the capsular pressure and
high filtration of glomerulus20. ACEI and ARB reduce the capsular pressure of
glomerulus through the diastole of efferent arterioles, thereby reducing eGFR and
decrease urine protein6. The combination therapy of SGLT-2 inhibitors and ACEI/ARB

may complement each other and produce more significant effects. The abnormality of
UACR reflects the patient's proteinuria. The results suggested that SGLT-2 inhibitors
in combination with ACEI/ARB further decreased UACR than ACEI/ARB alone and
delayed the progression of DKD.
Our meta-analysis also showed the reduction of eGFR in the intervention group versus
the control group. This may result in a short-term decline in renal function. The
previous meta-analysis showed that short-term application of SGLT-2 inhibitors
monotherapy may reduce eGFR levels, but the long-term renal function has not
deteriorated 42. Evidence showed initial acute fall in eGFR was associated with long-
term renal preservation 43, and the reduction of eGFR is completely reversible after drug
discontinuation41. Sha’s and Kario’s studies showed combination therapy increased
serum creatinine and blood urea nitrogen (BUN), and decreased eGFR25,30. The
combination therapy may have the ability to protect long-term renal function. Therefore,
patients with eGFR less than 45 mL/min per 1·73 m² should be suggested not to receive
this combination therapy. When patients treat with the combination therapy, they need
to monitor the renal function every month by checking eGFR, serum creatinine and
BUN. When renal function declines gradually or abruptly, the drug dosage should be
reduced or the combination therapy stopped.
In our study, SGLT2 inhibitors in combination with ACEI/ARB also produced

reductions in Hb1Ac and FPG, which may be associated with reduced reabsorption of
glucose and increased urinary glucose excretion. Obesity and overweight are the
principal factors of the worldwide diabetes epidemic 2. SGLT2 inhibitors plus
ACEI/ARB also reduce serum uric acid, which may be related to the increased urinary
glucose excretion, and the body reactively increases uric acid secretion in exchange for
glucose reabsorption, resulting in increased uric acid excretion. We found the
combination therapy could lower the body weight, which may be attributed to osmotic
diuresis caused by glucosuria and increase of heat loss 44.
Overall, the combination therapy with SGLT2 inhibitors and ACEI/ARB was well
tolerated. Although SGLT-2 inhibitors should not raise the risk of hypoglycemia as they
do not activate insulin secretion 45, the results showed an increased risk of
hypoglycemia when treating with SGLT2 inhibitors in combination with ACEI/ARB.
This may be attributed to no restrictions on background hypoglycemic therapy or
heterogeneity due to study design, and the combined effect should be further explored.
The previous meta-analysis reported that SGLT2 inhibitors monotherapy resulted in
rather frequent but mild genital and urinary tract infections 46. Our study demonstrated
9
that genital and urinary tract infections occurred more often in the combination therapy
compared with the control group but with no statistical significance. Therefore, further
long-term clinical trials are needed to monitor the incidence of urinary and genital
infection of therapy with SGLT2 inhibitors in combination with ACEI/ARB.
In our meta-analysis, we found a high level of heterogeneity between studies when

assessing the efficacy of the combination therapy with SGLT2 inhibitors and
ACEI/ARB. Different types and doses of SGLT2 inhibitors and different background
drugs may lead to clinical heterogeneity. Publication bias of body weight may
contribute to its heterogeneity as well. To examined other reasons for high
heterogeneity, we performed sensitivity analyses and meta-regression. Sensitivity
analysis showed that the effect of combination therapy would not be nullified with the
omission of any study. The results suggested that the high heterogeneity of uric acid
may due to the level of HbA1c on the baseline. However, the high heterogeneity of
other outcomes was not resolved by meta-regression.
Our study had the following limitations. First, the main limitation of this meta-analysis
was the limited number of studies included. Only 7 studies met the inclusion criteria,
and there were even fewer studies for most of the outcomes. Second, this meta-analysis
did not include the RCT of long-term efficacy and safety of the combination therapy.
Third, some outcomes had a high level of heterogeneity and the cause of the
heterogeneity was still not clear.
5. CONCLUSION
Compared with ACEI/ARB alone, the combination therapy with SGLT2 inhibitors and
ACEI/ARB in T2DM was effective and well-tolerated, and could achieve additional
effects, including better control of blood pressure, improvement of renal outcomes,
alleviation of long-term renal function, and decrease of blood glucose and body weight.
The combination therapy showed an increased risk of hypoglycemia.
CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.
AUTHORS’ CONTRIBUTIONS
Min Han and Gang Xu conceived and designed the study, reviewed the draft. Beichen
Tian screened the abstract and full text, extracted data, assessed studies, performed
statistical analyses and wrote the draft. Yuanjun Deng screened the abstract and full
text, extracted data and assessed studies. Yang Cai assisted in statistical analyses. All
authors read the draft and approved the final version.
FUNDING
This work was supported by the National Nature Science Foundation of China (NSFC)
(No. 81770686 and 81970591 for Min Han; No. 81670633 for Gang Xu).
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DATA AVAILABILITY STATEMENT
The data underlying this article are available in the article and in its online
supplementary material.
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double-blind, placebo-controlled trial. The lancet diabetes and endocrinology.
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32. Weir MR, Henrich WL. Theoretical basis and clinical evidence for differential effects of
angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 blockers. Curr
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33. Ott C, Jumar A, Striepe K, et al. A randomised study of the impact of the SGLT2 inhibitor
dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol.
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34. Chilton R, Tikkanen I, Hehnke U, Woerle HJ, Johansen OE. Impact of empagliflozin on blood
pressure in dipper and non-dipper patients with type 2 diabetes mellitus and hypertension.
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Empagliflozin in Black Patients With Type 2 Diabetes Mellitus and Hypertension. Circulation.

2019;139(18):2098-2109.
36. Shin SJ, Chung S, Kim SJ, et al. Effect of Sodium-Glucose Co-Transporter 2 Inhibitor,
Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes.
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37. Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2)
inhibitors. J Am Soc Hypertens. 2014;8(5):330-339.
38. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and
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TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7(8):606-617.
39. Neuen BL, Ohkuma T, Neal B, et al. Effect of Canagliflozin on Renal and Cardiovascular
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13
eGFR
Sam- Follow- T2DM
Age Male HbA1c (mL/min
Study ple Intervention Control up duration
(years) (%) (%) per 1·73
Size (weeks) (years)
m²)
Sha canagliflozin 300 mg Placebo+

36 12 62.8 86.1 8.5 7.6 97.3
2014 [25] +ACEI/ARB ACEI/ARB
Townsend canagliflozin 100mg, Placebo+

169 6 58.6 58 9 8.1 86.9
2016 [26] 300 mg+ACEI/ARB ACEI/ARB
Weber1 dapagliflozin 10 mg Placebo+

613 12 56 57.1 8 8 85.9
Weber2 dapagliflozin 10 mg Placebo+

449 12 56.5 55 7.5 8.1 85.9
Petrykiv dapagliflozin 10 mg Placebo+

66 6 61 75.8 10 7.5 72
Kario empagliflozin 10 mg Placebo+

131 12 70.1 52.7 10.1 6.6 69.2
Pollock dapagliflozin 10 mg Placebo+

293 24 64.7 70.6 17.6 8.5 48.9
Table 1. Baseline characteristics of included studies
Summary of Findings Table
SGLT2 inhibitors plus ACEI/ARB compared to ACEI/ARB alone for T2DM
Patient or population: patients diagnosed with T2DM
Intervention: SGLT2 inhibitors and ACEI/ARB
Comparison: ACEI/ARB alone
Outcomes No of Quality of the Relative effect Anticipated absolute effects
participants evidence (95% CI) Risk with Risk difference with
(studies) (GRADE) conparison intervention
1499 ⨁⨁⨁◯ The mean SBP was MD 3.84 lower

SBP -
(6 RCTs) MODERATE a,b 0 (5.4 lower to 2.28 lower)
1167 ⨁⨁⨁◯ The mean DBP was MD 1.06 lower

DBP -
(4 RCTs) MODERATE a,b 0 (2.1 lower to 0.02 lower)
1139 ⨁⨁⨁◯ The mean 24h SBP MD 4.59 lower

24h SBP -
(4 RCTs) MODERATE a,b was 0 (6.54 lower to 2.63 lower)
830 ⨁⨁⨁◯ The mean 24h DBP MD 2.08 lower

24h DBP -
(3 RCTs) MODERATE a,b was 0 (3.29 lower to 0.87 lower)
MD 29.7 lower
463 ⨁⨁◯◯ The mean UACR
UACR - (42.48 lower to 16.92
(3 RCTs) LOW a,b,c was 0
lower)
497 ⨁⨁◯◯ The mean eGFR MD 3.46 lower

eGFR -
(4 RCTs) LOW a,b,c was 0 (4.85 lower to 2.07 lower)
1396 ⨁⨁◯◯ SMD 0.48 lower

Hb1Ac - -
(5 RCTs) LOW a,b,d (0.68 lower to 0.28 lower)
14
1353 ⨁⨁◯◯ SMD 0.28 lower
FDP - -
1416 ⨁⨁◯◯ SMD 0.35 lower

Uric acid - -
1676 ⨁◯◯◯ SMD 0.29 lower

Body weight - -
(7 RCTs) VERY LOW a,b,d,e (0.50 lower to 0.08 lower)

1757 ⨁⨁◯◯ RR 1.08 29 more per 1,000
AEs 361 per 1,000
(7 RCTs) LOW a,b,e (0.96 to 1.22) (14 fewer to 79 more)
1590 ⨁⨁◯◯ RR 1.37 29 more per 1,000

Hypoglycemia 79 per 1,000
(5 RCTs) LOW a,b,c (1.03 to 1.82) (2 more to 65 more)
Genital 1421 ⨁⨁◯◯ RR 1.88 12 more per 1,000

14 per 1,000
infection (4 RCTs) LOW a,b,c (0.90 to 3.95) (1 fewer to 41 more)
Urinary tract 1355 ⨁⨁◯◯ RR 2.04 14 more per 1,000

13 per 1,000
infection (3 RCTs) LOW a,b,c (0.92 to 4.50) (1 fewer to 46 more)
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the
relative effect of the intervention (and its 95% CI).
CI: Confidence interval; MD: Mean difference; SMD: Standardised mean difference; RR: Risk ratio
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
a. No details of random protocol; b. No detailed blinding implementation plan; c. Total population size or total number of events is small;
d. I2> 50% for heterogeneity; e. Publication bias
Table 2. GRADE Summary of Findings Table
Figure 1. PRISMA Flow diagram of the selected studies.
Figure 2. Risk of bias assessment of included studies.
Figure 3. Forest plot depicting the effect of SGLT-2 inhibitors plus ACEI/ARB group
versus ACEI/ARB group on the level of blood pressure, urine albumin-to-creatinine
ratio (UACR) and evaluated GFR (eGFR). A. Effect on systolic blood pressure (SBP).
B. Effect on diastolic blood pressure (DBP). C. Effect on 24h ambulatory SBP. D.
Effect on 24h ambulatory DBP. E. Effect on UACR. F. Effect on eGFR. WMD:
weighted mean difference, CI: confidence interval.
Figure 4. Forest plot depicting the effect of SGLT-2 inhibitors plus ACEI/ARB group
15
and ACEI/ARB group on the level of blood glucose, uric acid and body weight. A.
Effect on HbA1c. B. Effect on fasting plasma glucose (FPG). C. Effect on uric acid. D.
Effect on body weight. SMD: standard mean difference. SMD: standard mean
difference, CI: confidence interval.
Figure 5. Forest plot depicting relative risks (RR) on adverse events (AEs). A. RR on

the incidence of total AEs. B. RR on the incidence of Hypoglycemia. C. RR on genital
infection. D. RR on the incidence of urinary tract infection. CI: confidence interval.
16
106x256mm (300 x 300 DPI)
Identification
Records identified Additional records

through database identified through
searching other sources
(n = 1014) (n = 0)
Records after duplicates removed

(n = 772)
Screening
Records screened
(n = 772)
Records excluded
(n = 746)
Full-text articles assessed

for eligibility
(n = 26)
Full-text articles excluded,

with reasons (n = 19):
• Wrong study design
Eligibility
(n = 9)
• Non-randomized
controlled trials (n = 5)
• Non-relevant drug (n = 2)
• Duplications with the
same samples (n = 2)
• Full-text unavailable
(n = 1)
Studies included in
qualitative synthesis
(n = 7)
Included
Studies included in
quantitative synthesis
(meta-analysis)
(n = 7)
NDT-01708-2020.R1-fig1
180x234mm (300 x 300 DPI)
A B
Random sequence generation ? + ? ? + + +

(selection bias)
Allocation concealment + ? ? ? + + ?

(selection bias)
Blinding of participants and personnel + + + + + + +
(performance bias)
Blinding of outcome assessment + + + + + + +
(detection bias)
Incomplete outcome data + – + + + + +
(attrition bias)
Selective reporting + + ? + + + +
(reporting bias)
Other bias + + + + + + +
16
16
16
14
19
17
18
0 25 50 75 100
20
20
20
20
20
20
20
Percentage (%)
2
ck
iv
rio
er
er
en
Sh
k
llo
Ka
try
eb
eb
ns
Po
Pe
W
w
To
Low risk of bias Unclear risk of bias High risk of bias
NDT-01708-2020.R1-fig2
180x249mm (300 x 300 DPI)
A SBP B DBP
Study ID WMD (95% CI) % weight Study ID WMD (95% CI) % weight
Sha 2014 −13.10 (−21.37, −4.83) 3.54 Sha 2014 −6.80 (−11.73, −1.87) 4.48
Townsend 2016 −2.49 (−7.29, 2.31) 10.52 Townsend 2016 −0.25 (−2.89, 2.39) 15.64
Weber1 2016 −3.10 (−5.54, −0.66) 40.70 Weber1 2016 −1.00 (−2.56, 0.56) 44.95
Weber2 2016 −4.28 (−7.24, −1.32) 27.73 Weber2 2016 −0.77 (−2.53, 0.99) 34.94
Petrykiv 2017 −5.30 (−11.40, 0.80) 6.52
Pollock 2019 −2.90 (−7.60, 1.80) 10.99

Overall (I2 = 15.7%, p = 0.313) −3.84 (−5.40, −2.28) 100.00 Overall (I2 = 47.2%, p = 0.128) −1.06 (−2.10, −0.02) 100.00
–45 0 15 –15 0 5
C 24 h ambulatory SBP D 24 h ambulatory DBP

Townsend 2016 −4.09 (−7.45, −0.73) 33.93 Townsend 2016 −2.40 (−4.32, −0.48) 39.67
Weber1 2016 −2.90 (−6.33, 0.53) 32.55 Weber1 2016 −0.70 (−3.03, 1.63) 26.86
Weber2 2016 −5.80 (−10.64, −0.96) 16.33 Kario 2018 −2.80 (−4.89, −0.71) 33.47
Kario 2018 −7.60 (−12.32, −2.88) 17.19
–20 0 5 –12 0 4
E UACR F eGFR
Petrykiv 2017 −40.00 (−62.07, −17.93) 33.52 Sha 2014 −4.10 (−8.68, 0.48) 9.22
Kario 2018 −29.00 (−52.68, −5.32) 29.13 Petrykiv 2017 −5.70 (−8.62, −2.78) 22.70
Pollock 2019 −21.00 (−41.91, −0.09) 37.35 Kario 2018 −2.90 (−5.26, −0.54) 34.68
Pollock 2019 −2.33 (−4.73, 0.07) 33.39
Overall (I = 0.0%, p = 0.471)

2
−29.70 (−42.48, −16.92) 100.00 Overall (I = 12.0%, p = 0.333)
2
−3.46 (−4.85, −2.07) 100.00
–150 0 40 –18 0 4
NDT-01708-2020.R1-fig3
180x246mm (300 x 300 DPI)
A Hb1Ac B FPG
Study ID SMD (95% CI) % weight Study ID SMD (95% CI) % weight
Weber1 2016 −0.46 (−0.63, −0.29) 26.45 Townsend 2016 −0.21 (−0.53, 0.11) 17.22
Weber2 2016 −0.64 (−0.84, −0.44) 24.56 Weber1 2016 −0.36 (−0.53, −0.19) 31.77
Petrykiv 2017 −0.34 (−0.83, 0.14) 11.30 Weber2 2016 −0.42 (−0.61, −0.22) 28.40
Kario 2018 −0.79 (−1.15, −0.43) 16.19 Pollock 2019 −0.03 (−0.28, 0.23) 22.61
Pollock 2019 −0.15 (−0.41, 0.10) 21.51

NOTE: Weights are from random effects analysis NOTE: Weights are from random effects analysis
−4 0 1 −3 0 1
C Uric acid D Body weight

Study ID SMD (95% CI) % weight Study ID SMD (95% CI) % weight
Sha 2014 −0.48 (−1.15, 0.19) 7.78 Sha 2014 −1.60 (−2.37, −0.84) 5.59
Weber1 2016 −0.31 (−0.48, −0.15) 26.70 Townsend 2016 −0.50 (−0.83, −0.18) 14.52
Weber1 2016 −0.00 (−0.17, 0.17) 19.58
Weber2 2016 −0.32 (−0.51, −0.12) 25.15
Weber2 2016 −0.21 (−0.40, −0.03) 18.99
Kario 2018 −0.83 (−1.18, −0.47) 17.00
Petrykiv 2017 −0.29 (−0.78, 0.19) 10.16
Pollock 2019 −0.04 (−0.27, 0.19) 23.37
Kario 2018 −0.25 (−0.59, 0.10) 13.93
Pollock 2019 −0.14 (−0.38, 0.10) 17.24
NOTE: Weights are from random effects analysis NOTE: Weights are from random effects analysis
−3 0 1 −4 0 1
NDT-01708-2020.R1-fig4
180x251mm (300 x 300 DPI)
A AEs B Hypoglycemia
Study ID RR (95% CI) % weight Study ID RR (95% CI) % weight
Sha 2014 1.57 (0.79, 3.12) 2.26 Townsend 2016 0.99 (0.31, 3.15) 8.58
Townsend 2016 1.35 (0.73, 2.49) 4.75 Weber1 2016 2.57 (0.82, 8.12) 6.32
Weber1 2016 1.05 (0.85, 1.30) 34.69 Weber2 2016 2.15 (0.83, 5.55) 9.67
Weber2 2016 1.05 (0.85, 1.30) 30.10
Petrykiv 2017 5.00 (0.25, 100.32) 0.80
Petrykiv 2017 2.33 (0.66, 8.25) 0.97
Pollock 2019 1.17 (0.85, 1.61) 74.63
Kario 2018 1.85 (0.59, 5.85) 1.34
Pollock 2019 1.00 (0.81, 1.23) 25.89

Overall (I2 = 0.0%, p = 0.583) 1.08 (0.96, 1.22) 100.00 Overall (I2 = 0.0%, p = 0.411) 1.37 (1.03, 1.82) 100.00
0.01 1 15 0.0001 1 250
C Genital infection D Urinary tract infection

Study ID RR (95% CI) % weight Study ID RR (95% CI) % weight
Weber1 2016 1.24 (0.38, 4.01) 47.23 Weber1 2016 3.09 (0.84, 11.30) 33.14
Weber2 2016 1.49 (0.43, 5.22) 38.43 Weber2 2016 1.99 (0.37, 10.76) 22.47
Petrykiv 2017 3.00 (0.33, 27.38) 9.59 Pollock 2019 1.28 (0.35, 4.66) 44.39
Pollock 2019 9.18 (0.50, 169.08) 4.74
Overall (I2 = 0.0%, p = 0.587) 1.88 (0.90, 3.95) 100.00 Overall (I2 = 0.0%, p = 0.638) 2.04 (0.92, 4.50) 100.00
0.001 1 300 0.01 1 30
NDT-01708-2020.R1-fig5

Efficacy and Safety of Combination Therapy With and in Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis

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Efficacy and Safety of Combination Therapy With and in Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis

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Efficacy and safety of Combination Therapy with Sodium-glucose

Transporter 2 Inhibitors and Renin-Angiotensin System Blockers

in Patients with Type 2 Diabetes: A Systematic Review and Meta-

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Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong

* These authors contributed equally to this work.

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Abbreviations: SGLT2 inhibitors = sodium-glucose transporter 2(SGLT2) inhibitors,

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KEY LEARNING POINTS

Over two-thirds of patients with T2DM develop hypertension 4. In the diabetic

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A novel sort of antidiabetic drug, called sodium-glucose transporter 2 (SGLT-2)

When ACEI/ARB cannot control symptoms, we need to find a new treatment to

2. MATERIALS AND METHODS

2.2 Study selection

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2.3 Risk of bias assessment

2.4 Data extraction

2.5 Statistical analysis

2.6 Quality of evidence

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3.2 Primary Outcomes

3.2.3 Renal function

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3.2.5 Uric acid

3.2.6 Body weight

3.3 Safety Outcomes

3.4 Quality of evidence

3.5 Publication bias

3.6 Sensitivity analyses and meta-regression

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enhanced blocking effect on RAS of ACEI/ARB by SGLT2 inhibitors. In addition, the

Evidence showed beneficial effects on renal outcomes of SGLT-2 inhibitors

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In our study, SGLT2 inhibitors in combination with ACEI/ARB also produced

In our meta-analysis, we found a high level of heterogeneity between studies when

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CONFLICT OF INTEREST STATEMENT

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Sha canagliflozin 300 mg Placebo+

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Townsend canagliflozin 100mg, Placebo+

Weber1 dapagliflozin 10 mg Placebo+

Weber2 dapagliflozin 10 mg Placebo+

Petrykiv dapagliflozin 10 mg Placebo+

Kario empagliflozin 10 mg Placebo+

Pollock dapagliflozin 10 mg Placebo+

Table 1. Baseline characteristics of included studies

Summary of Findings Table

SGLT2 inhibitors plus ACEI/ARB compared to ACEI/ARB alone for T2DM

Patient or population: patients diagnosed with T2DM

Intervention: SGLT2 inhibitors and ACEI/ARB

Comparison: ACEI/ARB alone

Outcomes No of Quality of the Relative effect Anticipated absolute effects

participants evidence (95% CI) Risk with Risk difference with