Annals of Medicine

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Recent advances in the treatment of patients with

obesity and chronic kidney disease

Roshaida Abdul Wahab, Ricardo V. Cohen & Carel W. le Roux

To cite this article: Roshaida Abdul Wahab, Ricardo V. Cohen & Carel W. le Roux (2023) Recent
advances in the treatment of patients with obesity and chronic kidney disease, Annals of
Medicine, 55:1, 2203517, DOI: 10.1080/07853890.2023.2203517

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Annals of Medicine
2023, VOL. 55, NO. 1, 2203517
https://doi.org/10.1080/07853890.2023.2203517

REVIEW ARTICLE

Recent advances in the treatment of patients with obesity and chronic

kidney disease
Roshaida Abdul Wahaba, Ricardo V. Cohenb and Carel W. le Rouxa
Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland; bCenter for the Treatment of Obesity and
a

Diabetes, Hospital Oswaldo Cruz, Sao Paulo, Brasil

ABSTRACT ARTICLE HISTORY

Received 6 January 2023
Obesity is a chronic disease characterised by excess adiposity, which impairs health. The high Revised 7 April 2023
prevalence of obesity raises the risk of long-term medical complications including type 2 diabetes Accepted 11 April 2023
and chronic kidney disease. Several studies have focused on patients with obesity, type 2 diabetes
KEYWORDS
and chronic kidney disease due to the increased prevalence of diabetic kidney disease. Several
Obesity;
randomized controlled trials on sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 diabetic kidney disease;
analogues, and bariatric surgery in diabetic kidney disease showed renoprotective effects. sodium-glucose
However, further research is critical to address the treatment of patients with obesity and chronic cotransporter 2
kidney disease to lessen morbidity. inhibitors;
glucagon-like peptide-1
KEY MESSAGE analogues;
• Obesity is a driver of chronic kidney disease, and type 2 diabetes, along with obesity, bariatric surgery;
chronic kidney disease;
accelerates chronic kidney disease. randomized controlled
• Several randomized controlled trials on sodium-glucose cotransporter 2 inhibitors, glucagon-like trial
peptide-1 analogues, and bariatric surgery in diabetic kidney disease demonstrate the
improvement of renal outcomes.
• There is a need to address the treatment of patients with obesity and CKD to lessen morbidity.

1.  Introduction trials (RCT) showed that weight loss interventions such
as bariatric surgery, medications and dietary strategies
Obesity is a chronic disease characterised by excess
improve renal outcomes [6–9]. Due to the high prev-
adiposity, which impairs health [1]. Obesity reduces
alence of diabetic kidney disease (DKD), many studies
lifespan and raises the risk of long-term medical com-
have focused on patients with obesity, T2D and CKD.
plications [2]. The pathogenesis of obesity lies in
energy homeostasis disorder, in which the body In this narrative review, we searched PubMed from its
defends against fat loss through either inherited or inception until March 2023 for the term obesity and
acquired mechanisms that cause ‘upward setting’ or chronic kidney disease, limited to English-language
‘resetting’ of the level of body-fat mass [3]. The increas- articles. We focused on RCTs with renal outcomes from
ing prevalence of obesity has implications for the risk anti-obesity medications such as sodium-glucose
of type 2 diabetes (T2D), obstructive sleep apnoea, cotransporter 2 inhibitors (SGLT2i), glucagon-like
cardiovascular diseases (CVD), non-alcoholic fatty liver peptide-1 analogues (GLP-1a), bariatric surgery and
disease, cancer, osteoarthritis, urinary incontinence [4] other pharmacotherapies. Evidence derived mainly
and chronic kidney disease (CKD) [5]. Obesity is a from randomized clinical trials, meta-analyses and rel-
major cause of CKD and there is a need to address evant narrative reviews. The aim of this review is to
the treatment of patients with obesity and CKD to highlight current and ongoing RCTs examining renal
lessen its morbidity. Several randomized controlled outcomes in patients with obesity, T2D and CKD.

CONTACT Carel W. le Roux [email protected] Diabetes Complications Research Centre, University College Dublin, Ireland
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/),
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article
has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 ABDUL WAHAB R ET AL.

2.  Obesity as a driver of chronic kidney prevalence. Zhu et  al. revealed that both central
disease (waist-to-hip ratio) and general adiposity (BMI)
appear to be independent and substantial causes
Obesity and CKD are common to complex disorders of CKD, with associations mainly explained by dia-
with increasing clinical and economic impact on betes, blood pressure (BP), and their correlates [19].
healthcare around the globe. The prevalence of CKD Genetic approaches estimate that each 0.06 increase
is estimated to be over 10% of adults worldwide, in the waist-to-hip ratio is linked with a 30%
with more than 50% in high-risk subpopulation increased risk of CKD, and each 5 kg/m 2 increase in
groups [10]. Population-based observational studies BMI is associated with a 50% increase in CKD risk.
have established a significant association between Recently, using data from MR studies on over
obesity and the development and progression of 300,000 participants from UK Biobank, obesity was
CKD [11–14]. A cross-sectional study among South linked to different kidney disorders across a spec-
Koreans showed obesity was more prevalent in trum of various aetiologies [17]. Additionally, this
patients with CKD than those without CKD [11]. The obesity-CKD link was largely independent of BP and
prevalence of obesity with increased visceral adi- T2D. Furthermore, the signatures of obesity on the
posity was highest in stage 2 CKD and stage 3a human kidney transcriptome, i.e. groups of genes
CKD. In a systematic review and meta-analysis inves- and pathways that may explain the effects of obe-
tigating the combined effects of body mass index sity on the kidney, were studied in 467 kidney tissue
(BMI) and metabolic status on CKD risk, individuals samples [17].
with obesity were shown to have a higher risk of Obesity increased CKD’s lifetime risk by 25% com-
C K D c o m p a r e d t o m e t a b o l i c a l l y h e a l t hy pared to individuals with a BMI <25 kg/m2. The under-
normal-weight individuals, even in the absence of lying pathophysiology of obesity-related kidney disease
re m a r k a b l e m e t a b o l i c a b n o r m a l i t i e s [ 1 5 ] . involves several mechanisms. Due to adipose tissue
Furthermore, obesity and CKD were associated in accumulation and infiltration of the kidney, alterations
individuals with and without diabetes, hypertension occur in the kidney haemodynamic, leading to increase
and cardiovascular disease [16], indicating that obe- tubular sodium reabsorption, volume overload/hyper-
sity may partly mediate CKD risk via mechanisms tension, and glomerular hyperfiltration, which causes
independent of its effects on T2D and cardiovascu- kidney injury (glomerulomegaly, glomerular hyperfil-
lar disease risks. Obesity can also directly cause CKD tration, podocyte dysfunction, tubulointerstitial dam-
[17–19]. A mendelian randomization (MR) analysis age and fibrosis) [20].
in n = 11,384 East Asians investigated the causal Increased adiposity also modulates inflammatory
associations of obesity with CKD and arterial stiff- adipokines (the cell signalling molecules secreted
ness [18]. Using the genetic risk score as the instru- by adipose tissue) such as leptin, adiponectin,
mental variable, a causal relationship was shown tumour necrosis factor α (TNF-α), resistin, visfatin,
for each 1-SD increment in BMI with CKD (OR: plasminogen-activator inhibitor and interleukin 6
2.36;95% CI, 1.11–5.00) and arterial stiffness (OR: (IL6). There are several potential mechanisms in the
1.71;95% CI, 1.22–2.39). Using 14 single–nucleotide literature explaining the effects of these adipokines
variations individually as instrumental variables, o n r e n a l f u n c t i o n [ 2 1 ] . Fo r e x a m p l e ,
each 1–SD increment in BMI was casually associated obesity-augmented leptin secretion promotes hyper-
with CKD (OR: 2.58;95% CI, 1.39–4.79) and arterial tension via activation of the sympathetic nervous
stiffness (OR: 1.87;95% CI, 1.24–2.81) in the inverse– system, oxidative stress, fatty acid oxidation and
variance weighted analysis and MR–Egger regression secretion of proinflammatory cytokines monocyte
demonstrated no evidence of horizontal pleiotropy chemoattractant protein 1 (MCP-1). Conversely,
(both P for intercept >/= 0.34). The causality obesity-related reduction in adiponectin is associ-
between obesity and CKD was validated in a ated with impaired glucose and fatty acids metab-
2-sample MR analysis among Europeans (681,275 of olism and may contribute to albuminuria through
Genetic Investigation of Anthropometric Traits and alterations in the renal podocyte effacement [22].
133,413 of CKD Genetics). The study emphasizes The secretion of aldosterone and other angioten-
the importance of weight management for primary sinogen from adipose tissue in obesity further reg-
prevention and control of subclinical vascular dis- ulates the renin-angiotensin-aldosterone system
eases. Another study using genetic analyses from (RAAS) leading to further adipocyte differentiation
281,228 UK Biobank participants estimated the rel- a n d o b e s i t y- re l ate d hy p e r te n s i o n [2 3 – 2 5 ] .
evance of waist-to-hip ratio and BMI to CKD Furthermore, intracellular accumulation of adipose
 Annals of Medicine 3

within the kidney exerts a lipotoxic activity leading In the Empagliflozin Cardiovascular Outcome Event
to oxidative stress and cell apoptosis [26]. Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG
OUTCOME), 7020 patients with T2D and established
CVD were randomized to either empagliflozin 10 mg,
3.  How type 2 diabetes, together with
25 mg or placebo daily. At baseline, the glycated hae-
obesity, accelerate chronic kidney disease
moglobin (HbA1c) and BMI were 8% and 30.6 kg/m2
T2D is an obesity complication and is closely associ- respectively. Patients with a minimum estimated glo-
ated with kidney inflammation through different merular filtration rate (eGFR) of 30 ml/min/1.73m2 were
molecular pathways. Insulin resistance increases the included, and the median follow-up was 3.1 years. In
risk of CKD progression through glomerular haemo- the main study, the risk of a 3-point major adverse
dynamic alterations and podocyte function disruption. cardiovascular event (MACE) was significantly lower in
Insulin acts directly on the podocytes’ insulin recep- the empagliflozin compared to the placebo group (HR
tors involving intracellular AKT/mTOR or glucose 0.86, 95% CI 0.74 − 0.99; p = 0.04 for superiority) [34].
transporter 4 (GLUT4) signalling [27]. At least three In the follow-up analysis, there was a significant reduc-
mechanisms in which augmented insulin secretion tion in weight (2–3 kg in empagliflozin 25 mg) and
due to insulin resistance in T2D cause kidney injury. systolic blood pressure (4–6 mmHg) compared to the
Firstly, insulin promotes oxidative stress within podo- placebo group [35]. Moreover, the investigators eval-
cytes by activating NADPH oxidase [28]. Secondly, uated the composite microvascular outcome, defined
insulin stimulates transforming growth factor (TGF) as the first occurrence of initiation of retinal photoco-
beta-1 and collagen IV formation, possibly leading to agulation, vitreous haemorrhage, diabetes-­ related
tubulointerstitial fibrosis [29]. Thirdly, in individuals blindness, and incident or worsening of nephropathy.
with T2D, insulin changes tubular sodium avidity, Overall, there was a 38% relative risk reduction in the
which promotes water reabsorption, raises BP and composite microvascular outcome following empagli-
glomerular hyperfiltration and subsequently increases flozin compared to placebo. The incident or worsening
albumin permeability [28]. Overall, T2D contributes of nephropathy and the progression to macroalbumin-
to insulin resistance which leads to increased insulin uria were reduced by 39% and 38%, respectively. In
secretion, growth factor release and oxidative stress, comparison, 44% and 55% relative risk reduction in
and dysregulates the glomerular filtration barrier, the doubling of serum creatinine levels and initiation
which changes the kidney haemodynamic and ulti- of renal replacement therapy were demonstrated in
mately causes obesity-related glomerulopathy (ORG) the empagliflozin group compared to the placebo.
and kidney injury [30]. There was no difference in the incidence of albumin-
uria between groups [36]. The addition of empagli-
flozin to the standard care in patients with T2D with
4.  Randomized controlled trials on sodium- high cardiovascular risk was shown to reduce the pro-
glucose  cotransporter 2 inhibitors (SGLT2i) in gression of kidney disease compared to placebo.
diabetic kidney disease These positive findings on renal outcomes were
further supported by the follow-on trials of empagli-
There is a need for interventions with reliable evidence flozin in participants with heart failure with reduced
for effectiveness in preventing and/or slowing the pro- ejection fraction (HFrEF);the EMPEROR-Reduced trial,
gression of CKD. SGLT2i is a group of medications that and participants with heart failure with preserved ejec-
inhibits renal glucose absorption and promotes glu- tion fraction (HRpEF);the EMPEROR-Preserved trial.
cosuria, resulting in a caloric loss of approximately Nearly half of the total participants in EMPEROR-Reduced
300 kcal/day which explains the average 2-3kg weight (n = 3730) and EMPEROR-Preserved (n = 5988) have T2D
loss achieved in the clinical trials [31,32]. To date, there with a mean eGFR and BMI of 61–62 ml/min/1.73m2
is no data on the use of SGLT2i as part of the weight and 28–30 kg/m2. Both trials showed a reduction in
loss strategy in patients with obesity. In the recent the composite primar y outcome, 25% in
guideline, SGLT2i is considered to have an intermediate EMPEROR-Reduced (HR 0.75, 95% CI 0.65 − 0.86;p < 0.001)
action in promoting weight loss and is an option in and 21% in EMPEROR-Preserved (HR 0.79, 95% CI
treating patients with obesity and T2D [33]. As obesity, 0.69 − 0.90;p < 0.001). The rate of eGFR decline in the
T2D and CKD are closely interlinked, all available trials EMPEROR-Reduced was slower in the empagliflozin
to date that evaluate the role of SGLT2i in overweight, (–0.55 ml/min/1.73m2/year) compared to the placebo
obesity and renal disease were derived from RCTs group (–2.28 ml/min/1.73m2/year) with a between-group
involving patients with T2D. difference in slope of 1.73 ml/min/1.73m2/year (95% CI
4 ABDUL WAHAB R ET AL.

1.1 − 2.37;p < 0.001) [37]. Similarly, in the (week 13) or placebo in the CANVAS-R trial. A com-
EMPEROR-Preserved trial, the rate of eGFR decline was posite of death from CV causes, non-fatal myocardial
also slower in the empagliflozin (–1.25 ml/min/1.73m2/ infarction or non-fatal stroke, was the primary out-
year) compared to the placebo group (–2.62 ml/ come. Secondary outcomes included death from any
min/1.73m2/year) with a between-group difference in cause, death from CV causes, albuminuria progression
slope of 1.36  ml/min/1.73m 2 /year (95% CI and the composite of death from CV causes and hos-
1.06 − 1.66;p < 0.001) [38]. pitalization from heart failure. A composite renal out-
The role of empagliflozin in patients with CKD was come included a 40% reduction in eGFR, requirement
further investigated in the EMPA-KIDNEY trial. A total of renal replacement therapy or death from any renal
of 6609 patients with multiple causes of CKD and a causes. Mean BMI and eGFR at baseline were 32.0 kg/
wide range of eGFR from at least 20 ml/min/1.73m2 m2 and 76.5 ml/min/1.73m2 respectively. Median urine
with a minimum urinary albumin-to-creatinine ratio ACR was 12.3 mg/g, with 22.6% and 7.6% having
(ACR) of 200 mg/g were randomly assigned to empagli- microalbuminuria and macroalbuminuria, respectively.
flozin 10 mg daily or placebo for a median of 24 months, There was a 14% reduction in the primary outcome
with a composite progression of kidney disease as the in the canagliflozin group compared to the placebo
primary outcome. This was defined as a composite of (HR 0.86, 95% CI 0.75 − 0.97; p < 0.001). Progression of
end-stage kidney disease, a sustained decrease in eGFR albuminuria was reduced by 27% (HR 0.73, 95% CI
to less than 10 ml/min/1.73m2, a sustained reduction 0.67 − 0.79) with a 40% reduction in the composite
in eGFR ≥40% from baseline, or death from renal or renal outcome (HR 0.6, 95% CI 0.47 − 0.77) in the cana-
CV cause. There were 1525 (46.2%) and 1515 (45.8%) gliflozin group compared to placebo. The mean weight,
patients with diabetes, with a mean eGFR of 37.4 and systolic blood pressure (SBP) and diastolic blood pres-
37.3 ml/min/1.73m2, a BMI of 29.7 and 29.8 kg/m2, and sure (DBP) differences in the canagliflozin group com-
a median urine ACR of 331 and 327 mg/g in the pared to placebo, were −1.6 kg, −3.9 mmHg and
empagliflozin and placebo group respectively. The pri- −1.39 mmHg, respectively [40].
mary outcome was reduced by 28% in the empagli- The Evaluation of the Effects of Canagliflozin on
flozin group (HR 0.72, 95% CI 0.64 − 0.82;p < 0.001) Renal and Cardiovascular Outcomes in Participants
compared to placebo, irrespective of diabetes status, with Diabetic Nephropathy (CREDENCE trial) was
across subgroups of eGFR ranges. The proportion of designed to evaluate the effects of canagliflozin in
risk reduction was significant among patients with the patients with T2D and CKD with specific renal end-
highest urinary ACR >300 mg/g. There was a 14% points. A total of 4401 participants with T2D with CKD
reduction in hospitalisation rate from any cause in the (eGFR 30–90 ml/min/1.73m2) and albuminuria (urine
empagliflozin group (HR 0.86, 95% CI 0.78 − 0.95;p-0.003) ACR >300 to 5000 mg/g) on a stable dose of
with no difference in the composite outcome of hos- renin-angiotensin system blockade were randomized
pitalization for heart failure or death from CV causes to canagliflozin 100 mg or placebo. The primary out-
between both groups. The between-group difference come was a composite of end-stage renal disease, a
in the eGFR slope was 0.75 ml/min/1.73m2/year (95% doubling of creatinine level, or death from renal or
CI 0.54 − 0.96) in favour of empagliflozin. There was a CV causes. The definition of end-stage renal disease
small improvement in weight (–0.9 kg), systolic included a requirement for dialysis, transplantation, or
(–2.6 mmHg) and diastolic blood pressure (0.5 mmHg), a sustained eGFR <15 ml/min/1.73m2. The mean base-
favouring empagliflozin [39]. line HbA 1c, eGFR, and BMI were 8.3%, 56.2 ml/
Through the CANagliflozin cardioVascu- min/1.73m2, and 31.3 kg/m2 respectively, while the
lar  Assessment Study (CANVAS), data from 10,142 par- median urine ACR was 927 mg/g. After a median
ticipants from CANVAS and CANVAS-R (renal) trials follow-up of 2.62 years, the primary outcome was
were integrated to evaluate the effects of canagliflozin reduced by 30% in the canagliflozin group (HR 0.7,
on CV and renal outcomes in participants with T2D 95% CI 0.59 − 0.82, p = 0.00001) compared to placebo,
and high CV risk. This was defined as either age and this was consistent across regions and prespecified
≥30 years old with a history of symptomatic athero- subgroups. The renal-specific composite outcome
sclerotic CV disease or ≥50 years old with two or more (end-stage renal disease, doubling of serum creatinine
risk factors for CV disease. eGFR at entry was >30 ml/ or renal-related death) was reduced by 34% (HR 0.66,
min/1.73m2 and the mean follow-up was 188.2 weeks. 95% CI 0.53 − 0.81, p < 0.001) while end-stage kidney
Patients were randomised to either canagliflozin disease (initiation of dialysis for at least 30 days, kidney
100 mg, 300 mg or placebo (CANVAS trial) or canagli- transplantation, or eGFR <15 ml/min/1.73m2 for at least
flozin 100 mg with the option to increase to 300 mg 30 days) was reduced by 32% (HR 0.68, CI 0.54 − 0.86,
 Annals of Medicine 5

p = 0.002) in the canagliflozin group. There was a 31% without T2D in the Dapagliflozin in Patients with
reduction in the composite of cardiovascular death or Heart Failure and Reduced Ejection Fraction
hospitalization for heart failure (HR 0.69, 95% CI (DAPA-HF) trial (n = 4744). Nearly 42% had T2D, with
0.57 − 0.83, p < 0.001), a 20% reduction in cardiovascu- a baseline BMI and eGFR of 28 kg/m 2 and 66 ml/
lar death, myocardial infarction, or stroke (HR 0.8, 95% min/1.73m2 respectively. In each group 41% of par-
CI 0.67 − 0.95, p = 0.01), and a 39% reduction in hospi- ticipants had eGFR <60 ml/min/1.73m2. While there
talization for heart failure (HR 0.61, 95% CI 0.47 − 0.8, was a reduction in the composite primary outcome
p < 0.001) in canagliflozin group compared to placebo. (HR 0.74, 95% CI 0.65 − 0.85; p < 0.001) and key com-
SBP and weight were reduced by 3.3 mmHg (95% CI posite secondary outcome (HR 0.75, 95% CI
2.73 − 3.87) and 0.8 kg (95% CI 0.69 − 0.92), respectively, 0.65 − 0.85; p < 0.001), there was no difference in the
while the geometric mean of urine ACR was reduced composite renal outcome (HR 0.71, CI 0.44 − 1.16)
by 31% (95% CI 26 to 35) in favour of canagliflozin [41]. following dapagliflozin [43].
Like the CANVAS program, the Dapagliflozin Effect To evaluate the effect of dapagliflozin in patients
on Cardiovascular Events (DECLARE-TIMI 58) trial with CKD, 4304 participants with or without diabetes,
involved a large number of patients (n = 17,160) with with eGFR of 25–75 ml/min/1.73m2 and urine ACR of
T2D randomised to either dapagliflozin 10 mg or pla- 200 to 5000 mg/g, were randomized to either dapagli-
cebo, with a follow-up period of 4.2 years. Participants flozin 10 mg or placebo in the DAPA-CKD trial. The
involved were either individuals with established ath- primary composite renal outcome included an eGFR
erosclerotic CV disease (40.6%, n = 6974) or had mul- decline of at least 50%, the onset of end-stage kidney
tiple risk factors for it (59.4%, n = 10,186). A MACE disease or death from a renal or cardiovascular cause.
composite of cardiovascular death, myocardial infarc- The 1st secondary renal outcome was a composite of
tion or ischaemic stroke was the primary safety out- sustained decline in eGFR of at least 50%, end-stage
come. MACE and a composite of CV death or kidney disease or death from renal causes. The 2nd
hospitalization for heart failure were the two primary secondary outcome was a composite of death from
efficacy outcomes. The renal composite outcome CV causes or hospitalization for heart failure, while the
included a sustained decrease of 40% or more in eGFR, final secondary outcome was death from any causes.
new end-stage renal disease or death from renal or The baseline BMI in each group was 29.5 kg/m2 and
CV causes. The mean baseline HbA1c and BMI were 67.5% of participants in each group had T2D. The
8.3% and 32.0 kg/m2 respectively. The median diabetes mean eGFR at baseline was 43.1 ml/min/1.73m2 with
duration was 11 years, and 10% of participants had a 14.5% of participants having eGFR < 30 ml/min/1.73m2.
diagnosis of heart failure. The baseline mean eGFR was The median urinary ACR was 949 mg/g, while 48.7%
85.2 ml/min/1.73m2, with 45% and 7% having eGFR (dapagliflozin) and 47.9% (placebo) of participants had
between 60–90 ml/min/1.73m2 and < 60 ml/min/1.73m2 a baseline urinary ACR > 1000 mg/g. This trial was
respectively. There was a 17% reduction in the com- stopped early by an independent data monitoring
posite CV death or hospitalization for heart failure in committee, at 2.4 years, due to the demonstration of
the dapagliflozin group (HR 0.83, 95% CI 0.73 − 0.95, apparent efficacy. The primary renal composite out-
p = 0.005), primarily driven by a lower rate of heart come was reduced by 39% in the dapagliflozin group
failure hospitalization (HR 0.73, 95% CI 0.61 − 0.88). (HR 0.61, 95% CI 0.51 − 0.72, p < 0.001) with an NNT of
There were no differences in the event of CV death 19 to prevent one primary outcome. This benefit was
(HR 0.98, 95% CI 0.82 − 1.17) or MACE (HR 0.93, CI consistent across all subgroups, including in patients
0.84 − 1.03, p = 0.17) between dapagliflozin and pla- with or without T2D. The 1st secondary renal outcome
cebo. The following results within this study were was reduced by 44% (HR 0.56, 95% CI 0.45 − 0.68,
hypothesis generating rather than hypothesis testing. p < 0.001), while the 2nd and final secondary outcome
The Dapagliflozin group had a lower incidence of the was decreased by 29% (HR 0.71, 95% CI 0.55 − 0.92,
renal composite outcome by 24% (HR 0.76, 95% CI p = 0.009) and 31% (HR 0.69, 95% CI 0.53 − 0.88,
0.67 − 0.87), and there was no difference in the rate of p = 0.004) respectively, in favour of dapagliflozin [44].
death from any causes between groups (HR 0.93, 95% In the Evaluation of Ertugliflozin Efficacy and
CI 0.82 − 1.04). The least-squares mean difference in Safety Cardiovascular Outcomes Trial (VERTIS CV),
weight, SBP and DBP was 1.8 kg, 2.7 mmHg and 8246 participants with T2D and established CV dis-
0.7 mmHg, favouring dapagliflozin [42]. eases were randomized to either ertugliflozin 5 mg,
Similar to the EMPEROR trials, the role of dapagli- 15 mg or placebo for 3.5 years. A composite of death
flozin was evaluated against placebo, for a median from CV causes, nonfatal myocardial infarction or
of 18.2 months, in participants with HFrEF with and non-fatal stroke, was the primary outcome. The 1st
6 ABDUL WAHAB R ET AL.

secondary outcome was a composite of death from limb amputation, urinary tract infection (UTI), mycotic
CV causes or heart failure hospitalisation and death genital infections, hypoglycaemia, and bone fractures,
from CV causes. In contrast, the 2nd secondary out- were also evaluated. There were 13 trials included,
come was a composite of doubling serum creatinine, with a total of 90,409 participants (82.7% with T2D).
renal replacement therapy or death from renal The range of trial baseline eGFR levels were 74–85 ml/
causes. At baseline, the mean BMI and eGFR were min/1.73m2 (T2D with high atherosclerotic CV disease
32 kg/m2 and 76 ml/min/1.73m2, while 22% of par- trials), 51–66 ml/min/1.73m2 (heart failure trials) and
ticipants in each group had eGFR < 60 ml/min/1.73m2. 37–56 ml/min/1.73m2 (CKD trials). SGLT2i reduces the
There was no significant reduction in the primary risk of kidney disease progression by 37% (RR 0.63,
outcome (HR 0.97, 95% CI 0.85 − 1.11), 1st secondary 95% CI 0.58 –0.69), with similar benefits seen in
outcome (HR 0.88, 95% CI 0.75 − 1.03) and the com- patients with (RR 0.62, 95% CI 0.56–0.68) and without
posite renal outcome (HR 0.81, 95% CI 0.63 − 1.04) diabetes (RR 0.69, 95% CI 0.57 –0.82), compared to
in the pooled ertugliflozin group compared to pla- placebo. Data derived from the CKD trials demon-
cebo [45]. strated a 38% (RR 0.62, 95% CI 0.56 –0.69) reduction
To evaluate the efficacy of sotagliflozin in prevent- in kidney disease progression irrespective of the aeti-
ing CV events in patients with T2D and CKD with and ology of CKD. In this analysis, SGLT2i also reduces the
without albuminuria, 10,584 participants were random- risk of AKI by 23% (RR 0.77, 95% CI 0.7–0.84), with a
ized to either sotagliflozin 200 mg daily (with an similar reduction in patients with (0.79, 95% CI 0.72
increase to 400 mg if tolerated) or placebo in the Effect –0.88) and without diabetes (0.66, 95% CI 0.54–0.81).
of Sotagliflozin on Cardiovascular and Renal Events in The composite outcome of CV death or hospitalisation
Participants with Type 2 Diabetes and Moderate Renal for heart failure was reduced by 23% (RR 0.77, 95%
Impairment Who Are at Cardiovascular Risk (SCORED) CI 0.74 –0.81), while the risk of CV death was reduced
trial. This study was discontinued early due to loss of by 14% (RR 0.86, 95% CI 0.81 –0.92) in favour of
funding, and consequently, the endpoints underwent SGLT2i, irrespective of diabetes status. In this study,
several changes. The composite of the total number SGLT2i did not have any impact in reducing the risk
of deaths from CV causes, hospitalizations for HF and of non-CV death compared to the placebo (RR 0.94,
urgent visits for HF was the composite primary end- 95% CI 0.88 –1.02). There was a doubling in the risk
point. The specific renal secondary endpoint was a of ketoacidosis (RR 2.12, 95% CI 1.49–3.04), with a 15%
composite of a sustained decrease of >50% eGFR for increased risk of lower limb amputation (RR 1.15, 95%
≥ 30 days, long-term dialysis, renal transplantation, or CI 1.02–1.30) in patients with diabetes allocated SGLT2i
a sustained eGFR < 15 ml/min/1.73m2 for ≥ 30 days. At compared to placebo. Overall, SGLT2i resulted in a
baseline, the mean BMI, median eGFR and urinary ACR 3-fold increase in mycotic genital infections (RR 3.57,
were 31.8 kg/m2, 44.5 ml/min/1.73m2 and 74 mg/g, 95% CI 3.14–4.06), an 8% increase in UTI (RR 1.08, 95%
respectively. After a median follow-up of 16 months, 1.02–1.15) and a trend for bone fractures (RR 1.07,
the primary outcome was reduced by 26% (HR 0.74, 95% CI 0.99–1.14) compared to placebo. With all the
95% CI 0.63 − 0.88, p < 0.001) in the sotagliflozin group trials to date, the absolute benefit of SGLT2i outweighs
compared to the placebo group, while no difference the potential harm. It is estimated that treating 1000
was seen in the secondary renal outcome (HR 0.71, patients with diabetes and CKD using SGLT2i for one
95% CI 0.46 − 1.08) [46]. year will result in 11 fewer patients developing kidney
In a recent collaborative meta-analysis, all large disease progression, four fewer patients with AKI, 11
placebo-controlled clinical trials evaluating the effects fewer patients with CV death or hospitalisation for
of SGLT2i in participants with CKD, heart failure and heart failure and only one potential ketoacidosis and
T2D were included. The analyses aimed to assess the one lower limb amputations [47].
effects of SGLT2i on kidney disease progression, acute All evidence to date demonstrates the benefit of
kidney injury (AKI) and other outcomes in patients SGLT2i as part of optimising diabetes care and CV
with and without diabetes. The definition of kidney outcomes, exacerbation of heart failure and hospital-
disease progression includes a sustained decrease in ization. SGLT2i plays a central role as a disease-modifying
eGFR (>50%), end-stage renal disease, a sustained low agent in patients with CKD, irrespective of diabetes
eGFR (<15 ml/min/1.73m2 or <10 ml/min/1.73m2), or status and the aetiology of kidney disease. While there
kidney failure resulting in death. AKI, a composite of is an increase in the relative risk of adverse reactions
hospitalisation for heart failure or CV death, CV and (mycotic genital infection, UTI, and lower limb ampu-
non-CV death and all-cause mortality were also inves- tation), the absolute benefit currently outweighs the
tigated. Safety outcomes, including ketoacidosis, lower risk. Several meta-analyses involving the above trials
 Annals of Medicine 7

have demonstrated a positive weight loss outcome The Liraglutide Effect and Action in Diabetes:
with SGLT2i compared to placebo [48,49]. However, to Evaluation of Cardiovascular Outcome Results (LEADER)
date, there are no published trials of SGLT2i specifically trial involved participants with T2D and high CV risk,
in patients with obesity. with a total of 9340 participants randomized to either
liraglutide (1.8 mg/day or maximum tolerated dose) or
placebo for a median of 3.8 years. The baseline HbA1c
5.  Randomized controlled trials on glucagon-
was 8.7%, with 25% of participants having CKD stage
like peptide-1 (GLP-1) analogues in diabetic
3-4. There was a 13% reduction in the primary com-
kidney disease
posite outcome (death from CV causes, nonfatal myo-
GLP-1 analogue (GLP-1a) is licensed in the manage- cardial infarction, or nonfatal stroke) in the liraglutide
ment of T2D and/or obesity. It promotes group compared to placebo (HR 0.87, 95% CI 0.78–
glucose-dependent insulin secretion and glucagon 0.97, p < 0.001). The secondary composite renal or ret-
suppression, improves satiety, and reduces gastric inal microvascular outcome was also reduced in the
motility and appetite, with an intermediate to a high liraglutide group (HR 0.84, 95% CI 0.73–0.97, p = 0.02),
level of weight loss outcome [33,50]. The SCALE and predominantly driven by a lower rate of nephropathy
STEP clinical trials provided evidence of the use of (HR 0.78, 95% CI 0.67–0.92, p = 0.003). The liraglutide
high-dose liraglutide (3.0 mg) and semaglutide (2.4 mg) group had a mean difference in HbA1c of –0.4% and
in participants living with obesity either with and with- 2.3 kg more weight loss than the placebo [54]. In a
out diabetes or pre-diabetes. These trials vary in dura- secondary analysis of this trial, the renal outcome was
tion, aims, and comparators and none included renal defined as a composite of new-onset persistent mac-
outcome as a primary endpoint [51]. To date, the reno- roalbuminuria, doubling of creatinine, end-stage renal
protective effects of GLP1 analogue in obesity and disease or death due to renal disease. At baseline, the
renal disease are derived from RCTs involving patients mean eGFR was 80 ml/min/1.73m2, with 20.7% having
with T2D. eGFR of 30–59 ml/min/1.73m2 and 2.4% having eGFR
The Evaluation of Lixisenatide in Acute Coronary < 30 ml/min/1.73m2. Microalbuminuria and macroalbu-
Syndrome (ELIXA) trial examined the CV safety out- minuria were identified in 26.3% and 10.5% of partic-
comes of lixisenatide in participants with T2D and ipants, respectively. The composite renal outcome was
recent acute coronary syndrome (n = 6068). Participants reduced by 22% in the liraglutide group (HR 0.78, 95%
were randomized to either lixisenatide (10 to 20 mcg CI 0.67–0.92, p = 0.003), predominantly driven by a 26%
daily) or placebo with a median of 25 months follow-up. reduction in the new onset macroalbuminuria (HR 0.74,
The mean HbA1c, BMI and eGFR at baseline were 7.6%, 95% CI 0.6–0.91, p = 0.004) [55].
30.1 kg/m2 and 76 ml/min/1.73m2 respectively. There In the Semaglutide in Subjects with Type 2 Diabetes
was no difference in the occurrence of the composite (SUSTAIN-6) trial, 3297 participants with high CV risk
primary outcome event (CV death, myocardial infarc- T2D were randomized to either semaglutide (0.5 mg
tion, stroke, or hospitalization for unstable angina) in or 1.0 mg) or placebo for 104 weeks. At baseline, 83%
the lixisenatide group compared to placebo (HR 1.02, of participants had established CV disease and CKD
95% CI 0.89– 1.17). HbA1c and BMI were better in the stage 3 or higher, while 10.7% had CKD only. The
lixisenatide group compared to the placebo, with an mean diabetes duration, HbA1c and BMI were 13.9 years,
average between-group difference of –0.27% and 8.7% and 33.0 kg/m2 respectively. There was a 26%
–0.7 kg (p < 0.001 for both), respectively [52]. To eval- reduction in the primary outcome (composite of CV
uate the possible effect of lixisenatide on the renal death, nonfatal myocardial infarction, or nonfatal
outcome, a follow-up exploratory analysis examined stroke) in the semaglutide group compared to placebo
the percentage change in urinary ACR and eGFR based (HR 0.74, 95% CI 0.58– 0.95, p < 0.001). There was also
on the baseline albuminuria status in both groups. a 36% reduction in the secondary renal outcome (new
Normo-, micro- and macroalbuminuria were identified or worsening nephropathy) (HR 0.64, 95% CI 0.46–
in 74%, 19% and 7% of participants. The macroalbu- 0.88, p = 0.005), but a 76% increase in the onset of
minuria group significantly reduced urinary ACR with diabetes retinopathy (HR 1.76, 95% CI 1.11–2.78,
lixisenatide (–39.2%, p = 0.07) compared to the placebo. p = 0.02) in the semaglutide group. Compared to pla-
No eGFR changes in treatment groups in any urinary cebo, the mean HbA1c and weight differences in the
ACR group. Lixisenatide was associated with a reduc- semaglutide group were –0.7% (semaglutide 0.5 mg),
tion in new-onset macroalbuminuria (HR 0.81), adjusted –1.0% (semaglutide 1.0 mg), –2.9 kg (semaglutide
for both baseline HbA1c (p = 0.04) and on-trial HbA1c 0.5 mg) and –4.3 kg (semaglutide 1.0 mg) respec-
(p = 0.05) [53]. tively [56].
8 ABDUL WAHAB R ET AL.

The Exenatide Study of Cardiovascular Event dulaglutide [59]. A further exploratory analysis was
Lowering Trial (EXSCEL) examined the CV effects of conducted to evaluate the effects of dulaglutide on
once-weekly exenatide (2.0 mg) versus placebo in the renal outcome in the REWIND trial. The largest
14,752 participants with T2D with or without CV dis- component of reduction in the renal outcome came
ease over a median of 3.2 years. At baseline, the from the decrease in the new onset macroalbuminuria
median diabetes duration and HbA1c were 12.0 years (HR 0.77, 95% CI 0.68– 0.87, p < 0.0001) rather than
and 8.0%. The mean BMI and eGFR were 32 kg/m2 and the sustained decline in eGFR (HR 0.89, 95% CI 0.78–
76 ml/min/1.73 m2. There was no difference in the pri- 1.01, p = 0.06) or chronic renal replacement therapy
mary composite outcome (death from CV causes, non- (HR 0.75, 95% CI 0.39–1.44, p = 0.39) [60].
fatal myocardial infarction, or nonfatal stroke) in the To evaluate the CV and renal outcomes of efpe-
exenatide group vs placebo (HR 0.91, 95% CI 0.83– glenatide, 4076 participants with T2D and CV dis-
1.0). The mean difference in HbA1c and weight was ease or current kidney disease were randomized to
–0.53% and –1.27 kg, favouring exenatide [57]. A post weekly efpeglenatide (4 mg or 6 mg) vs placebo for
hoc analysis examined the effects of once-weekly exen- a median of 1.81 years (AMPLITUDE-O trial). The pri-
atide on the eGFR slope and the change in urinary mary composite outcome was the first major MACE.
ACR in a subset of EXSCEL participants. There were In contrast, one of the secondary outcomes was a
3503 and 2828 participants with eGFR and urinary ACR composite renal outcome (defined as incident mac-
data available. Once weekly exenatide improved the roalbuminuria, increase in urinary ACR ≥ 30% from
eGFR slope in participants with a baseline urinary ACR baseline, a sustained > 40% decrease in eGFR, renal
> 100 mg/g (0.79 ml/min/1.73m2/year (95% CI 0.24– replacement therapy, and a sustained eGFR < 15 ml/
1.34)) and a baseline urinary ACR >200 mg/g (1.32 ml/ min/1.73m 2). At baseline, 89.6% had a history of CV
min/1.73m2/year (95% CI 0.57–2.06)). Urinary ACRs disease, 31.6% had eGFR < 60 ml/min/1.73m 2, and
were also reduced by 28.2%, 22.5% and 34.5% in the 21.8% had both CV disease and low eGFR. The base-
subgroup baseline urinary ACR > 30 mg/g, >100 mg/g line mean BMI, eGFR and median urinary ACR were
and >200 mg/g following once-weekly exenatide. In 33 kg/m 2, 72 ml/min/1.73m2 and 28.3 mg/g, respec-
this analysis, once weekly exenatide reduces urinary tively. There was a 27% reduction in the primary
ACR and improves eGFR slope in participants with T2D MACE outcome (HR 0.73, 95% CI 0.58–0.92, p < 0.001)
with higher baseline urinary ACR [58]. and a 32% reduction in the secondary composite
Participants with T2D, with or without CV disease, were renal outcome (HR 0.68, 95% CI 0.57– 0.79, p < 0.001)
randomized to either weekly dulaglutide 1.5 mg or pla- in the efpeglenatide group compared to placebo,
cebo for a median of 5.4 years as part of the CV trial for independent of the baseline use of SGLT2i, met-
dulaglutide in the Dulaglutide and cardiovascular out- formin and baseline eGFR. The LSM for HbA1c, BMI
comes in type 2 diabetes (REWIND) trial (n = 9901). The and weight were –1.24%, –0.9 kg/m 2 and –2.6 kg
primary composite outcome includes nonfatal myocardial favouring the efpeglenatide group [61].
infarction, nonfatal stroke, or death from CV causes In the most recent meta-analysis of published RCTs,
(including unknown causes). There were seven secondary 8 out of 98 articles fulfilled the pre-specified criteria
outcomes, including a composite microvascular outcome to evaluate the benefit or risks of GLP-1a in cardio-
(diabetes retinopathy) and renal outcomes. The baseline vascular and kidney outcomes in participants with T2D
median diabetes duration, HbA1c and eGFR were 9.5 years, (n = 60,080). Overall, all-cause mortality was reduced
7.2% and 74.9 ml/min/1.73 m2 respectively, while the by 12% (HR 0.88, 95% CI 0.82– 0.94, p = 0.0001) with
mean BMI was 32.3 kg/m2. A total of 7.9% of participants GLP-1a compared to placebo. The composite renal
had macroalbuminuria at baseline. There was a 12% outcome (development of macroalbuminuria, doubling
reduction in the primary outcome in the dulaglutide serum creatinine, or at least 40% decline in eGFR, renal
group compared to the placebo (HR 0.88, 95% CI 0.79– replacement therapy, or death due to renal disease)
0.99, p = 0.026). A 13% reduction in the composite micro- was reduced by 21% (HR 0.79, 95% CI 0.73–0.87,
vascular outcome in the dulaglutide group (HR 0.87, 95% p < 0.0001). The worsening renal function outcome was
CI 0.79– 0.95, p = 0.002), predominantly driven by the 15% significantly reduced by 18% (HR 0.82, 95% CI 0.69–
reduction (HR 0.85, 95% CI 0.77–0.93, p = 0.0004) in the 0.98, p = 0.03) following sensitivity analysis, where the
renal outcomes (defined as development of urinary ACR ELIXA trial was omitted as it was restricted to partic-
>33.9 mg/mmol, a sustained ≥ 30% decline in eGFR, or ipants with acute coronary syndrome. There was no
chronic renal replacement therapy) was revealed. The increase in the risk of hypoglycaemia, worsening ret-
least-square mean (LSM) HbA1c, weight and BMI were inopathy or pancreatic side effects following GLP-1a
–0.61%, –1.46 kg and –0.53 kg/m 2, in favour of therapy [62].
 Annals of Medicine 9

The dual glucose-dependent insulinotropic polypep- component of composite CV outcome. This study is
tide (GIP) and GLP-1a, tirzepatide, was shown to reduce currently in the recruitment phase [67]. In these 3
HbA 1c and weight in patients with T2D in the trials, renal endpoints are included as part of the sec-
Tirzepatide versus insulin glargine in type 2 diabetes ondary outcomes in addition to the main primary
and increased cardiovascular risk (SURPASS-4) trial [63]. outcome of first composite CV death, non-fatal MI and
Recently, a post-hoc analysis was performed to eval- non-fatal stroke. Finally, the SUMMIT (A Study of
uate the rates of eGFR decline, the urinary ACR and Tirzepatide in Participants With Heart Failure With
the kidney composite outcome in participants with Preserved Ejection Fraction and Obesity) trial aims to
T2D who were randomized to either once weekly tirze- recruit 700 participants with obesity and heart failure
patide (5, 10 or 15 mg) or titrated insulin glargine. A with preserved ejection fraction, randomized to either
total of 2002 participants with T2D and established tirzepatide or placebo. The primary outcome is a hier-
CV disease or at a high risk of CV disease had a archical composite of all-cause mortality, heart failure
median treatment duration of 85 weeks. The baseline events, 6-minutes’ walk test distance and Kansas City
mean eGFR and median urinary ACR were 81.3 ml/ Cardiomyopathy Questionnaire Clinical Summary Score
min/1.73m2 and 15 mg/g, respectively. The mean eGFR category. The study is due to be completed in July
slope was lower for tirzepatide compared to the insulin 2024 [68]. Renal endpoints are not part of this study
group at –1.4 ml/min/1.73m2/year compared to –3.6 ml/ outcome, however, participants with eGFR between 15
min/1.73m2/year respectively (between-group differ- to 75 ml/min/1.73m2 will be included.
ence of 2.2, 95% CI 1.6– 2.8, p < 0.05). The mean per- In conclusion, evidence supports the benefit of
centage change in urinary ACR was lower in the GLP-1a in reducing CV and renal outcomes in patients
tirzepatide group (-4.4%) compared to the insulin with T2D linked with a previous history or at high risk
group (+56.7%) with a between-group difference of of CV disease, with minimal effects on hypoglycaemia,
–39.0% (95% CI –50.6 to –24.6, p < 0.0001). There was retinopathy or pancreatic adverse events. Evidence also
a 57% reduction in the worsening of urinary ACR showed that GLP-1a contributes to more weight loss
stages in the tirzepatide group compared to the insulin than SGLT2i, with an additional positive renal outcome.
glargine group (HR 0.43, 95% CI 0.27– 0.71, p = 0.0008). However, SGLT2i contributes to more positive renal
The risk of reaching the composite renal outcome was outcomes in patients with T2D and obesity, with a
reduced by 42% (HR 0.58, 95% CI 0.43– 0.8, p = 0.0008), smaller weight loss compared to GLP-1a.
predominantly driven by the reduction in the new
onset macroalbuminuria component [64].
6.  Randomized controlled trials of bariatric
To date, GLP-1a or GLP-1a/GIP-based therapies pro-
surgery in diabetic kidney disease
vide vast evidence in the pharmacotherapy of obesity.
There are several ongoing CVO trials involving GLP-1a Bariatric surgery is the most effective and sustained
or GLP-1a/GIP which may provide further evidence of weight loss procedure that may regress or diminish
the renal outcome. The Semaglutide Effects on Heart obesity-related complications such as cardiopulmonary
Disease and Stroke in Patients With Overweight or disease and T2D [4], with T2D as the leading cause
Obesity (SELECT) trial included 17,500 participants with of CKD [69]. Figure 1 shows a simplified management
overweight or obesity with established CVD random- pathway for obesity and CKD in which bariatric sur-
ized to either semaglutide 2.4 mg or placebo. This gery can be employed in the early stage of CKD.
study is due to be completed in September 2023 [65]. Mounting epidemiological evidence showed that bar-
The SURPASS CVOT (Study of Tirzepatide Compared iatric surgery has renoprotective effects on diabetic
With Dulaglutide on Major Cardiovascular Events in kidney disease (DKD) [70]. However, data from ran-
Participants With Type 2 Diabetes) trial included 13,299 domized trials are limited. Recently, emerging RCTs
participants with overweight or obesity with T2D and revealed that bariatric surgery reduces the incidence
established CVD, randomized to either tirzepatide or of albuminuria and slows CKD progression over
dulaglutide weekly. This study is due to be completed extended follow-up, and therefore may have a poten-
in October 2024 [66]. The SURMOUNT-MMO (A Study tial complementary role to medical treatment in man-
of Tirzepatide on the Reduction on Morbidity and aging DKD.
Mortality in Adults With Obesity) trial will include Schauer et  al. conducted the Surgical Treatment
15,000 participants with obesity and established or at and Medications Potentially Eradicate Diabetes
risk of CVD. Participants will be randomized to either Efficiently (STAMPEDE) trial randomizing patients
tirzepatide or placebo. The primary outcome within with obesity and T2D (n = 150) to intensive medical
the following 5 years is the first occurrence of any therapy alone, intensive medical therapy plus
10 ABDUL WAHAB R ET AL.

Figure 1.  A simplified management pathway for obesity and CKD in which bariatric surgery can be employed in the early stage
of CKD. SGLT2i, sodium-glucose cotransporter 2 inhibitors;ACEi, angiotensin-converting enzyme inhibitor;ARB, angiotensin receptor
blocker;GLP-1a, glucagon-like peptide-1 analogues; CKD, chronic kidney disease;T2D, type 2 diabetes;BP, blood pressure;ESRD,
end-stage renal failure.

Roux-en-Y-gastric bypass (RYGB), or intensive med- persist after five years follow up, RYGB improved gly-
ical therapy plus sleeve gastrectomy (SG) in a 5-year caemia, diastolic blood pressure, lipids, body weight,
follow-up study. The primary outcome was glycaemic and quality of life. The long-term control of these risk
control, while the prespecified secondary endpoint factors may halt the progression of CKD. Furthermore,
included kidney outcomes. At five years, the urinary there was no difference in the serious adverse events
albumin-to-creatinine ratio (uACR), measured in mil- between the surgical versus medical group (p = 0.8).
ligrams of albumin to grams of creatinine, had Ongoing RCT to investigate patients with CKD
decreased significantly from baseline in the SG stages 3 to 5, such as the Randomized Study Comparing
group (p < 0.001) and was considerably lower in the Metabolic Surgery with Intensive Medical Therapy to
SG group than in the medical therapy group Treat Diabetic Kidney Disease (OBESE-DKD), may sup-
(p < 0.001). There was no significant change from port the notion that bariatric surgery may stop the
baseline in albuminuria rates in any group at five evolution of CKD in more advanced kidney disease.
years but there were within-group reductions in This clinical trial will randomize 60 patients with type
serum creatinine and eGFR observed in the two sur- 2 diabetes proteinuria, obesity, and CKD stage 3 to
gical arms. metabolic surgery or the best medical therapy. The
In the Microvascular Outcomes after Metabolic endpoints to be assessed include directly measured
Surgery (MOMS) trial, a total of 100 patients with T2D, GFR, albuminuria, weight loss, metabolic and cardio-
obesity and CKD were randomized to best medical vascular parameters, and health care costs [72].
treatment (n = 49) versus RYGB (n = 51) [6]. The primary
outcome was albuminuria remission (uACR < 30 mg/g),
7.  Randomized controlled trials of other
while secondary outcomes included CKD remission
obesity-related pharmacological agents in
rate and absolute change in uACR. The 2-year data
kidney disease
revealed that RYGB was more effective than the best
medical treatment for achieving albuminuria remission Several pharmacotherapies proven to aid weight loss,
and early-stage CKD in patients with DKD and obesity have either been removed or suspended from the
(BMI 30-35 kg/m2). Subsequently, MOMS 5-year data market. Sibutramine was removed from the European
showed that albuminuria remission was not statistically market due to the increased risk of CV outcome [73].
different between best medical treatment versus RYGB The CV outcome trials for rimonabant were prema-
in the T2D, early CKD and Class 1 obesity cohort [71]. turely discontinued due to the increased risk of suicide
Although diabetic kidney disease remission did not [74] while the CV outcome of naltrexone-bupropion
 Annals of Medicine 11

is still unknown due to the termination of its trial pressure, body weight, low-density lipoprotein choles-
following a breach of confidentiality [75]. None were terol, and uACR by efpeglenatide also appeared to be
designed to evaluate the impact on kidney disease independent of concurrent SGLT2i use (all interactions
related to obesity. p ≥ 0.08). Therefore, the study supports the usage of
The CAMELLIA-TIMI-61 (Cardiovascular and Metabolic combined SGLT2i and GLP-1a in the management of
Effects of Lorcaserin in Overweight and Obese T2D with evidence of additive or synergistic effects
Patients-Thrombolysis in Myocardial Infarction 61) trial on renal events.
evaluated the CV outcome of lorcaserin compared to There is no data on combination therapies of bar-
placebo. Lorcaserin is proven to aid weight loss via iatric surgery plus SGLT2i plus GLP-1a for DKD in the
appetite regulation through the activation of the background of obesity. Therefore, trials examining the
proopiomelanocortin (POMC) pathway. This study effect of these therapies on kidney protection in
included 12,000 participants who were overweight or patients at high risk of DKD progression are warranted.
obese (median BMI = 35 kg/m2) with CV diseases or Nevertheless, our findings have shown that the clinical
CV risk factors, randomized to either lorcaserin 10 mg management of DKD is evolving. Indeed, there is a
BD or placebo. There were triple odds of 5% weight need to address the treatment of patients with obesity
loss in lorcaserin group and no differences in primary and CKD to lessen morbidity. With the rapid growth
CV outcome were demonstrated when compared to and high prevalence of obesity in the CKD population,
placebo (HR 0.99, 95% CI 0.85–1.14) [76]. A composite this area of research is critical and should take
of new or worsening persistent micro- or macroalbu- precedence.
minuria, new or worsening CKD, doubling of serum
creatinine, ESRD, renal transplant or renal death was
the primary renal outcome of this trial. Close to 24% Acknowledgement
of participants had a baseline eGFR of < 60 ml/ None.
min/1.73m2 while 19% had urinary albumin: creatinine
ratio ≥ 30 mg/g indicating albuminuria. The primary
renal outcome was reduced in the lorcaserin group Author contributions
(HR 0.87, 95% CI 0.79– 0.96, p = 0.0064) compared to
RAW, ClR and RVC were responsible for the conception;RAW
placebo. It is not known if this benefit is related to was responsible for the acquisition of the literature for the
the weight loss of a direct action of the medication [8]. manuscript. RAW wrote the original draft of the manuscript.
ClR and RVC reviewed and edited. ClR and RVC supervised
the paper. All authors have read and agreed to the published
8.  Conclusion version of the manuscript.
There is a dearth of RCT data in combination therapies
of SGLT2i plus GLP-1a for DKD. Recently, Lam et  al.
Disclosure statement
performed an exploratory analysis of the AMPLITUDE-O
trial in which cardiovascular and renal outcomes were ClR reports grants from the Irish Research Council, Science
analyzed with Cox proportional hazards models Foundation Ireland, Anabio, and the Health Research Board.
He serves on advisory boards of Novo Nordisk, Herbalife,
adjusted for region, SGLT2i randomization strata, and
GI Dynamics, Eli Lilly, Johnson & Johnson, Glia, and
the SGLT2 inhibitor–by–treatment interaction [77]. The Boehringer Ingelheim. ClR is a member of the Irish Society
trial stratified randomization by baseline or anticipated for Nutrition and Metabolism outside the area of work
use of SGLT2i and included the highest prevalence at commented on here. He was the chief medical officer and
baseline of SGLT2i use among GLP-1a cardiovascular director of the Medical Device Division of Keyron in 2011.
Both of these are unremunerated positions. ClR was a
outcome trials (n = 618, 15.2%). Results were analyzed
previous investor in Keyron, which develops endoscopically
to estimate the combined effect of SGLT2i and the implantable medical devices intended to mimic the surgical
GLP-1a on clinical outcomes. The effect (hazard ratio procedures of sleeve gastrectomy and gastric bypass. The
(95% CI)) of efpeglenatide versus placebo in the product has only been tested in rodents and none of
absence and presence of baseline SGLT2i on MACEs Keyron’s products is currently licensed. They do not have
(0.74 (0.58–0.94) and 0.70 (0.37–1.30), respectively), any contracts with other companies to put their products
into clinical practice. No patients have been included in
expanded MACEs (0.77 (0.62–0.96) and 0.87 (0.51–
any of Keyron’s studies and they are not listed on the
1.48)), renal composite (0.70 (0.59–0.83) and 0.52 stock market. ClR was gifted stock holdings in September
(0.33–0.83)), and MACEs or death (0.74 (0.59–0.93) and 2021 and divested all stock holdings in Keyron in
0.65 (0.36–1.19)) did not differ by baseline SGLT2i use September 2021. He continues to provide scientific advice
(p for all interactions >0.2). The reduction of blood to Keyron for no remuneration. RVC reports research grants
12 ABDUL WAHAB R ET AL.

from Johnson & Johnson Brazil and Medtronic, and serves [10] Eckardt KU, Coresh J, Devuyst O, et  al. Evolving impor-
as the speaker for Johnson & Johnson Brazil and Medtronic. tance of kidney disease: from subspecialty to global
He also serves on advisory boards of Johnson & Johnson health burden. Lancet. 2013;13382(9887):158–169.
Brazil, Medtronic, Keyron, GI Dynamics and Baritek. The [11] Evangelista LS, Cho WK, Kim Y. Obesity and chronic
authors have no other relevant affiliations or financial kidney disease: a population-based study among South
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cial interest in or financial conflict with the subject matter [12] Kuma A, Uchino B, Ochiai Y, et  al. Relationship between
or materials discussed in the manuscript apart from those abdominal adiposity and incident chronic kidney dis-
disclosed. ease in young- to Middle-aged working men: a retro-
spective cohort study. Clin Exp Nephrol. 2019;23(1):76–
84.
Funding [13] Madero M, Katz R, Murphy R, et  al. Comparison be-
tween different measures of body fat with kidney func-
The author(s) reported there is no funding associated with tion decline and incident CKD. Clin J Am Soc Nephrol.
the work featured in this article. 2017;12(6):893–903.
[14] Xu H, Kuja-Halkola R, Chen X, et  al. Higher body mass
index is associated with incident diabetes and chronic
ORCID kidney disease independent of genetic confounding.
Kidney Int. 2019;95(5):1225–1233.
Carel W. le Roux http://orcid.org/0000-0001-5521-5445
[15] Alizadeh S, Esmaeili H, Alizadeh M, et  al. Metabolic
phenotypes of obese, overweight, and normal weight
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Data availability statement tematic review and meta-analysis. Arch Endocrinol
Metab. 2019;2963(4):427–437.
Data sharing is not applicable to this article as no new [16] Herrington WG, Smith M, Bankhead C, et  al. Body-mass
data were created or analyzed in this study. index and risk of advanced chronic kidney disease:
prospective analyses from a primary care cohort of 1.4
million adults in England. PLoS One. 2017;12(3):e0173515.
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