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Type 2 diabetes is the leading cause of impaired kidney function, albuminuria, and renal replacement therapy globally, Lancet Diabetes Endocrinol 2018
thus placing a large burden on health-care systems. Current treatment strategies rely on intensive glucose lowering, Published Online
and strict blood pressure control targeting blockade of the renin–angiotensin–aldosterone system. Such approaches December 19, 2018
http://dx.doi.org/10.1016/
might slow decline in kidney function, but many patients progress to end-stage kidney failure despite optimal therapy.
S2213-8587(18)30263-8
In recent clinical trials, new-generation glucose-lowering drug classes, the sodium-glucose co-transporter-2 inhibitors
Diabetes Centre, Department
and agents that target the incretin pathway, have been shown to improve kidney outcomes in patients with type 2 of Internal Medicine, VU
diabetes. Other new approaches, which have been developed on the basis of an improved understanding of the University Medical Centre,
mechanisms that contribute to kidney damage in the context of diabetes, include use of drugs that block endothelin Amsterdam, Netherlands
(M H A Muskiet MD); Centre for
receptors (eg, atrasentan) and non-steroidal mineralocorticoid receptors (eg, finerenone). In this Review, we provide
Nephrology, University College
an overview of recent clinical data relevant to these new therapeutic approaches for management of kidney disease in London, London, UK
the context of type 2 diabetes. (Prof D C Wheeler MD); and
Department of Clinical
Introduction effective renoprotective strategy in patients with type 2 Pharmacy and Pharmacology,
University of Groningen,
Patients with type 2 diabetes who develop a reduction in diabetes in the early 2000s was a major step forward, but University Medical Centre
estimated glomerular filtration rate (eGFR) to less than was followed by several years without much progress.3 Groningen, Groningen,
60 mL/min per 1∙73 m², albuminuria (eg, urinary However, emerging data from clinical outcome trials Netherlands
(Prof H J L Heerspink PhD)
albumin-to-creatinine ratio [UACR] >3 mmol/mol), or suggest that new-generation glucose-lowering drug
Correspondence to:
both, sustained over at least 3 months, are considered to classes (sodium-glucose co-transporter-2 [SGLT2] inhibi
have chronic kidney disease according to current inter tors and certain incretin-based therapies) might protect Prof David C Wheeler, Centre for
Nephrology, University College
national guidelines.1 Chronic kidney disease identified the kidney through mechanisms not directly related to London, London NW3 2PF, UK
in the context of type 2 diabetes is usually referred to as glucose lowering.4,5 Furthermore, there are several novel d.wheeler@ucl.ac.uk
diabetic nephropathy or diabetic kidney disease, even pharmacological agents under development that target
when kidney histology has not been formally assessed newly identified mechanistic pathways underlying dia
by biopsy. The clinical assumption that kidney betic kidney disease (figure 1). In this Review, we
dysfunction is a consequence of diabetes might be re summarise current knowledge of the clinical benefits of
inforced by the presence of other diabetes complications new strategies that are either approved for clinical use or
(such as retinopathy) and by blood tests excluding other have shown promising efficacy and safety in advanced
causes of chronic kidney disease, such as systemic development programmes.
vasculitis or myeloma. A diagnosis of chronic kidney
disease in a person with type 2 diabetes has important Current treatment strategies in diabetic kidney
implications in terms of prognosis. Not only is the risk disease
of developing end-stage kidney disease increased, Recommended treatment strategies for patients with
potentially requiring renal replacement therapy (such as type 2 diabetes and chronic kidney disease are to initiate
dialysis or kidney transplantation), but patients with appropriate lifestyle changes (eg, weight management,
diabetes and chronic kidney disease are also at physical activity, dietary recommendations, and smoking
substantially increased risk of mortality and non-fatal cessation) and to target high blood pressure and poor
cardiovascular events compared with people with glycaemic control.
diabetes but without chronic kidney disease.2 The risk of
these adverse outcomes is further increased at lower Glycaemic control
levels of eGFR and higher levels of albuminuria.1 As the Optimisation of glycaemic control reduces the risk of
prevalence has increased, type 2 diabetes has emerged microvascular complications in diabetes, including the
as the leading cause of chronic kidney damage. onset and progression of albuminuria and, in post-hoc
Monitoring for the development and progression of follow-up analysis of the ADVANCE trial, the risk of end-
chronic kidney disease can be achieved through regular stage kidney disease.5,6 Yet reaching and maintaining
blood testing to allow estimation of glomerular filtration HbA1c targets can be more challenging in patients with
rate (GFR) and analysis of urine samples (preferably diabetic kidney disease because an eGFR lower than
early morning) for UACR. 60 mL/min per 1∙73 m² restricts the use, or dose, of
The aims of medical management in diabetic kidney several oral and injectable glucose-lowering drugs.7 For
disease are to reduce the level of albuminuria and prevent example, most guidelines recommend discontinuation
a progressive decline in eGFR. Identification of renin– of metformin when eGFR falls below 30 mL/min
angiotensin–aldosterone system (RAAS) inhibition as an per 1∙73 m² to reduce the risk of lactic acidosis, a rare but
Obesity
SGLT2 inhibitors
and Hyperglycaemia
incretin-based therapies
RAAS inhibitors
SGLT2 inhibitors Glomerular hyperfiltration RAAS
MRAs
Incretin-based therapies Dyslipidaemia
Inflammation
Figure 1: Pathophysiology of diabetic kidney disease and targets of promising renoprotective drugs in type 2 diabetes based on clinical trial data
SGLT2=sodium-glucose co-transporter-2. RAAS=renin–angiotensin–aldosterone system. ET-1=endothelin-1. MRAs=mineralocorticoid receptor antagonists.
AGEs=advanced glycation end products.
serious adverse effect.8 Accumulation of sulfonylureas albuminuria develops. Although most classes of anti
and their active metabolites because of reduced renal hypertensive medication can be used to control hyper
excretion increases the likelihood of hypoglycaemia, and tension in patients with type 2 diabetes and chronic
necessitates the avoidance of first-generation agents kidney disease, guide lines generally recommend in
(eg, tolbutamide) and dose restriction of some second- clusion of angiotensin recep tor blockers (ARBs) or
generation agents (eg, glimepiride) in patients with angiotensin-converting enzyme (ACE) inhibitors in the
chronic kidney disease.9 Largely because of these antihypertensive regimen, on the basis of evidence from
risks, arguments have been made for less stringent randomised controlled trials done almost two decades
HbA1c targets for patients with type 2 diabetes and low ago.5 These RAAS blockers reduce albuminuria, probably
eGFR levels by some experts.10 by reducing intraglomerular pressure, and might also
prevent renal inflammation and fibrosis. Although
Blood pressure control renoprotective in the longer term, their use might be
The best method to assess blood pressure in patients limited by acute reductions in eGFR or the development
with type 2 diabetes (eg, whether to use resting of hyperkalaemia. There are few studies directly com
office readings or 24 h assessment) is not universally paring ACE inhibitors with ARBs in diabetic kidney
agreed and guidelines differ in recommending target disease, but the available data suggest that the two classes
systolic and diastolic pressures.5,11 Lower targets (eg, have similar beneficial effects on kidney outcomes.12
<130/80 mm Hg) are generally considered appropriate to Declining kidney function is often associated with fluid
reduce cardiovascular risk and slow eGFR decline once retention, which exacerbates hypertension, resulting in
peripheral and pulmonary oedema. Loop diuretics are (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1)
often used to offset volume expansion and treat associated receptor antagonists. Other new therapeutic approaches
symptoms but might have a detrimental effect on eGFR include mineralocorticoid receptor antagonists (MRAs;
as a result of intravascular volume depletion. figure 1).
* Inhibition
SGLT2 inhibitors Stimulation
Insulin↑
ET-1 receptor antagonist
GLP-1 receptor agonists
Nitric oxide
Diabetes-related
Afferent arteriole Vasodilation glomerular Vasoconstriction Efferent arteriole
hyperfiltration
Ang-II↑
TGF↑
Renin
SGLT1/2↑ NHE3↑ Glucagon↑ Amino acids↑
Figure 2: Putative effects and mechanisms of novel drugs on renal haemodynamics in diabetes-related glomerular hyperfiltration
SGLT=sodium-glucose co-transporter. GLP-1=glucagon-like peptide-1. ET-1=endothelin-1. TGF=tubuloglomerular feedback. NHE3=sodium–hydrogen exchanger 3.
TGF= tubuloglomerular feedback. Ang-I=angiotensin-I. Ang-II=angiotensin-II. *SGLT2 inhibitors do not directly inhibit insulin action, but lead to a reduction in
concentration.
The beneficial effects of SGLT2 inhibitors on cardio an RAAS inhibitor.36–41 Despite these results, it is
renal outcomes have been established in three landmark important to realise that EMPA-REG OUTCOME,
placebo-controlled cardiovascular outcome trials, EMPA- CANVAS, and DECLARE were not designed to assess the
REG OUTCOME (empagliflozin),35 the CANVAS renoprotective effects of SGLT2 inhibitors.42 Dedicated
Program (canagliflozin), and the DECLARE-TIMI 58 kidney outcome trials (currently in progress) are required
trial.36–38 In EMPA-REG OUTCOME, which included before recommendations on the use of SGLT2 inhibitors
7020 patients with type 2 diabetes with established as a renoprotective drug can be included in updated
cardiovascular disease, empagliflozin reduced the risks clinical practice guidelines.4
of the composite primary outcome (major adverse The renoprotective benefits of SGLT2 inhibitors are
cardiovascular events [MACE]) by 14% (95% CI 1–26%; likely to be explained by several mechanisms. Like ACE
p=0∙04) relative to placebo after a median follow-up of inhibitors and ARBs, these drugs are believed to have
3∙1 years.35 Similarly, in the CANVAS Program, which favourable effects on renal haemodynamics (figure 2).
included 1042 patients with type 2 diabetes and high Their proximal natriuretic effect, possibly enhanced
cardiovascular risk, canagliflozin reduced the risk of the by functional blockade of the sodium–hydrogen
primary MACE outcome by 14% (95% CI 3–25%; p=0∙02) exchanger 3 (NHE3),43 increases sodium delivery to the
relative to placebo after a mean of 118∙2 weeks.36 In downstream juxtaglomerular apparatus.44 In turn, tubulo
DECLARE-TIMI 58, among 17 160 patients with type 2 glomerular feedback signalling is activated, resulting in
diabetes, including 10 186 without prior cardiovascular afferent arteriolar vasoconstriction and decreased renal
disease, dapagliflozin reduced the risk of cardiovascular blood flow, attenuating glomerular hyperfiltration, which
death or hospitalisation for heart failure by 17% but did is a characteristic of diabetic kidney disease.16 In long-
not result in a lower rate of MACE overall in this term trials, SGLT2 inhibitors consistently reduce eGFR
population. Importantly, all three SGLT2 inhibitors after treatment initiation over a wide range of baseline
slowed the progression of eGFR decline and reduced the values, with the reduction reversed after washout of the
risk of a composite renal outcome by approximately 40%. study drugs, collectively suggesting renal haemodynamic
These effects were achieved in all three studies, which actions.45 Such early reductions in eGFR predict a slower
enrolled patients with baseline eGFR greater than subsequent decline in kidney function on long-term
30 mL/min per 1.73 m² (creatinine clearance greater than treatment.16,23,46 SGLT2 inhibitors might also reduce renal
60 mL/min in DECLARE) who were already well hypoxia, which is typically observed in the kidneys of
managed, with about 80% of all participants prescribed people with diabetes.47 By reducing sodium and glucose
transport activity in the proximal tubule, energy and partly responsible for the roughly 70% amplification of
oxygen demands decrease, resulting in preservation of insulin secretion in the context of nutrient (particularly
tubular cell structural integrity and possibly function.47 glucose) ingestion—the so-called incretin effect.63 This
SGLT2 inhibitors are not currently licensed for use in finding was rapidly followed by the demonstration that
patients with diabetic kidney disease and an eGFR below the glucoregulatory actions of GLP-1 also include sup
45 mL/min per 1∙73 m² in most countries (table 1), since pression of glucagon secretion, inhibition of gastric
their efficacy in terms of glucose lowering is attenuated emptying rate and small bowel motility, and reduction in
in stages 3b–5 chronic kidney disease.51–53 However, the appetite and food intake, transduced by a single GLP-1
effects of the drugs in reducing bodyweight, blood receptor (GLP-1R) located in many organs including the
pressure, and albuminuria persist in these populations.54,55 kidney.59
Additionally, findings from subgroup analyses of EMPA- The incretin effect is severely reduced or absent in
REG OUTCOME and the CANVAS Program suggest patients with type 2 diabetes,63 which is regarded as a key
that the efficacy of SGLT2 inhibitors to reduce the risks of pathophysiological defect that contributes to glucose
cardiovascular and renal outcomes does not depend on intolerance.64 The insulinotropic and glucose-lowering
eGFR.36,56 In recognition of these findings, Health Canada response to exogenous GLP-1 is preserved in human type 2 For the Health Canada guidance
allows physicians to consider the use of SGLT2 inhibitors diabetes,65 suggesting that pharmacological efforts aimed see http://guidelines.diabetes.ca/
cpg/chapter13
when indicated for cardiovascular and renal protection at therapeutic amplification of GLP-1-induced glucose-
down to an eGFR of 30 mL/min per 1∙73 m². lowering in this population are worthwhile. However, the
The effects of SGLT2 inhibitors in slowing progressive GLP-1 peptide is unstable in vivo and continuous infusion
kidney function loss seem to be independent of glycaemic would be required to overcome this problem, limiting
control. In a secondary analysis of CANTATA-SU, clinical application. Circulating GLP-1 is rapidly inactivated
a 2-year, phase 3 registration trial comparing canagliflozin (<2 min), primarily by DPP-4, to a metabolite that
with the sulfonylurea glimepiride, the rate of kidney stimulates insulin secretion.48 These findings prompted
function decline was significantly lower in the two strategies to extend and maintain incretin activity in
canagliflozin group, whereas the glycaemic control was type 2 diabetes: first, the use of injectable GLP-1 receptor
similar between the two classes.57 Also, data from post- agonists that are resistant to DPP-4 cleavage and provide
hoc analyses of EMPA-REG OUTCOME and earlier supraphysiological concentrations of ligands to the GLP-1
phase 3 studies suggested that UACR lowering was receptor; and second, the use of oral DPP-4 inhibitors,
statistically independent of concomitant changes in which prevent de gradation of endogenously secreted
HbA1c.4,40 Collectively, these data suggest that reno GLP-1 and glucose-dependent insulinotropic polypeptide
protective effects are unlikely to be mediated by (also known as gastric inhibitory polypeptide, GIP),
improvements in glycaemic control, but rather by the another incretin hormone.48
other mechanisms outlined earlier. Renal outcome trials Several incretin-based drugs with different structures,
of SGLT2 inhibitors in patients with diabetic kidney modes of administration, and pharmacokinetic prop
disease are ongoing. One of these, CREDENCE erties (separating the GLP-1 receptor agonist class into
(canagliflozin; NCT02065791),58 was stopped early at short-acting [prandial] and long-acting compounds) have
the recommendation of the data safety monitoring been introduced as treatments for type 2 diabetes.59,63
committee, on the basis of achievement of prespecified GLP-1 receptor agonists reduce fasting glucose and
kidney efficacy criteria. Finally, since glomerular HbA1c levels by 0∙5–1∙3%, the reductions achieved
hyperfiltration is involved in the pathophysiology of depending on choice of agent, dose, baseline HbA1c, and
various kidney diseases beyond diabetic kidney disease, background therapy.48 Although less effective when
there is a rationale to extend the use of SGLT2 inhibitors compared with GLP-1 receptor agonists, DPP-4 inhibitors
in non-diabetic kidney disease such as chronic kidney promote reductions in HbA1c of 0∙6–0∙9%.48 Given their
disease induced by obesity, secondary focal segmental glucose-dependent mode of action, incretin-based drugs
glomerulosclerosis, or hypertensive nephrosclerosis.59 As are associated with low risk of hypoglycaemia, and they
such, a dedicated renal outcome trial of dapagliflozin are generally well tolerated.61,62,48
(DAPA-CKD; NCT03036150) is recruiting patients with As pharmacokinetic data and clinical experience with
chronic kidney disease with or without type 2 diabetes, GLP-1 receptor agonists in patients with type 2 diabetes
with an announcement for plans for a similar study and chronic kidney disease are scarce, caution or
assessing empagliflozin (EMPA-KIDNEY trial60). discontinuation is advised when kidney function is
severely impaired (table 1). DPP-4 inhibitors are well
Incretin-based therapies tolerated in stages 3b–5 chronic kidney disease,48
Glucagon-like peptide-1 (GLP-1) is secreted from gut although most manu facturers recom mend dose re
enteroendocrine L-cells at low tonic rates in the fasting ductions, with the exception of linagliptin, which is
and interprandial state. Circulating levels of this gut mainly eliminated through biliary excretion.65
hormone rise briskly within minutes of food intake.61,62 As with SGLT2 inhibitors, off-target effects of
Initial studies focused on its role as an incretin hormone, incretin-based drug classes might favourably modify the
Brand name Approval Dosing Plasma Elimination route Use in patients with renal insufficiency
(agency half-life (h)
[year] or
year)
Mild Moderate Severe or ESRD
(CrCl 50–89 mL/min) (CrCl 30–50 mL/min) (CrCl <30 mL/min)
SGLT2 inhibitors
Dapagliflozin Forxiga (EU), EMA (2012), 5–10 mg once per day 12∙9 Renal 75%, faeces 21% No adjustment Not approved Not approved
Farxiga (USA) FDA (2014)
Canagliflozin Invokana 2013 100–300 mg once per day 10∙6–13∙1 Renal 34%, faeces 52% No adjustment Not approved Not approved
Empagliflozin Jardiance 2014 10–25 mg once per day 12∙4 Renal 54%, faeces 41% No adjustment Not approved Not approved
Ertugliflozin Steglatro 2017 5–15 mg once per day 11∙0–17∙0 Renal 50%, faeces 41% No adjustment Not approved Not approved
GLP-1 receptor agonists
Exenatide Byetta 2005 5–10 μg twice per day 2∙4 Mainly renal No adjustment Conservative Not recommended
(short-acting) (short-acting) dose escalation
Liraglutide Victoza EMA (2009), 0∙6–1∙2–1∙8 mg once 11∙6–13∙0 Peptidases, renal 6%, No adjustment No adjustment Not recommended
FDA (2010) per day (long-acting) faeces 5%
Exenatide Bydureon EMA (2011), 2 mg once per week Not specified* Mainly renal No adjustment Not recommended Not recommended
(long-acting) FDA (2012) (long-acting)
Lixisenatide Lyxumia (EU), EMA (2013), 10–20 μg once per day 3∙0 (short- Mainly renal No adjustment No adjustment Not recommended
Adlyxin (USA) FDA (2016) acting)
Albiglutide Eperzan (EU), 2014 30–50 mg once per week 120∙0 Peptidases, renal No adjustment No adjustment Not recommended
Tanzeum (USA) (long-acting)
Dulaglutide Trulicity 2014 0∙75–1∙5 mg once 112∙8 Peptidases, renal No adjustment No adjustment Not recommended
per week (long-acting)
Semaglutide Ozempic 2017 0∙5–1∙0 mg once per week 165∙0–184∙0 Peptidases, renal No adjustment No adjustment Not recommended
(long-acting)
DPP-4 inhibitors
Sitagliptin Januvia FDA (2006), 100 mg once per day 12∙4 Renal 87%, faeces 13% No adjustment Dose reduction Dose reduction
EMA (2007) (50 mg per day) (25 mg per day)
Vildagliptin Galvus 2007 50 mg twice per day 2∙0 Renal 85%, faeces 15% No adjustment Dose reduction Dose reduction
(50 mg per day) (50 mg per day)
Saxagliptin Onglyza 2009 5 mg once per day 2∙5 Renal 12–29%, faeces 22% No adjustment Dose reduction Dose reduction
(2∙5 mg per day) (2∙5 mg per day)
Linagliptin Trajenta (EU), 2011 5 mg once per day 12∙0 Renal ~5%, faeces ~80% No adjustment No adjustment No adjustment
Tradjenta (USA)
Alogliptin Nesina (USA) 2013 25 mg once per day 21∙0 Renal ~76%, faeces ~13% No adjustment Dose reduction Dose reduction
(12∙5 mg per day) (6∙25 mg per day)
CrCl=creatinine clearance. DPP-4=dipeptidyl peptidase-4. EMA=European Medicines Agency. ESRD=end-stage renal disease. EU=European Union. FDA=US Food and Drugs Administration. GLP-1=glucagon-like
peptide-1. SGLT2=sodium-glucose co-transporter-2. *The pharmacokinetic profiles of exenatide once per week and exenatide twice per day are similar, except that subcutaneous absorption is prolonged with the
once per week formulation. Data derived from SPCs and Muskiet et al,48 Tahrani et al,49 and Deacon.50
Table 1: Antihyperglycaemic drugs available in Europe and North America with dose reductions in chronic kidney disease
cardiorenal risk profile and effects on clinical outcomes (the putative gut–renal axis69), specifically by enhancing
beyond glycaemia.5 First, GLP-1-receptor-mediated re renal solute excretion in response to acute solute ingestion,
ductions in appetite and food intake result in a loss of forming a feed-forward loop between the gut and the
roughly 0∙8–1∙4 kg in bodyweight,66 albeit with much kidneys.48 GLP-1-receptors have been identified at various
variation in individual responses and within-class locations in the kidney, including preglomerular vascular
differences. DPP-4 inhibitors tend to have no effect on smooth muscle cells and proxi mal tubular cells,
bodyweight, as they do not induce satiety.48,67 Second, emphasising a potential physiological role of GLP-1 in
sustained GLP-1 receptor agonist treatment consistently kidney function.48 Administration of GLP-1 and GLP-1
reduces systolic blood pressure by about 2–3 mm Hg,5,48,68 receptor agonists induces natriuresis, diuresis, and urinary
whereas DPP-4 inhibitors have no uniform anti hyper alkalinisation in healthy men70,71 and people with type 2
tensive effect.5,66 Third, incretin-based therapies modestly diabetes, possibly mediated by inhibition of NHE3 in the
improve fasting and particularly postprandial lipid profiles.5 brush border of the proximal tubule.72–74 As with
Fourth, GLP-1 might modulate inflammation or fibrosis at SGLT2 inhibitors, such proxi mal natriuresis would be
multiple sites.48 Finally, GLP-1 has been implicated in the expected to stimulate tubuloglomerular feedback
enteroendocrine regulation of water and electrolyte balance (TGF) signalling, leading to afferent vasoconstriction and a
reduction in renal blood flow and GFR. However, in baseline and on-trial HbA1c and other traditional renal
patients with type 2 diabetes, mechanistic studies and risk factors.83 Both LEADER (liraglutide)84 and SUSTAIN-6
clinical trials have not identified (consistent) effects of (semaglutide)85 included a prespecified composite kidney
GLP-1 receptor agonists on renal haemodynamics72–75 or outcome, defined as progression to macroalbuminuria,
acute reductions in (estimated) GFR on initiation of doubling of serum creatinine, end-stage kidney disease
therapy.48 This finding might be explained by direct nitric (ESKD), or kidney death. The kidney composite outcome
oxide-dependent vasodilatory actions of GLP-1 receptor was reduced by 22% with liraglutide in 9340 patients after
agonists at the afferent arteriole, which might override or 3∙8 years83 and 36% by semaglutide in 3297 patients after
offset vasoconstriction induced by TGF (figure 2).71 Renal 104 weeks.86 Notably, in both trials, the effects were driven
response to DPP-4 inhibition might be even more by a 26−46% reduction in macroalbuminuria, rather than
complicated, as DPP-4 inhibitors induce natriuresis, at more clinically relevant kidney endpoints. In LEADER,
least partly independently of GLP-1.69, 76 the difference in kidney outcome was not altered by
Data from placebo-controlled phase 3 trials of adjustment for change in glycaemic control, bodyweight,
GLP-1 receptor agonists in patients with type 2 diabetes or systolic blood pressure.87 Finally, liraglutide modestly
have shown inconsistent effects on albuminuria and slowed eGFR decline by 2% compared with placebo after
generally no effect on eGFR. In the SCALE Diabetes trial, 36 months (−7∙44 vs −7∙82 mL/min per 1∙73 m²), the
56 weeks of liraglutide resulted in dose-dependent clinical relevance of which is uncertain.83,85
reductions in UACR,77 whereas the 26-week LIRA-RENAL In parallel to its finite effect on cardiovascular outcomes
trial in patients with type 2 diabetes and moderate-to- or mortality, DPP-4 inhibitor therapy might have, at best,
severe kidney impairment did not show reductions in a modestly beneficial effect on kidney endpoints in at-risk
UACR.78 In a small crossover trial in patients with type 2 patients with type 2 diabetes. In a pooled analysis of
diabetes and albuminuria who were on RAAS inhibitors, placebo-controlled trials, linagliptin reduced kidney disease
liraglutide given for 12 weeks reduced 24 h urinary events by 16%, driven by an 18% reduction in moderate
albumin excretion by 32% compared with placebo, albuminuria and a 14% reduction in severe albuminuria,
independent of HbA1c reductions and possibly driven with no effects on eGFR.88 Moreover, combined data from
by blood pressure lowering.77 Integrated data from randomised controlled trials including 217 patients with
nine registration trials of dulaglutide, which included type 2 diabetes and albuminuria suggested that linagliptin
6005 patients with type 2 diabetes, showed lower UACRs reduced UACR by 28%, independent of HbA1c or systolic
than with placebo (−16∙7% vs 10∙0%), insulin glargine blood pressure.89 However, MARLINA-T2D, which included
(−16.7% vs 3∙7%), and other active comparators 360 patients with type 2 diabetes on stable RAAS inhibition
(−20∙0% vs −12∙5%).79 Although no differences in serum and was sufficiently powered to test superiority of
creatinine levels were observed over 104 weeks, fewer linagliptin in reducing albuminuria, did not confirm these
patients receiving dulaglutide rather than insulin findings.90 Five cardio vascular outcome trials involving
glargine experienced a 40% decline in eGFR at any point DPP-4 inhibitors have provided data on kidney endpoints.
during a 1-year treatment period.80 In the AWARD-7 trial, In a secondary analysis of SAVOR-TIMI 53, which included
which included 577 patients with type 2 diabetes and 16 492 patients with type 2 diabetes at high risk of
moderate-to-severe chronic kidney disease, dulaglutide cardiovascular events, saxagliptin led to reclassification of
versus once-daily titrated insulin glargine (with similar patients into a lower UACR category, irrespective of
HbA1c reductions) resulted in a higher eGFR after baseline UACR.91 An overall mean reduction in UACR
52 weeks, and reduced UACR in patients with baseline of 34 mg/g was seen with saxagliptin, which was
macroalbuminuria.81 independent of HbA1c lowering, although the drug did not
Kidney outcome data have been collected as secondary affect other more clinically relevant kidney endpoints after
and exploratory endpoints in previous (table 2) and on 2∙1 years. In TECOS,92 which included 14 671 patients, there
going (table 3) cardiovascular safety trials of GLP-1 receptor was no clinically relevant difference in either eGFR or
agonists and DPP4 inhibitors in patients with type 2 UACR between the sitagliptin and placebo groups. In the
diabetes and high cardiovascular risk.48 In ELIXA, which MK-3102-018 cardiovascular outcome trial, which was
assessed the cardiovascular safety of lixisenatide versus terminated early in 2016 based on a business decision by
placebo in 6068 patients with type 2 diabetes and a the sponsor not to submit a marketing application, there
previous acute coronary event, the percentage change in were no clinically meaningful changes from baseline in
UACR showed a modest difference in favour of the eGFR at any timepoint between the once-weekly DPP-4
GLP-1 receptor agonist after 25 months of follow-up inhibitor omarigliptin and placebo in 4202 patients with
(24% vs 34%).82 However, in the total population, post-hoc type 2 diabetes and established cardiovascular disease after
adjustment for HbA1c levels attenuated the lixisenatide- a median follow-up of 96 weeks.93 Finally, in CARMELINA,
induced kidney benefit, suggesting some glucose linagliptin versus placebo did not significantly affect the
dependency. Nevertheless, in a recent exploratory analysis secondary kidney composite outcome (sustained >40%
of ELIXA, lixisenatide was associated with a lower risk of decrease in eGFR from baseline, ESKD or renal death) in
new-onset macroalbuminuria after adjustment for 6979 patients with type 2 diabetes at high cardiovascular
Drug n Main Follow-up Mean Mean Mean Mean Baseline Renal outcome
inclusion (years) age type 2 baseline baseline albuminuria
criteria* (years) diabetes HbA1c eGFR status
duration (%) (mL/min
(years) per 1∙73 m²)
SGLT2 inhibitors
EMPA-REG Empagliflozin 7020 CVD history 3∙1 63∙1 57% >10 8∙1 74∙0 Micro 29%; Secondary: composite (macroalbuminuria, dSCr,
OUTCOME (2016) (median) macro 11% ESKD, renal death); HR 0∙61, 95% CI 0∙53–0∙70
CANVAS Program Canagliflozin 10 142 CVD risk or 3∙6 (mean) 63∙3 13∙5 8∙2 76∙5 Micro 22∙6%; Secondary: composite (macroalbuminuria, dSCr,
(2017) history macro 7∙6% ESKD, renal death); HR 0∙58, 95% CI 0∙50–0∙67
DECLARE-TIMI 58 Dapagliflozin 17 160 CVD risk or 4∙2 63∙8 11∙8 8∙3 86∙1 Micro: 23∙4%; Secondary: composite (>40% decrease in eGFR
(2018) history (median) macro 6∙8% to <60 ml/min per 1∙73 m2, ESKD, renal death)
HR 0∙53 (0∙43–0∙66)
GLP-1 receptor agonists
ELIXA (2015) Lixisenatide 6068 ACS <180 2∙1 60∙3 9∙3 7∙7 76∙0 Micro 19∙2%; Secondary: change in UACR; month 24,
days before (median) macro 6∙5% 34% vs 24%
start of trial
LEADER Liraglutide 9340 CVD risk or 3∙8 64∙3 12∙7 8∙7 80∙0 Micro 26∙3%; Secondary: composite (macroalbuminuria, dSCr,
(2016/2017) history (median) macro: 10∙5% ESKD, renal death); HR 0∙78, 95% CI 0∙67–0∙92
SUSTAIN-6 Semaglutide 3297 CVD risk or 2∙1 64∙6 13∙9 8∙7 NR NR Secondary: composite (macroalbuminuria, dSCr,
(2016) (subcutaneous) history (median) ESKD, renal death); HR 0∙64 95% CI 0∙46–0∙88
EXSCEL (2017) Exenatide 14 752 CVD risk 3∙2 62∙7 12∙0 8∙0 79∙0 NR NR
(long-acting) (median)
HARMONY Albiglutide 9463 CVD history 1∙6 64∙1 14∙1 8∙7 79∙0 NR Safety: eGFR difference: at 8 months: –1·11
Outcomes (2018) (median) (95% CI –1·84 to –0·39), at 16 months: –0·43
(–1·26 to 0·41)
DPP-4 inhibitors
EXAMINE (2013) Alogliptin 5380 ACS <90 1∙5 61∙0 7∙2 8∙0 71∙2 NR Secondary: change in eGFR mL/min per 1∙73 m²
days before (median) per eGFR subgroup for alogliptin and
start of trial placebo: eGFR >90 (–4∙5/−6∙7); 60–90 (1∙0/0∙6);
30–60 (2∙1/1∙1); <30 (1∙6/0∙2)
SAVOR-TIMI 53 Saxagliptin 16 492 CVD risk or 2∙1 65∙1 10∙3 8∙0 72∙6 Micro 28∙1%; Secondary: change in UACR 34∙3 mg/g; dSCr
(2013) history (median) macro 10∙4% HR 1·1, 95% CI 0∙89–1∙36; ESKD HR 0·90, 95% CI
0∙61–1∙32
TECOS (2015) Sitagliptin 14 671 CVD history 3∙0 65∙5 11∙6 7∙2 75∙1 Micro 23∙3%; Secondary: eGFR difference −1∙34 (95% CI
(median) macro 4∙8% −1∙76 to −0∙91); UACR difference −0∙18 mg/g
(95% CI −0∙35 to −0∙02)
MK-3102-018 Omarigliptin 4202 CVD history 1∙8 63∙7 12∙1 8∙0 86∙2 NR Safety: eGFR difference −2∙43 (95% CI
(2017) (median) −5∙36 to 0∙51)
CARMELINA Linagliptin 6979 CKD and 2∙2 65∙8 14∙7 7∙9 54∙6 Micro 41∙5%; Secondary: composite (≥40% eGFR reduction,
(2018) CVD history (median) macro 38∙6% ESKD, renal death) HR, 1∙04; 95% CI, 0∙89-1∙22.
or risk Exploratory: albuminuria progression HR 0∙86
(0∙78–0∙95)
ACS=acute coronary syndrome. CVD=cardiovascular disease. DPP-4=dipeptidyl peptidase-4. dSCr= doubling of serum creatinine concentration. eGFR=estimated glomerular filtration rate. ESKD=end-stage
kidney disease. GLP-1=glucagon-like peptide-1. HR=hazard ratio. NR=not reported. SGLT2=sodium-glucose co-transporter-2. UACR=urinary albumin-to-creatinine ratio. *All patients in all trials had type 2
diabetes.
Table 2: Effect of new-generation glucose-lowering drugs in completed cardiovascular outcome trials on secondary and exploratory renal outcomes in patients with type 2 diabetes and
high cardiovascular risk
and renal risk (ie, impaired eGFR and microalbuminuria (NCT01243424; comparing linagliptin and glimepiride)
or macroalbuminuria) after a median of 2∙2 years. In and GRADE (NCT01794143; comparing liraglutide,
exploratory renal analyses, the progression of the sitagliptin, glimepiride, and insulin glargine) are antici
albuminuria category occurred less frequently in the pated. However, by contrast with SGLT2 inhibitors, there
linagliptin group (hazard ratio [HR] 0∙86; 95% CI are no ongoing studies of incretin-based therapies
0∙78–0∙95).94 recruiting patients with diabetic kidney disease with a
Although incretin-based therapies (particularly primary objective of determining the effects of these
GLP-1 receptor agonists) might improve albuminuria in drugs on kidney endpoints.
type 2 diabetes, effects on more clinically relevant kidney
outcomes such as time to starting dialysis remain Endothelin receptor antagonists
uncertain. The results of active-comparator studies that The endothelin family comprises three endothelins
include secondary kidney endpoints such as CAROLINA (ET-1, ET-2, and ET-3) that bind to either the ETA or the
ClinicalTrials. Drug n Main inclusion Follow-up Mean Mean Mean Mean Baseline Trial status Renal outcome
gov (class) criteria (years) age type 2 baseline baseline albuminuria (expected
registration (years) diabetes HbA1c eGFR status completion
number duration (%) (mL/min date)
(years) per 1∙73 m2)
Renal outcome trials
SONAR NCT01858532 Atrasentan 5112 Type 2 diabetes, ~4 64∙8 16∙7 7∙8 43∙8 Macro 100% Terminated Primary:
(ETA receptor eGFR 25–75 mL/ (December, composite (dSCr,
antagonist) min per 1∙73 m², 2017) ESKD, renal death)
macroalbuminuria
CREDENCE NCT02065791 Canagliflozin 4401 Type 2 diabetes, Up to 5∙5 63∙0 15∙8 8∙3 56∙2 Macro 100% Terminated Primary:
(SGLT2 macroalbuminuria (July, 2018) composite (ESKD,
inhibitor) dSCr,
cardiovascular
death, renal death)
FIDELIO-DKD NCT02540993 Finerenone 4800 Type 2 diabetes, Up to 4 ∙∙ ∙∙ ∙∙ ∙∙ Macro 100% Ongoing Primary:
(MRA) macroalbuminuria, (April, 2020) composite (ESKD,
potassium ≥40% reduction in
≤4∙8 mmol/L eGFR, renal death)
DAPA-CKD NCT03036150 Dapagliflozin 4000 eGFR Up to 4 ∙∙ ∙∙ ∙∙ ∙∙ ∙∙ Ongoing Primary: composite
(SGLT2 25–75 mL/min per (November, (>50% reduction in
inhibitor) 1∙73 m², increased 2020) eGFR, ESKD,
albuminuria cardiovascular
death, renal death)
EMPA- NCT03594110 Empagliflozin 5000 eGFR 20-45 mL/ ~3∙1 Ongoing Primary: composite
KIDNEY (SGLT2 min per 1∙73 m² or (June, 2022) of kidney disease
inhibitor) 45-90 mL/min per progression (ESKD,
1∙73 m² with eGFR <10 mL/min
albuminuria per 1∙73 m², renal
death, or ≥40%
reduction in eGFR)
or cardiovascular
death
Cardiovascular outcome trials
FREEDOM- NCT01455896 Exenatide 4156 Type 2 diabetes, 2 NR NR NR NR NR Completed NR
CVO DUROS† CVD history (March,
(GLP-1 2016)
receptor
agonist)
REWIND NCT01394952 Dulaglutide 9901 Type 2 diabetes, 6.5 66∙2 10∙0 7∙3 77∙6 Micro/macro Completed Secondary:
(GLP-1 CVD risk or history 35∙3% (August, composite
receptor 2018) (retinopathy,
agonist) proteinuria, >30%
reduction in eGFR,
ESKD)
CAROLINA NCT01243424 Linagliptin* 6103 Type 2 diabetes, 8∙3 64∙0 6∙2 7∙2 77∙0 Micro 21∙2%; Completed Secondary:
(DPP-4 CVD risk or history macro 4∙3% (August, transition in
inhibitor) 2018) albuminuria
classes, change in
eGFR, change in
UACR
PIONEER-6 NCT02692716 Semaglutide 3183 Type 2 diabetes, Up to 1∙6 66∙1 14∙9 8∙2 74∙2 NR Completed NR
(GLP-1 CVD risk or history (September,
receptor 2018)
agonist
[oral])
VERTIS-CV NCT01986881 Ertugliflozin 8000 Type 2 diabetes, Up to 6∙1 .. .. .. .. .. Ongoing Secondary:
(SGLT2 CVD history (September, Composite (dSCr,
inhibitor) 2019) ESKD, renal death)
FIGARO-DKD NCT02545049 Finerenone 6400 Type 2 diabetes, Up to 4∙4 .. .. .. .. Macro 100% Ongoing Secondary:
(MRA) macroalbuminuria, (June, composite (ESKD,
potassium 2021) ≥40% reduction in
≤4∙8 mmol/L eGFR, renal death),
change in UACR
(Table 3 continues on next page)
ClinicalTrials. Drug (class) n Main inclusion Follow-up Mean Mean Mean Mean Baseline Trial status Renal outcome
gov criteria (years) age type 2 baseline baseline albuminuria (expected
registration (years) diabetes HbA1c eGFR (mL/ status completion
number duration (%) min per date)
(years) 1∙73 m2)
(Continued from previous page)
Heart failure outcome trials
DAPA-HF NCT03036124 Dapagliflozin 4744 Type 2 diabetes, Up to 3 .. .. .. .. .. Ongoing Secondary:
(SGLT2 HFrEF (December, composite
inhibitor) (NYHA II–IV), 2019) (>50% reduction
LVEF ≤40%, high in eGFR, ESKD,
NT-proBNP renal death)
EMPEROR- NCT03057951 Empagliflozin 4126 HFpEF Up to 3∙2 .. .. .. .. .. Ongoing Secondary: eGFR
preserved (SGLT2 (NYHA II–VI), LVEF (June, slope, ESKD,
inhibitor) >40%, high 2020) or ≥40% reduction
NT-proBNP in eGFR
EMPEROR- NCT03057977 Empagliflozin 2850 HFrEF Up to 3∙2 .. .. .. .. .. Ongoing Secondary: eGFR
reduced (SGLT2 (NYHA II–VI), (June, slope, ESKD,
inhibitor) LVEF ≤40%, high 2020) or ≥40% reduction
NT-proBNP in eGFR
CKD=chronic kidney disease. CVD=cardiovascular disease. DPP-4=dipeptidyl peptidase-4. dSCr= doubling of serum creatinine concentration. eGFR=estimated glomerular filtration rate. ESKD=end-stage kidney
disease. ETA= endothelin A. GLP-1=glucagon-like peptide-1. SGLT2=sodium-glucose co-transporter-2. HFpEF=heart failure with preserved ejection fraction. HFrEF=heart failure with reduced ejection fraction.
LVEF=left ventricular ejection fraction. MRA=mineralocorticoid receptor antagonist. NR=not reported. NT-proBNP=N-terminal pro-B-type natriuretic peptide. NYHA=New York Heart Association. UACR=urinary
albumin-to-creatinine ratio. *Versus active comparator glimepiride. †The DUROS delivery system paired with exenatide (ITCA650) is a matchstick-sized, miniature osmotic pump that is inserted subcutaneously
to provide continuous and consistent treatment with exenatide therapy.
Table 3: Recently completed and ongoing clinical outcome trials assessing the effect of new drugs in type 2 diabetes on renal outcomes
ETB receptor. Generally, ETA receptor activation causes increase in effective renal blood flow and reduction in
vasoconstriction, matrix accumulation, and cell pro filtration fraction, suggesting that ET-1 causes vaso
liferation, whereas ETB receptor activation opposes constriction mediated by the efferent arteriole.101,102 In
these effects.95,96 The endothelin system also has an addition to haemodynamic effects, use of the ERA
important role in sodium and water regulation. atrasentan led to a reduction in albuminuria in one study,
Although ETB activation has a sodium and water re possibly through protection of the glycocalyx.103 Other
taining effect, ETA exerts a natriuresis effect, particularly potential mechanisms of ERA-induced renoprotection
via ETA receptors located in the collecting duct.97,98 involve preservation of podocyte morphology104 and
Pharmacological blockade of endothelin receptors is changes in production of growth factors and vaso
associated with sodium and water retention and this constrictors (eg, angiotensin II).105 Avosentan was the first
effect has made development of endothelin blockers ERA to be tested in a large, randomised, placebo-
challenging. controlled trial, which included 286 patients with diabetic
The endothelin system is believed to be involved in the kidney disease and macroalbuminuria. This 12-week trial
development and progression of diabetic kidney disease.99 showed a dose-dependent reduction in proteinuria, with
Patients with diabetic kidney disease generally have an optimal dose of 10 mg per day. Higher doses (≥25 mg
hyperglycaemia, insulin resistance, obesity, dyslipid per day) increased the risk of the main adverse outcome,
aemia, RAAS activation, endothelial dysfunction, and peripheral oedema (12%).106 Following this dose-finding
increased oxidative stress, all of which increase pro study, a large phase 3 trial assessing the effect of avosentan
duction of ET-1 in the kidney.99 Apart from its potent (at 25 and 50 mg per day) versus placebo on kidney
vasoconstrictive effects on the efferent renal vasculature, outcomes in 1392 patients with type 2 diabetes (ASCEND)
which can result in a reduction of renal blood flow and was undertaken, but was terminated early because of an
glomerular hyperfiltration,16 ET-1 might promote kidney excess of congestive heart failure and mortality associated
injury by activating pro-inflammatory and profibrotic with the ERA.21 These results show the narrow therapeutic
pathways.97,98 window of ERAs and the importance of careful dose
Data from multiple experimental and clinical selection to avoid adverse consequences of sodium and
mechanistic studies have supported the hypothesis that fluid retention.
endothelin blockade might delay the progression of Atrasentan, which has a higher ERA selectivity than
kidney disease in the long term. Endothelin receptor avosentan and might therefore exert less sodium
antagonists (ERAs) attenuate the vasoconstrictor effect of retention, has also been tested in diabetic kidney disease.
ET-1 and thereby reduce intraglomerular pressure and In a phase 2 trial (RADAR), atrasentan given at doses of
hyperfiltration (figure 2). In patients with hypertension 0∙75 mg or 1∙25 mg per day, reduced albuminuria versus
and chronic kidney disease, ERAs cause a significant placebo by 35% and 38%, respectively, in 211 patients
Panel 2: Hurdles to the development of novel therapies to reduce the burden of Search strategy and selection criteria
diabetic kidney disease
We searched MEDLINE, PubMed, Google Scholar, and the
Several challenges are apparent for the development of new treatments or combinations Cochrane Library for English-language abstracts and full-text
of drugs for chronic kidney disease, including factors that must be considered in trial articles published up to Nov 30, 2018. We focused on new
design and the identification of appropriate endpoints and efficacy biomarkers. potentially renoprotective drugs in type 2 diabetes, with
Additionally, testing of novel therapies aimed at slowing the progression of diabetic kidney particular attention paid to sodium-glucose
disease must be done in patients with diabetes who are already receiving standard care, co-transporter-2 (SGLT2) inhibitors, incretin-based therapies,
including optimal risk factor control such as the use of renin–angiotensin– aldosterone endothelin receptor antagonists, and mineralocorticoid
system (RAAS) blockers. receptor antagonists. The keywords used included
“diabetic kidney disease”, “diabetic nephropathy”,
Diagnosis
“renoprotection”, “type 2 diabetes”, “sodium-glucose
• Disease awareness in patients with chronic kidney disease stages 1–3 is ~5%
cotransporter-2 inhibitor”, “SGLT2 inhibitor”, “incretin-based
• Physicians might neglect to inform patients that they have chronic kidney disease
therapy”, “glucagon-like peptide-1”, “GLP-1 receptor agonist”,
Clinical trial recruitment “dipeptidyl-peptidase-4 inhibitor”, “DPP-4 inhibitor”,
• Recruitment rates for diabetic kidney disease are ~0∙20 patients per site per month “endothelin receptor antagonist”, “mineralocorticoid
(~25% of the number of patients enrolled per month for a diabetes trial) receptor antagonist”, and “MRA”. These keywords were used
• Low rates delay timelines, increase costs, and negatively affect willingness of as single search terms and in combination. We also searched
pharmaceutical companies to invest the reference list of original articles, narrative reviews, clinical
• Clinical trial networks and patient registries could help to address this challenge guidelines, and systematic reviews and meta-analyses for
further relevant material. The evidence discussed in this
Patient selection
Review is mainly restricted to clinical studies, including
• Elimination of probable biological non-responders who decrease trial efficiency vs
cohort studies, randomised controlled trials, and
patient heterogeneity with respect to rate of renal function loss
meta-analyses of randomised clinical trials.
• Widespread use of RAAS blockers restricts recruitment of patients with high levels of
albuminuria and so-called rapid progressors
• Increasing numbers of patients with diabetic kidney disease who progress without as the diuretic properties of the SGLT2 inhibitor could
developing proteinuria; ~25% do not follow the classic paradigm mitigate the sodium and fluid retaining effects of the
• Development of novel biomarkers could supplement proteinuria in predicting ERA. Additionally, the renal haemodynamic benefits of
progression of renal disease SGLT2 inhibitors involves the afferent arteriole via TGF
Clinical endpoints signalling, whereas the ERAs reduce glomerular pressure
• Characterising the effect of a drug on renal markers (surrogates) vs parameters of by directly reducing efferent arteriolar resistance.
patient wellbeing and hard outcomes vs a composite of these Finally, although nearly all patients with type 2 diabetes
• Intermediate events and surrogates should match with the appropriate mechanisms will require multiple therapies to maintain glycaemic
of action of the drug (ie, acute reductions in renal function with RAAS blockers and control, no large-scale studies have provided definite data
sodium-glucose co-transporter-2 inhibitors) as to which are the best combinations to use. The ideal
• Using intermediate eGFR decrements (ie, 30%, or 40%, or eGFR slope) as surrogates of combination should correct multiple pathophysiological
accepted outcomes (ie, doubling of serum creatinine) defects in type 2 diabetes, while being well tolerated and
safe, easy to administer, and cost-effective. Based on their
different mechanisms of action in terms of reducing
phenotypes and it seems probable that not all patients glucose, bodyweight, blood pressure, and other cardio
will benefit from these drugs.121 Between-patient variation renal risk factors, combination therapy with an SGLT2
in underlying pathophysiology results in a wide diversity inhibitor and a GLP-1 receptor agonist might be expected
of individual drug responses, as described in more detail to fulfil (most of) these criteria.123 Hitherto, two trials have
elsewhere.122 This variation in individual drug response assessed this combination in patients with poorly
was addressed in the design of the SONAR trial described controlled type 2 diabetes and have shown useful
previously, which selected only responder patients reductions in glycaemic measures and additive effects on
(albuminuria reduction >30%) and excluded those who weight loss and lowering of blood pressure.117,118 Such
do not tolerate atrasentan.108 However, whether non- combination therapy might be even more powerful in
responders to atrasentan (in terms of albuminuria) slowing the progression of diabetic kidney disease beyond
might benefit from an SGLT2 inhibitor, an incretin-based either drug class used alone, but dedicated studies to
drug, or an MRA is an important question to be answered assess the effects of this combination on albuminuria and
in the future. kidney outcomes are needed to investigate this
It is also probable that future studies will start possibility.124,125 We believe that well designed mechanistic
combining new therapies to further slow the progression studies that aim to characterise individual drug responses
of diabetic kidney disease. Theoretically, the effect of an on the basis of phenotypic traits, as well as large-sized
SGTL2 inhibitor and an ERA would be complementary, prospective outcome trials that assess the cardiorenal
effects of different combinations of drugs, are necessary 7 Roussel R, Lorraine J, Rodriguez A, Salaun-Martin C. Overview of
to advance treatment approaches in patients with type 2 data concerning the safe use of antihyperglycemic medications in
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novel therapies to reduce the burden of diabetic kidney 8 Hung SC, Chang YK, Liu JS, et al. Metformin use and mortality in
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retrospective, observational, cohort study. Lancet Diabetes Endocrinol
type 2 diabetes are outlined in panel 2. 2015; 3: 605–14.
9 Scheen AJ. Pharmacokinetic considerations for the treatment of
Conclusions diabetes in patients with chronic kidney disease.
Expert Opin Drug Metab Toxicol 2013; 9: 529–50.
Several promising new approaches are emerging to 10 Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of
protect kidney function in patients with type 2 diabetes. hyperglycemia in type 2 diabetes, 2015: a patient-centered approach:
Such progress should offer hope to patients in whom update to a position statement of the American Diabetes
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initiate renal replacement therapy. Many such trials are Angiotensin converting enzyme inhibitors and angiotensin II
receptor antagonists for preventing the progression of diabetic
ongoing and several will be reported within the next kidney disease. Cochrane Database Syst Rev 2006; 4: CD006257.
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disease resulting from pathological processes other than
14 Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on
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16 Tonneijck L, Muskiet MH, Smits MM, et al. Glomerular
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for renoprotection in patients with type 2 diabetic nephropathy:
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Contributors 19 Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end
All authors are fully responsible for all content, were involved at all points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;
stages of writing and development of the Review, and have approved the 367: 2204–13.
final version. 20 Packham DK, Wolfe R, Reutens AT, et al. Sulodexide fails to
demonstrate renoprotection in overt type 2 diabetic nephropathy.
Declaration of interests
J Am Soc Nephrol 2012; 23: 123–30.
MHAM is a consultant for Eli Lilly & Co and Novo Nordisk (all honoraria
21 Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic
paid to his employer). DCW has received honoraria or consultancy fees
nephropathy. J Am Soc Nephrol 2010; 21: 527–35.
from Akebia, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim,
22 de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in
GlaxoSmithKline, Janssen, and Vifor Fresenius. HJLH is a consultant
type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med
for AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Fresenius, 2013; 369: 2492–503.
Gilead, Janssen, and Merck (all honoraria paid to his employer).
23 Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ.
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