Impact of CVOTs in primary and secondary prevention of kidney disease

diabetes research and clinical practice

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Contents available at ScienceDirect

Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locat e/dia bre s

Impact of CVOTs in primary and secondary prevention of kidney disease Salvatore De Cosmo a,1, Francesca Viazzi b, Pamela Piscitelli a, Giovanna Leoncini b, Antonio Mirijello a, Barbara Bonino b, Roberto Pontremoli b,2,* a b

Unit of Internal Medicine, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG 71013, Italy Universita` degli Studi and IRCCS Ospedale Policlinico San Martino, Genoa, Italy

A R T I C L E I N F O

A B S T R A C T

Article history:

Type 2 diabetes mellitus is the leading cause of end stage renal disease worldwide. Diabetic

Received 1 October 2019

kidney disease, whose main clinical manifestations are albuminuria and decline of

Accepted 7 October 2019

glomerular filtration rate, affects up to 40% of patients. Sodium Glucose cotransporter-2

Available online xxxx

inhibitors (SGLT2-is) and Glucagon-like peptide-1 receptor agonists (GLP-1ras) are new classes of anti-hyperglycemic drugs which have demonstrated to improve renal outcome.

Keywords: Type 2 diabetes mellitus Albuminuria Glomerular filtration rate Sodium Glucose cotransporter-2 inhibitors (SGLT2-is)

Renal benefits of both SGLT2-is and GLP-1ras are acknowledged from data of large randomized phase III clinical trials conducted to assess their cardiovascular safety. In this review, we will focus on renal results of major cardiovascular outcome trials, and we will describe direct and indirect mechanisms through which they confer renal protection. Ó 2019 Elsevier B.V. All rights reserved.

Glucagon-like peptide-1 receptor agonists (GLP-1ras)

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SGLT2-is and renal protection: Lessons from clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How do SGLT2-is work? A look at potential mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidences from cardiovascular safety studies with GLP1-ras . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GLP-1ras and kidney protection: Putative direct and indirect actions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New guidelines recommendations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Financial disclosures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declaration of Competing Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Universita` degli Studi e IRCCS Ospedale Policlinico San Martino, Viale Benedetto XV, 6 -16132 Genoa, Italy. E-mail addresses: [email protected] (S. De Cosmo), [email protected] (R. Pontremoli). 1 Department of Clinical Science, IRCCS Casa Sollievo della sofferenza, Viale dei Cappuccini, 71013 San Giovanni Rotondo, FG, Italy. 2 Department of Internal Medicine, Universita` degli Studi and IRCCS Ospedale Policlinico San Martino, Viale Benedetto XV, 6, 16132 Genova, Italy. https://doi.org/10.1016/j.diabres.2019.107907 0168-8227/Ó 2019 Elsevier B.V. All rights reserved.

Please cite this article as: S. De Cosmo, F. Viazzi, P. Piscitelli et al., Impact of CVOTs in primary and secondary prevention of kidney disease, Diabetes Research and Clinical Practice, https://doi.org/10.1016/j.diabres.2019.107907

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1.

diabetes research and clinical practice

Introduction

Type 2 diabetes mellitus (T2D) entails an increased risk of premature cardiovascular (CV) events as well as long term complications such as heart failure (HF) and chronic kidney disease (CKD). While morbidity and mortality from stroke and miocardial infarction has been decreasing in western countries over the last 20 years, the prevalence and incidence of microvascular complications such as CKD has remained relatively steady in patients with diabetes [1]. Pharmacologic interventions to prevent the development of renal complication and to retard progression towards end stage renal disease (ESRD), traditionally based on multifactorial intervention on CV risk factors, has been shown to be only partially effective [2]. Furthermore, some anti-hyperglycemic drugs may have unfavorable side effects, which limit their cost-benefit ratio. Since about a decade ago, the Food and Drug Administration started a policy requiring that CV safety be tested in large clinical trials before approving new glucose lowering agents [3]. Several cardiovascular outcome trial (CVOT) have been completed since then, mostly with the use of two new drug classes, namely Sodium-Glucose transport type 2-inhibitors (SGLT2-is) and Glucagon-like peptide-1 receptor agonists (GLP-1ra). As far as renal outcomes are concerned, available evidence has been collected from about 80 thousand patients and a median follow-up of 3–4 year. Results of these trials have clearly shown that these two drug classes are safe and effective and may offer considerable additional benefits as compared to traditional oral agents in term of CV and especially renal protection.

2. SGLT2-is and renal protection: Lessons from clinical trials From november 2015 when results of the first large randomized clinical trial (RCT) with Emagliflozin was published [4] to the very recent results of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, a sequence of several studies have consistently shown additional renal protective action of SGLT2-is beyond their glucose lowering effect. In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, 7020 patients with T2D at high CV risk were randomized to Empagliflozin (10–25 mg/day) or placebo and followed up for a median of 3.1 years. Empagliflozin treatment was associated to a striking 38% lower CV mortality as compared to placebo. Furthermore, there was a 35% reduction in HF hospitalization and a 32% reduction in total mortality. Specific renal outcomes were significantly and consistently reduced with Empagliflozin with a 44% lower occurrence of serum creatinine doubling and a 55% reduction in the incidence of renal replacement therapy [5]. Although no difference in the incidence of microalbuminuria was observed between study arms, virtually every other intermediate renal end-point was favorably influenced by Empagliflozin. Subsequent analyses showed that Empagliflozin retards glomerular filtration

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rate (GFR) deterioration independently of the presence of albuminuria and the degree of baseline GFR reduction. Only a few months after publication of the EMPA-REG OUTCOME trial, results from the canagliflozin cardiovascular assessment study (CANVAS) program were distributed [6]. Canagliflozin at 100–300 mg/day was compared to placebo in 10,142 patients with diabetes at high CV risk. Mean age of study patients was 63 years and disease duration was, on average, 13 years. Canagliflozin was associated with a 14% significant reduction of the primary composite endpoint (CV death, stroke and non fatal miocardial infarction). Moreover, in the renal substudy (CANVAS-R) Canagliflozin treatment almosted halved the doubling of serum creatinine (
47%), albuminuria progression and mean annual loss of GFR (with a delta of 1.2 ml/min/year in favor of Canagliflozin between study arms) [7]. Finally, the Dapagliflozin Effect on Cardiovascular Events– Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial, published in november 2018, evaluated Dapagliflozin 10 mg/day as compared to Placebo over a median 4.2 year study period in a large (n = 17160) cohort of patients with T2D at relatively low CV risk. Although Dapagliflozin did not result in a lower rate of major cardiovascular events, it was associated with a significant renal benefit (24% relative risk reduction as compared to placebo). Altogether, these results are taken to indicate a clear renal benefit with SGLT2-is beyond their glucose lowering effect. While the magnitude of CV risk reduction seems to be influenced by overall CV risk in individual patients, with greater benefit observed in patients at higher risk, renal protection seems to be consistent across different degrees of urine albumin excretion as well as GFR strata [8]. Confirmation of a class effect which compares and likely exceeds that observed with renin-angiotensin-aldosterone inhibitors (RAAS-is) in terms of renal protection, has been very recently obtained in the Credence study [9]. The Credence trial was carried out on 4401 patients with diabetic kidney disease with several degrees of albuminuria and eGFR values between 30 and 90 ml/min. The study was terminated prematurely because of an excess of benefit in the Canagliflozin arm, wherein a 20% reduction of major CV events was recorded. This goes along a 30% reduction in the composite renal endpoint as compared to placebo.

3. How do SGLT2-is work? A look at potential mechanisms of action Inhibition of SGLT2 selectively blocks glucose reabsortion at the renal proximal tubule, thereby allowing glucose filtered at the glomerulus to remain in the urine and to be excreted. Besides attenuating hyperglycemia in a self limiting fashion (i.e. with virtually no risk of hypoglycemia), these drugs improve insulin sensitivity, attenuate synpathetic tone, reduce extracellular volume and blood pressure and induce a negative caloric balance of about 500 Kcal/week through glycosuria. While these effects make it for a successful antidiabetic action, there is more to these drugs that may catch the interest of the clinicians. In fact, by enhancing natriuresis

Please cite this article as: S. De Cosmo, F. Viazzi, P. Piscitelli et al., Impact of CVOTs in primary and secondary prevention of kidney disease, Diabetes Research and Clinical Practice, https://doi.org/10.1016/j.diabres.2019.107907

diabetes research and clinical practice

trough complex and so far only partly clarified mechanisms, SGLT2-is operate at the macula densa via an adenosine dependent mechanism and activate the tubular glomerular feed back, thereby inducing an increase in afferent arteriole tone. The result is a reduction in intraglomerular pressure and filtration fraction, a condition that lowers eGFR in the short term but provides a reduction in intraglomerular pressure that may attenuate glomerulosclerosis in the long term [10] (Fig. 1), These changes in renal hemodynamics have been shown to be additive to the effect of RAAS-i [11]. Nearly all of the clinical studies carried out so far have confirmed the noteworthy renal protective effect of the class, alongside with an improvement in heart failure endpoints in many different patient subgroups and independently of the degree of renal function impairment [12].

4. Evidences from studies with GLP1-ras

cardiovascular

safety

In the last decade, another class of new anti-hyperglycemic drugs, based on the gut hormone glucagon-like peptide-1, has been introduced for the management of T2D, namely GLP-1ra [13]. A number of clinical trials have recently reported that GLP-1ra are able to prevent the onset of macroalbuminuria and, probably, reduce the decline in GFR in patients affected by T2D although the potential protective mechanisms of GLP-1ra on kidneys is still debated (Table 1) [13–22]. Renal outcomes of GLP-1ras have been explored, generally as secondary endpoints in large RCTs conducted over the last few years. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, 9340 T2D patients with CV disease or at high CV risk were randomly allocated to liraglutide or placebo [14]. Liraglutide significantly reduced the risk of developing the prespecified secondary renal outcome represented by a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level and eGFR < 45 ml/min/1.73 m2, ESRD, or renal

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death by 22% (p = 0.003). This result was primarily driven by a reduction of new onset of persistent macroalbuminuria. UrinaAlbuminuria was also reduced by 19% by active treatment and this difference persisted during the study. In addition, liraglutide slightly slowed the decline in eGFR over time compared to placebo. Subgroup analyses revealed that this decline occurred mainly in patients with macroalbuminuria or in those with an eGFR between 30 and 59 at baseline. No changes have been identified in ‘‘hard” renal outcomes, although the study was underpowered to detect differences in hard renal endpoints such as ESRD. Statistical adjustment for the glycated hemoglobin level (HbA1c), systolic blood pressure or weight change, did not affect the results [15]. In the Trial to Evaluate Cardiovascular and Other Longterm Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6), 3297 patients with T2D and CV disease or with CV risk factors were randomly allocated to receive semaglutide (at the dose of 0.5 or 1 mg once weekly) or placebo [16]. After a median follow-up of two years, new or worsening nephropathy, which included persistent macroalbuminuria, persistent doubling of the serum creatinine level and a creatinine clearance of less than 45 ml/ min/1.73 m2 occurred significantly less often in patients treated with semaglutide. As for LEADER trial, the renal outcome was driven by a reduction in new onset macroalbuminuria (semaglutide vs placebo; 2.5% vs 4.9%). Doubling of serum creatinine concentration to an eGFR  45 ml/min/1.73 m2, ESRD or renal death were unaffected, although the event rate was too low (<1%) to adequately explore these outcomes. Noteworthy, a higher rate of retinopathy complications (vitreous hemorrhage, blindness, or the need for treatment with an intravitreal agent or photocoagulation) occurred in the semaglutide group, although the overall number of retinal events was low. The trial Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide (ELIXA) investigated the CV safety of lixisenatide in 6068 patients with T2D

Fig. 1 – Hypothesized pathophysiologic mechanisms of cardiac and renal protection with SGLT2-is Sodium Glucose cotransporter-2 inhibitors (SGLT2-is); glycated hemoglobin level (HbA1c); angiotensin converting enzyme ACE. Please cite this article as: S. De Cosmo, F. Viazzi, P. Piscitelli et al., Impact of CVOTs in primary and secondary prevention of kidney disease, Diabetes Research and Clinical Practice, https://doi.org/10.1016/j.diabres.2019.107907

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Name of the Drug and Intervention study

Study population

ELIXA17

10–20 lg of Lixisenatide versus placebo

6068 patients with a myocardial infarction or hospitalization for unstable angina within the previous 180 days with a median follow-up of 108 weeks

LEADER14

Liraglutide 1.8 mg (or the maximum tolerated dose) versus placebo

SUSTAIN616

Semaglutide 0.5 mg vs 1.0 mg vs placebo

AWARD-721

Dulaglutide 0.75 or 1.5 mg versus insulin glargine

REWIND22

Change in uACR (%) from baseline to 108 weeks % Change in uACR in normoalbuminuria microalbuminuria macroalbuminuria Risk of new-onset macroalbuminuria 9340 patients high CV risk with a Composite end point median follow-up of 3.84 years New-onset persistent albuminuria Persistent doubling of sCr and eGFR < 45 ml/min/1.73 m2 Need for continuous RRT Death due to renal disease 3297 patients, 83% had established New or worsening nephropathy CV disease, CKD, or both. The median New onset of persistent follow-up was 108 weeks macroalbuminuria, Persistent doubling of the sCr and a eGFR < 45 ml/min/1.73 m2 Need for continuous RRT 577 patients with CKD 3–4 with a eGFR changes from baseline follow-up of 52 weeks uACR changes from baseline

Exploratory kidney outcomes (change from baseline placebo/ intervention or HR 95% CI)

Results

24% vs. 34%, p = 0.004
169% (11.69–8.30; p = 0.7398)
21.10% (42.25–0.04; p = 0.0502)
39.18% (68.53–9.84; p = 0.007) 0.808 (0.660–0.991; p = 0.0404)

Lixisenatide reduces progression of uACR in macroalbuminuric patients, with a lower risk of new-onset macroalbuminuria

0.78 0.74 0.89 0.87 1.59

(0.67–0.92, (0.60–0.91, (0.67–1.19, (0.61–1.24, (0.52–4.87,

p = 0.003) p = 0.004) p = 0.43) p = 0.44) p = 0.41)

Liraglutide determined a lower risk of the composite renal outcome than placebo, mainly owing to a lower rate of new-onset persistent macroalbuminuria.

0.64 0.54 1.28 0.91

(0.46–0.88, (0.37–0.77, (0.64–2.58, (0.40–2.07,

p = 0.005) p = 0.001) p = 0.48) p = 0.83)

The reduction in macroalbuminuria seems exclusively responsible for the favourable renal outcome of semaglutide

dulaglutide 1.5 mg: 34 ml/min per 1.73 m2; p = 0.005 vs insulin glargine; dulaglutide 0.75 mg :33.8 ml/min per 1.73 m2; p = 0.009 vs insulin glargine; insulin glargine 31.3 ml/min per 1.73 m2. Dulaglutide 1.5 mg
22.5%; NS vs insulin glargine; Dulaglutide 0.75 mg
20.1%; NS vs insulin glargine; Insulin glargine
13.0% Renal composite 2 (40% eGFR decline, 0.85 (0.73–0.98, p = 0.027) Extended-release exenatide 14,752 patients (73% with previous 2 mg or placebo once weekly CV disease) followed for a median of renal replacement, renal death or new macroalbuminuria) 3.2 years

Dulaglutide 1.5 mg once weekly versus placebo

9901 patients (31% with previous CV Composite: first occurrence of new 0.85 (0.77–0.93, p = 0.0004) event) macroalbuminuria, sustained decline 0.77 (0.68–0.87, p < 0.0001) followed for a median of 5.4 years in eGFR  30% or chronic RRT New macroalbuminuria

Dulaglutide produced glycemic control similarly to insulin glargine, with reduced decline in eGFR. Dulaglutide appears to be safe to achieve glycemic control in patients with moderate-to-severe CKD.

A composite of 40% eGFR decline, renal replacement, renal death or new macroalbuminuria was significantly reduced in an adjusted analysis by the addition of exenatide people with T2DM. Other renal outcomes were numerically but not statistically improved with exenatide. Long term use of Dulaglutide was associated with reduced renal composite endpoint

Abbreviations: uACR: urinary albumin-to-creatinine ratio (albumin measured in mg/g); CKD: chronic kidney disease, CV: cardiovascular, sCr; serum creatinine, CrCl: creatinine clearance; RRT: renal replacement therapy; eGFR: estimated glomerular filtration rate in ml/min/1.73 m2; SE: standard error; HR: hazard ratio: CI: confidence interval.

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EXSCEL19

Renal end points

diabetes research and clinical practice

Please cite this article as: S. De Cosmo, F. Viazzi, P. Piscitelli et al., Impact of CVOTs in primary and secondary prevention of kidney disease, Diabetes Research and Clinical Practice, https://doi.org/10.1016/j.diabres.2019.107907

Table 1 – Renal outcomes in clinical trials with GLP-1R agonists in patients with T2D.

diabetes research and clinical practice

and acute coronary syndrome who were randomized to receive lixisenatide or placebo [17]. The pre-specified analysis of the percentage change in the uACR from baseline to 108 weeks showed a slight difference in favor of lixisenatide over placebo (24% vs. 34%, p = 0.004). Adjustments for differences in HbA1c levels (~0.3%) during the first 3 months of the trial reduced the lixisenatide-induced renal benefit (p = 0.07), suggesting some glucose-dependency. More recently Muskiet et al. [18] have deeply explored the effect of lixisenatide on renal outcome. After a median follow-up time of 108 weeks, the authors reported that the placeboadjusted mean percentage change in uACR from baseline was significant only among patients with macroalbuminuria (
39.18%, p = 0.0070). Lixisenatide was also associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c. After two years, as expected, macroalbuminuric group had the faster eGFR decline from baseline, but no significant difference was observed between groups as far as eGFR decline wover time. In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial the CV safety of once-weekly exenatide was explored in 14,752 patients affected by T2D with (73%) or without previous CV disease [19]. Bethel MA et al. investigating the renal outcomes showed a significant reduction of the composite renal endpoint of 40% eGFR decline, renal replacement, renal death or new macroalbuminuria among patients in active treatment arm [20]. No difference was shown in eGFR levels or new occurrence of macroalbuminuria between exenatide and placebo groups [20]. The A Study Comparing Dulaglutide With Insulin Glargine on Glycemic Control in Participants With Type 2 Diabetes and Moderate or Severe Chronic Kidney Disease (AWARD-7), was a multicenter and open-label trial enrolling 577 patients with T2D and moderate to severe CKD [21]. Participants were randomized to receive (1:1:1) once-weekly injectable dulaglutide 1.5 mg, once-weekly dulaglutide 0.75 mg, or daily insulin glargine as basal therapy, all in combination with insulin lispro, for 52 weeks. The primary outcome was HbA1c at 26 weeks, with a 0.4% non-inferiority margin. Secondary outcomes included eGFR and uACR changes. At 52 weeks, eGFR levels were higher with dulaglutide 1.5 mg and dulaglutide 0.75 mg as compared to insulin glargine. The effect of dulaglutide 1.5 mg and 0.75 mg on uACR reduction did not significantly

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differ from that of insulin glargine. The results of trial AWARD-7 showed that once-weekly dulaglutide produced a significant improvement in glycemic control in T2D patients with moderate-to-severe CKD, with efficacy similar to that of daily insulin glargine as basal therapy in terms of change in HbA1c. The analysis of secondary endpoints suggested that dulaglutide attenuates eGFR decline compared with insulin glargine in patients with T2D and moderate-to-severe CKD after 52 weeks. This was the first clinical trial in patients with T2DM and moderate-to-severe CKD that has shown clear effects of a GLP-1ras on eGFR. Finally, renal data are available from Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial [22], a randomised, double-blind, placebo-controlled trial assessing the superior effect of dulaglutide 1.5 mg weekly on major adverse CV events in 9901 patients with T2D a mean eGFR of 77 ml/min/1.73 m2 and baseline prevalence of albuminuria of 35.0% (22). In an exploratory analysis, the renal component of the composite microvascular outcome defined as the first occurrence of new macroalbuminuria, a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy, were also investigated. During a median follow-up of 5.4 years, the renal outcome was recorded in a significantly smaller number of participants in the dulaglutide group (17.1%) than in the placebo group (19.6%). The favorable effect was largest for the onset of new macroalbuminuria (HR 0.77 [95% CI 0.68–0.87] p < 0.0001), with no significant impact on sustained eGFR decline or chronic renal replacement therapy. Sensitivity analysis, however, showed a beneficial effect of dulaglutide in reducing incidence of 40% and 50% decline in eGFR. The study was taken to suggest that this reduction occurs for reasons independent of antyhyperglycemic and blood pressure reduction as well as of RAAS inhibitors. Overall, results from CVOTs investigating safety of GLP1ras show a clear renal protective effect, mainly due to reduction of albuminuria. This seems to be confirmed also by a recent meta-analysis by Zelniker et al. [23] showing a waning of renal protection with GLP-1ras when the effect on macroalbuminuria is excluded. Similar results come from another recently published metanalysis by Kristensen SL et al. [24]. Nevertheless, a large body of evidence suggests that reduction in albuminuria is known to translate in long standing kidney protection [25].

Table 2 – Putative renoprotective actions and effects of GLP-1 receptor agonists on kidneys. Direct effects

Indirect effects

Proximal tubular natriuresis stimulation Modulation of cAMP/PKA signaling Inhibition of renin angiotensin system ; Renal hypoxia ; Glomerular atherosclerosis? Renal endothelial dependent vasodilation " Tubuloglomerular feedback (through ; NHE3 activity) " ANP

Improved glycemic control Improved blood pressure control Weight loss " Insulin sensitivity ; Postprandial glucagon ; Intestinal lipid uptake " Brown adipose tissue activation Effects on microbioma?

Abbreviations: cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; NHE3: sodium–hydrogen exchanger 3; ANP: atrial natriuretic peptide.

Please cite this article as: S. De Cosmo, F. Viazzi, P. Piscitelli et al., Impact of CVOTs in primary and secondary prevention of kidney disease, Diabetes Research and Clinical Practice, https://doi.org/10.1016/j.diabres.2019.107907

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diabetes research and clinical practice

5. GLP-1ras and kidney protection: Putative direct and indirect actions GLP-1ras may provide direct and indirect salutary effects on renal function (Table 2), as extensively discussed in a recent meta-analysis by Muskiet et al. [26]. Evidence from CVOTs suggests that adding a GLP-1ra to standard anti-hyperglycemic therapy, produces a reduction of HbA1c, ranging from
0.3 to
1.9%, as compared to control arm [27]. Several intervention studies have confirmed that intensive glucose treatment in patients with T2D translates in a favorable effect on renal outcome, with largest effect on albuminuria [28]. GLP-1ras may also exert favorable effect on blood pressure (with an average reduction of 2–5 mmHg), thereby contributing to albuminuria reduction [29]. The blood pressure lowering effect could be mediated by inducing natriuresis and diuresis, possibly involving the inhibition of sodium-hydrogen antiporter 3 (NHE3) localized at the brush border of the renal proximal tubular cells [30]. Indeed, the acute administration of GLP-1ra increases the effective renal plasma flow and eGFR, at least in healthy individuals, together with a transient increase in blood pressure, which in turn results from an increase in heart rate and cardiac output. Furthermore, chronic administration of GLP-1ras has been shown to reduce blood pressure, increase natriuresis and improve renal risk factors thereby supporting renal function preservation [31]. Additionally, GLP-1ras could also influence glomerular hemodynamics via activation of tubuloglomerular feedback, although this mechanism is still debated. Finally, obesity may directly contribute to glomerulopathy [32] and, consequently, loss of weight associated to GLP-1ra may contribute to renal protection. Interestingly, experimental studies indicate that GLP-1 receptors may be found in many extra-pancreatic tissues, including the kidneys [33,34]. From a chemical point of view, the GLP-1 receptor is a G-protein coupled receptor which stimulates adenyl cyclase and protein kinase A (PKA) [35]. GLP-1ra might also protect kidneys trough a reduction of inflammation and oxidative stress [36], two unfavorable conditions typically associated with diabetic kidney disease. Notably, GLP-1based therapies have shown renal protective effects also in nondiabetic models of kidney injury [37]. Increased renal oxidative stress induced by chronic hyperglycemia may upregulate fibrogenic cytokines such as TGFb1 and CTGF resulting in mesangial expansion and extracellular matrix production [38]. Accordingly, Fujita et al. [35] have recently shown that liraglutide suppresses the progression of nephropathy in a mouse model of T1D, decreasing levels of glomerular superoxide and renal nicotinamide adenine dinucleotide phosphate oxidases (NADPH) oxidase and elevated renal cyclic adenosine monophosphate (cAMP) and PKA activity. Aiming to explore whether the role of GLP-1 receptors signaling in the development and progression ofdiabetic nephropathy, these authors disrupted the GLP-1 receptor gene in the DN-resistant mouse model and investigated its renal phenotype. The loss of the GLP-1 receptor caused elevation of glomerular superoxide and renal oxidative stress. In addition, diabetic mice knockout for GLP-1 receptor showed mesangial expansion,

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increased glomerular deposit of fibronectin and fewer podocytes. The renal protective effect of reducing oxidative stress and TGFb expression with GLP1-ra has also been recently shown by Hendarto et al. with liraglutide in STZ model of T1D in rats [39]. Other studies have shown that GLP-1 receptor-induced cAMP activation might also result in reduced expression of the receptor of advanced glycation end products (AGE) [40] as well as inhibition of the RAAS [41].

6.

New guidelines recommendations

Enthusiastic results from RCTs with SGLT2-is and GLP-1ras have rapidly been acknowledged into International Guidelines. SGLT2-is are currently recommended in all patients with diabetes at renal or heart failure risk as add-on treatment to metformin or as a monotherapy should the latter not be tolerated [12]. GLP1-ra are to be preferred in patients at high CV risk from atherosclerotic disease. Although SGLT2-is are formally indicated only in patients with eGFR above 60 ml/min, analysis of studies published so far support a strong nephroprotective effect of this drugs even in patients with reduced GFR. Furthermore, preliminary evidence [42] suggests that most of the favorable effect of these drugs is mantained even in non diabetic patients with no additional risk of hypoglycemia. GLP1-ras have clearly demonstrated a favorable cardiovascular safety profile and exert several ancillary salutary effects. The renoprotective potential of this class deserves to be investigated in greater detail. Whether it is mainly limited to their anti-albuminuric action, it still compares favorably with traditional oral hypoglycemic drugs for patients at high renal risk.

Financial disclosures None.

Declaration of Competing Interest No conflicting relationship exists for any author.

R E F E R E N C E S

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Please cite this article as: S. De Cosmo, F. Viazzi, P. Piscitelli et al., Impact of CVOTs in primary and secondary prevention of kidney disease, Diabetes Research and Clinical Practice, https://doi.org/10.1016/j.diabres.2019.107907

diabetes research and clinical practice

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Please cite this article as: S. De Cosmo, F. Viazzi, P. Piscitelli et al., Impact of CVOTs in primary and secondary prevention of kidney disease, Diabetes Research and Clinical Practice, https://doi.org/10.1016/j.diabres.2019.107907