Gut-Renal Axis in Diabetic Nephropathy PDF

REVIEWS
The gutrenal axis: do incretin-based agents

confer renoprotection in diabetes?
Marcel H.A. Muskiet, Mark M. Smits, Linde M. Morsink and Michaela Diamant
Abstract | Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, and is associated
with a high risk of cardiovascular morbidity and mortality. Intensive control of glucose levels and blood
pressure is currently the mainstay of both prevention and treatment of diabetic nephropathy. However, this
strategy cannot fully prevent the development and progression of diabetic nephropathy, and an unmet need
remains for additional novel therapies. The incretin-based agentsagonists of glucagon-like peptide1
receptor (GLP1R) and inhibitors of dipeptidyl peptidase 4 (DPP4), an enzyme that degrades glucagon-like
peptide 1are novel blood-glucose-lowering drugs used in the treatment of type2 diabetes mellitus (T2DM).
Therapeutic agents from these two drug classes improve pancreatic islet function and induce extrapancreatic
effects that ameliorate various phenotypic defects of T2DM that are beyond glucose control. Agonists of
GLP1R and inhibitors of DPP4 reduce blood pressure, dyslipidaemia and inflammation, although only GLP1R
agonists decrease body weight. Both types of incretin-based agents inhibit renal tubular sodium reabsorption
and decrease glomerular pressure as well as albuminuria in rodents and humans. In rodents, incretin-based
therapies also prevent onset of the morphological abnormalities of diabetic nephropathy.
Muskiet, M.H.A. etal. Nat. Rev. Nephrol. 10, 88103 (2014); published online 24 December 2013; doi:10.1038/nrneph.2013.272
Introduction
Diabetes Centre,
Department of Internal
Medicine, VU University
Medical Centre,
DeBoelelaan 1117,
1081HV Amsterdam,
Netherlands
(M.H.A.Muskiet,
M.M.Smits,
L.M.Morsink,
M.Diamant).
Correspondence to:
M.Diamant
m.diamant@vumc.nl
Over the past four decades, the global prevalence of

obesity and type2 diabetes mellitus (T2DM) has continued to increase. The worldwide prevalence of diabetes
is expected to reach 552million by 2030.1 Diabetes is
associated with microvascular and macrovascular complications, which impose a burden not only on patients,
but also on their families and society. Complications
related to diabetes constitute a large proportion of healthcare costs. Diabetic nephropathy, defined as functional,
structural and clinical abnormalities of the kidney that are
exclusively caused by diabetes, is a highly prevalent complication, which accounts for up to 58% of incident cases
of end-stage renal disease (ESRD) requiring renal replacement therapy in Malaysia and up to 45% of these cases in
the USA.2 Additionally, diabetic nephropathy is strongly
associated with cardiovascular morbidity and mortality.3,4
Hyperglycaemia and hypertension frequently coexist in
patients with T2DM and contribute to the development
and progression of diabetic nephropathy.57 Reducing
levels of blood glucose and blood pressure, particularly
using agents that interfere with the reninangiotensin
aldosterone system (RAAS) are, therefore, important
therapeutic strategies for the prevention and treatment
of diabetic nephropathy. However, despite current
Competing interests
M. Diamant declares associations with the following companies:
Abbott, Astra Zeneca, BoehringerIngelheim, Bristol-Myers
Squibb, Eli Lilly, GI Dynamics, Medtronic, Merck Sharp & Dohme,
Novo Nordisk, Poxel Pharma and Sanofi. See the article online
for full details of the relationships. The other authors declare no
competing interests.
88 | FEBRUARY 2014 | VOLUME 10
multifactorial strategies for managing T2DM, a residual

risk of diabetic nephropathy remains,8,9 accentuating the
importance of developing new therapeutic agents.
In the past 8years, agonists of glucagon-like peptide1
receptor (GLP1R) and inhibitors of dipeptidyl peptid
ase4 (DPP4) have been introduced as novel bloodglucose-lowering agents for the treatment of T2DM.
These incretin-based therapies have potentially beneficial effects on multiple organ systems (pleiotropic
effects) that go beyond glucose control (Box1). Here,
we review current treatment strategies for the prevention
and progression of diabetic nephropathy, and discuss the
potential role of incretin-based therapies in this setting,
focusing on the beneficial effects of these agents on the
renal system and their underlying mechanisms.
Pathophysiology and clinical signs

The pathophysiology of diabetic nephropathy is multi
factorial, involving both genetic and environmental
components. Diabetic nephropathy develops as a result
of interactions between haemodynamic and metabolic
factors, among which chronic hyperglycaemia has a
central role.10,11 The natural history of diabetic nephro
pathy in type1 diabetes mellitus (T1DM) is fairly well
defined, as the onset of T1DM is usually acute and
hyperglycaemia is the only causal factor in its development and progression. By contrast, T2DM is preceded
by a long period during which a cluster of cardio
metabolic abnormalities (including central obesity,
hyperinsulinaemia, hypertension and dyslipidaemia)
adversely affect renal function and structure, before the
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2014 Macmillan Publishers Limited. All rights reserved
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Key points
Incretin-based therapiesglucagon-like peptide 1 receptor (GLP1R) agonists
and dipeptidyl peptidase 4 (DPP4) inhibitorsimprove glycaemic control by
ameliorating multiple phenotypic defects associated with type2 diabetes mellitus
GLP-1R agonists reduce body weight, whereas DPP4 inhibitors do not affect
body weight; both are generally well-tolerated by patients
Evidence from animal and human studies indicates that incretin-based
therapies might prevent the onset and progression of diabetic nephropathy, as
measured by clinical and histological improvements
Incretin-based therapies might positively influence haemodynamic variables
(hyperfiltration, glomerular capillary hydraulic pressure, and systemic blood
pressure), metabolic factors (glycaemia, dyslipidaemia, oxidative stress) and
inflammatory pathways in the pathogenesis of diabetic nephropathy
Inhibitors of DPP4 block the degradation of endogenous GLP1 and might also
influence circulating levels and activity of other vasoactive peptides that could
act on the kidney
development of hyperglycaemia. Below we summarize

the mechanisms of development of diabetic nephro
pathy, in order to i dentify targets for current and future
therapies(Figure1).
Early phase of diabetic nephropathy

The course of diabetic nephropathy can be divided
into an early phase and a late phase. The early phase is
asymptomatic but characterized by important changes
in renal function and structure, including glomerular
hyperfiltration and increased renal plasma flow (RPF).12
By the time of diagnosis of diabetic nephropathy, ~70%
of patients with T1DM and ~50% of those with T2DM
present with increases in glomerular filtration rate (GFR)
of 2550%.13 Increases in GFR and RPF are accompanied
by tubular hyperplasia and hypertrophy, and increased
kidney size.14 These abnormalities are well-documented
in patients with T1DM, but are less apparent in patients
with T2DM.15
Glomerular hyperfiltration is related to the degree
of hyperglycaemia.16 According to the tubular theory,
hyper-reabsorption of elevated amounts of intraluminal
glucose and sodium in the proximal tubule, which is
accompanied by upregulation and activation of proximal
Box 1 | Pleiotropic effects of incretin-based therapies
Glucagon-like peptide 1 receptor agonists have effects
beyond glucose control: they reduce body weight,
induce satiety and influence the gastrointestinal system
(gut motility, pancreatic exocrine enzyme secretion)
and the cardiovascular system (endothelial and
myocardialfunction).
Incretin-based therapies might also have beneficial effects
on cardiovascular and renal risk factors. Some of these
effects are body-weight dependent (decreases in central
obesity, liver fat content and Creactive protein levels, and
increases in insulin sensitivity and adiponectin levels).
However, other actions might occur, at least in part,
independently of weight loss (decrease in blood pressure,
low-grade inflammation and oxidative stress; improvement
of dyslipidaemia). Collectively, these pleiotropic effects
might reduce the risk of diabetic nephropathy in patients
with type 2 diabetes mellitus.
sodiumglucose co-transporters 1 and 2,14 and sodium

hydrogen exchanger 3 (NHE3),17 are important contributors to hyperfiltration. Proximal hyper-reabsorption
reduces salt delivery to the macula densa, which (via
tubuloglomerular feedback) leads to reduced resistance
to blood flow in the afferent arteriole of the glomerulus.
Collectively, these impairments in renal autoregulation
increase glomerular capillary hydraulic pressure (PGC),
which leads to glomerular hyperperfusion and hyper
filtration. Tubular hypertrophy, combined with proximal
tubular hyper-reabsorption, leads to reduced hydrostatic pressure in the Bowman capsule, thereby further
perpetuating glomerular hyperfiltration.15 Alternatively,
according to the vascular theory, defective regulation of
vascular function in the diabetic kidney causes a greater
decrease in resistance to blood flow in the afferent arter
iole compared to the efferent arteriole.12 Overactivation
of the sympathetic nervous system, along with unbalan
ced local or systemic formation of vasoactive factors,
further elevatesPGC.12 Although many factors, including
atrial natriuretic peptide (ANP), endothelin1 (ET1),
nitric oxide (NO), cyclooxygenase-derived metabolites
of arachidonic acid and the kallikreinkinin system,
contribute to impaired renal autoregulation, activation
of the RAAS (specifically elevation of circulating levels of
angiotensinII) is considered to be the key factor causing
glomerular vascular dysfunction. RAAS overactivity,
as is typically observed in patients with obesity and
T2DM, causes sodium and fluid retention, hypertension,
increased PGC and inflammation, all of which contribute
to end-organdamage.18
In addition to its effects on tubular and haemodynamic
functions, hyperglycaemia also initiates several welldefined pathogenic molecular mechanisms that worsen
renal function and structure:19 formation of advanced
glycation end products (AGEs); increased expression
of the AGE receptor (RAGE) and its activating ligands;
increased flux through the polyol and hexosamine pathways; and, finally, activation of protein kinase C isoforms.
Hyperglycaemia-induced mitochondrial overproduction
of superoxide, which increases and perpetuates oxidative stress, is at the root of all of these mechanisms.20,21
Oxidative stress also promotes the production of proinflammatory cytokines, profibrotic growth factors and
vascular growth factors. The inflammatory response,
together with the irreversible complexes formed by
crosslinking of AGEs and matrix proteins and the release
of profibrotic growth factors, promote functional and
structural renal injury.22
In addition to hyperglycaemia, the above-mentioned
cluster of obesity-related cardiometabolic abnormalities contributes to renal damage in patients with T2DM.
Hypertension, which is often present at the time of
T2DM diagnosis,57 is an important early contributor to
the unfavourable haemodynamic state associated with
development of diabetic nephropathy. Moreover, the
prevalence and severity of hypertension increases as
renal disease progresses. In contrast to its role in T2DM,
hypertension in T1DM develops only after renal damage
has occurred, and is a consequence rather than a cause of
NATURE REVIEWS | NEPHROLOGY
VOLUME 10 | FEBRUARY 2014 | 89

REVIEWS
Insulin resistance
and -cell dysfunction
Obesity
Vasoconstrictors Ang II, ET-1
Hyperglycaemia
Systemic hypertension
Mitochondria
ROS
Impaired renal
vascular regulation
Afferent
arteriole
Glomerular
hypertension
Dyslipidaemia
Mesangial expansion
Mesangial cell
proliferation
Glucose-dependent
pathways
Advanced glycation
Polyol
Hexosamine
Protein kinase C
+
Efferent
arteriole
+
PGC
Glomerular
capillary
PT
AGE formation
Growth factors
TGF, VEGF
Proinflammatory
cytokines
IL-1, IL-6, TNF
Oxidative stress
Afferent vasodilators
ANP, NO, kinins,
COX, metabolites
GBM
thickening
Podocytopathy
Macula densa signals

Tubuloglomerular
feedback
Figure 1 | Pathogenesis of kidney disease in patients with diabetes. Haemodynamic and metabolic factors, with a
central role for chronic hyperglycaemia, have pivotal roles in the pathophysiology of diabetic nephropathy. Obesity and
chronic hyperglycaemia alter vasoactive regulators of afferent and efferent arteriolar tone, leading to increased P GC,
hyperperfusion and hyperfiltration. These early renal haemodynamic changes, combined with systemic hypertension, are
important in the development and progression of renal disease in T2DM. Additionally, chronic hyperglycaemia and
dyslipidaemia induce mitochondrial superoxide overproduction, which activates several well-defined pathways leading to
the development and progression of diabetic nephropathy. Collectively, these factors in the diabetic milieu lead to
glomerular damage, histologically characterized by thickening of the glomerular and tubular basement membranes,
mesangial expansion and podocytopathy. Abbreviations: AGE, advanced glycation end products; AngII, angiotensin2;
ANP, atrial natriuretic peptide; COX, cyclooxygenase; ET1, endothelin1; GBM, glomerular basement membrane; IL,
interleukin; NO, nitric oxide; PGC,glomerular capillary hydraulic pressure; PT, proximal tubule; ROS, reactive oxygen
species; T2DM, type 2 diabetes mellitus; TGF, transforming growth factor; TNF, tumour necrosis factor; VEGF, vascular
endothelial growth factor A.
diabetic nephropathy;23 thus, diabetes and hypertension

independently and collectively cause and exacerb ate
renal damage. Obesity and dyslipidaemia might accelerate the development of diabetic nephropathy, in part by
activating some of the hyperglycaemia-induced pathways
leading to oxidative stress and inflammation.24
In the early asymptomatic phase, morphological
changes occur in the kidney, including thickening of the
glomerular basement membrane (GBM) and tubular
basement membrane, and mesangial expansion.15 GBM
thickening can be detected as early as 1.52.5years after
the onset of T1DM, whereas mesangial expansion can
only be detected 57years after the onset of T1DM.
Diffuse mesangial expansion, also termed diffuse diabetic glomerulosclerosis, can be associated with marked
segmental expansion of the mesangium (Kimmelstiel
Wilson nodules), which appear as large, round, fibrillar lesions that can compress the associated glomerular
capillaries. Tubulointerstitial changes also occur in the
early stages of diabetic nephropathy, whereas late tubulo
interstitial disease is probably the most important
morphological abnormality predicting the progression
from moderate renal insufficiency to ESRD.15 Hyalinosis
of the afferent and efferent arterioles can present within
a few years after diabetes diagnosis. These exudative
lesions can ultimately replace the smooth muscle cells of
the arterioles, and the severity of arteriolar hyalinosis is
associated with the proportion of sclerotic glomeruli.15
Late phase of diabetic nephropathy

The loss of negatively charged proteoglycans in the GBM,
together with injury to the highly differentiated glomerular podocytes and disturbances in protein handling
by tubular cells, collectively lead to albuminuriathe
clinical manifestation of diabetic nephropathy.25 Urinary
albumin excretion (UAE) is initially 30300mg daily
(microalbuminuria),26 but can progress to over 300mg
daily (macroalbuminuria or overt nephropathy). As
albuminuria perse might further exacerbate renal damage
and fibrosis, therapeutic interventions aimed at reducing
albuminuria would potentially be of great use in preventing diabetic nephropathy.27 An epidemiological analysis of
the UKPDS cohort, which included over 5,000 newly diagnosed patients with T2DM, revealed that 25% of patients
had developed microalbuminuria and 5.3% had developed macroalbuminuria by 10years of follow-up.28 The
natural history of albuminuria in patients with diabetes
is highly variable, as spontaneous regression to normo
albuminuria occurs in up to 40% of patients with T1DM
and 31% of patients with T2DM.29 Also, advanced diabetic
nephropathy might be present in the absence of albumin
uria.30 Additionally, in up to 33% of patients with T2DM
(depending on the population studied and the classification system used), albuminuria is not diabetes-related.15
Nevertheless, albuminuria in patients with both T1DM
and T2DM is associated with a linear decline in GFR,
progression to ESRD and c ardiovascular mortality.31,32
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Table 1 | Evidence of renoprotection in studies of antihyperglycaemic therapy for T2DM
Study
Duration
of T2DM
(years)
Number
ofpatients
Primary agent(s)*
Follow-up
(years)
Outcome parameters (risk)
UKPDS (1998)38
New onset
3,867
Sulphonylurea or insulin
10.0
Microalbuminuria (RR 0.76)

Macroalbuminuria (RR 0.67)
Doubling of SCr (RR 0.40)
ESRD (RR 0.73)
ADVANCE (2008)43
11,140
Gliclazide (90.5%)
5.0
Microalbuminuria (HR 0.91)

Macroalbuminuria (HR 0.70)
Doubling of SCr (HR 1.15)
ESRD or death (HR 0.64)
ACCORD (2008
and 2010)41,42
10
10,251
Metformin (86.9%) and

sulphonylurea (73.8%)
3.5
Microalbuminuria (HR 0.79)

Doubling of SCr (HR 1.07)
ESRD (HR 0.95)
VADT (2009
and2011)44,45
12
1,791
Rosiglitazone plus metformin

(inpatients with BMI 27kg/m2)
or Rosiglitazone plus glimepride
(in patients with BMI <27kg/m2)
5.6

ESRD (RR 0.64)
*Numbers in brackets refer to the percentage of patients that used the glucose-lowering drug at the end of follow-up. Indicates significant result. Study
stopped early due to excess mortality in the intensive treatment arm. Abbreviations: ESRD, end-stage renal disease; HR, hazard ratio; RR, relative risk; SCr,
serum creatinine; T2DM, type2 diabetes mellitus.
The late clinical phase of diabetic nephropathy is charac

terized by persistent proteinuria (total protein excretion
0.5g daily, corresponding to UAE 300mg daily), followed by a progressive decline in GFR leading ultimately
to ESRD. In T2DM, the rate of decline in GFR is highly
variable and largely influenced by glycaemic and blood
pressure control. In the UKPDS, 0.8% of patients with
T2DM had progressed to ESRD requiring renal replacement therapy at 10years of follow-up.28 This late phase of
diabetic nephropathy is accompanied by severe morphological abnormalities in the glomerulotubular junction,
including tubular atrophy and atubularglomeruli.15
Renoprotective strategies for T2DM

Next to lifestyle modifications aimed at improving
patients cardiovascular risk profiles, the results of
large randomized clinical trials suggest that intensive
glucose and blood pressure control might delay the
onset and halt the progression of diabetic nephropathy.29
However, in contrast to the established favourable effect
of such intensive therapy on cardiovascular disease
risk, the renal benefits from lipid-lowering treatments
remainuncertain.33
Glucose control
The importance of strict glycaemic control in preventing the development of microvascular complications in
T1DM was initially demonstrated in several small ran
domized studies,34 and definitively established in the
landmark DCCT.35 In this randomized controlled trial,
which included 1,441 patients with T1DM, 6.5years of
intensive diabetes therapy (three or more insulin injections per day or use of an insulin pump) to achieve a target
HbA1c level of 7% (versus a target HbA1c level of 9% in the
conventional treatment group) reduced the occurrence of
microalbuminuria by 39% and that of macroalbuminuria
by 54%.35 In the EDIC 17-year follow-up study of the trial
participants, the risk of having an impaired estimated GFR

was reduced by 50%36 and that of experiencing any cardiovascular disease events was reduced by 42% in the patients
previously assigned to intensive treatment, despite similar
HbA1c levels in both groups.37 However, until the publication of the UKPDS results,38 whether the DCCT findings35
could be extrapolated to T2DM remained unclear. In the
UKPDS, 10years of intensive glucose therapy to achieve
a HbA1c level of 7.0%, (versus a target of 7.9% with conventional therapy) conferred similarly beneficial effects on
renal end points in 3,867 newly diagnosed patients with
T2DM (Table1 and Supplementary Table1 online).38At
the 10-year post-trial follow-up, HbA1c levels were similar
in the treatment groups but a sustained reduction in
microvascular complications and a significantly reduced
risk of myocardial infarction was observed in the patients
who had received intensive treatment.39 The findings of
the DCCT35 and UKPDS38 suggest that early exposure to
hyperglycaemia predisposes individuals to the development of diabetic complications, a phenomenon referred
to as metabolic memory or the legacy effect.
Three very large trials have since revisited the comparison between intensive versus conventional glucose
control in high-risk patients with poorly controlled,
long-standing T2DM (Table1 and Supplementary
Table1 online).40 Intensive treatment reduced the incidence and progression of albuminuria in two of the three
trials, confirming the relevance of strict glucose control
in this population.4145 However, the ACCORD trial was
terminated early due to excess mortality in the intensive treatment arm.41,42 A subsequent systematic review
and meta-analysis, which evaluated seven landmark
treatment trials in patients with T2DM, concluded that
although intensive glycaemic control reduces the risk of
microalbuminuria and macroalbuminuria, it does not
reduce the risk of important clinical renal end points
(such as doubling of serum creatinine levels, ESRD or

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Table 2 | Evidence of renoprotection in studies of antihypertensive therapy for T2DM
Study
Duration
ofT2DM
(years)
Number
ofpatients
Treatment arms
Follow-up
(years)
Outcome parameters (renal risk)
UKPDS (1998)49
2.6
1,148
Intensive versus
standard
8.4

ESRD and death (RR 0.58)
ADVANCE (2007)51
8.0
11,140
Intensive versus
standard
4.3
Microalbuminuria (RRR 21%)*

Macroalbuminuria (RRR 18%)
ACCORD (2010 and

2012)52,53
1.1
4,733
Intensive versus
standard
4.7
Microalbuminuria (HR 0.84)*

ESRD (HR 1.00)
HOPE and MICRO-HOPE

(2000)60
11.0
3,577
Ramipril versus
placebo
4.5
Microalbuminuria (RRR 9%)

Macroalbuminuria (RRR 24%)*
ESRD (RRR 20%)
BENEDICT (2004)61
8.0
1,204
Trandolapril versus
placebo
3.6
Microalbuminuria (AF 0.47)*
ROADMAP (2011)62
6.0
4,447
Olmesartan versus
placebo
3.2
Microalbuminuria (HR 0.77)*

IRMA2 (2001)63
10.0
590
Irbesartan versus
placebo
2.0
Restore albuminuria (RRR 34%||)*

Macroalbuminuria (HR 0.30)*
IDNT (2001)64
NR
1,715
Irbesartan versus
placebo
2.6
Doubling of SCr (RR 0.67)*

ESRD (RR 0.77)
RENAAL (2001)65
NR
1,513
Losartan versus
placebo
3.4
Composite end point (RRR 16%)*

Doubling of SCr (RRR 25%)*
ESRD (RRR 28%)*
TRANSCEND (2008)66
NR
5,926
Telmisartan versus
placebo
4.7
Renal abnormalities (RR 1.86)

Cardiorenal end point (HR 0.85)*
Doubling of SCr (HR 1.60)*
ESRD (HR 0.67)
DIRECT-Protect 2
(2009)59
9.0
1,905
Candesartan versus
placebo
4.7
Microalbuminuria (HR 1.01 and 0.76#)

Increase in UAE (HR 0.95 and 0.93#)
*Indicates significant result. Study stopped early owing to consistent benefit of ramipril compared with placebo. Study stopped early because of new evidence
suggesting ACE inhibitors might be effective in reducing cardiovascular events in T2DM. ||Normalization of urinary albumin. Use of antihypertensive medication
at baseline. #Normotensive at baseline. Abbreviations: AF, acceleration factor (quantifies the effect of one treatment relative to another treatment in
accelerating or slowing the progression of the disease); ESRD, end-stage renal disease; HR, hazard ratio; NR, not reported; RR, relative risk; RRR, relative risk
reduction; SCr, serum creatinine; T2DM, type2 diabetes mellitus; UAE, urinary albumin excretion.
death from renal disease).46 Interestingly, a posthoc

analysis of the ADVANCE trial data indicated that intensive glucose-lowering regimens might protect against
the development of ESRD.47 Adequately powered trials,
using hard renal end points as prespecified outcomes
are, therefore, essential to demonstrate the p
otential
renoprotective benefits of strict glycaemic control.
Current guidelines recommend a target HbA1c level of
~7% to prevent or delay progression of diabetic microvascular complications.29,48 Further, these guidelines
recommend individualization of glycaemic targets and
treatments according to the patients age, comorbid
ities, susceptibility to hypoglycaemia, life expectancy
andpreference.
placebos), a decrease in blood pressure of 5.6/2.2mmHg

in high-risk patients with T2DM reduced the rate of renal
adverse events by 21%.51 However, in the ACCORD trial,
intensive blood pressure lowering did not reduce cardiovascular events compared to conventional therapy, and
increased rates of hyperkalaemia and renal dysfunction
were reported in the active treatment group (Table2 and
Supplementary Table2 online).52,53 Optimal blood pressure targets for patients with T1DM and T2DM remain
a much-debated topic; nevertheless, current Kidney
Disease Improving Global Outcomes guidelines recommend a blood pressure target of 140/90mmHg in
normoalbuminuric T2DM patients and 130/80mmHg
for patients with proteinuria >30mg per day.54
Blood pressure control

In the UKPDS itself,49 as well as at the postintervention
follow-up (median 8.4years), 50 intensive antihyper
tensive therapy was associated with a reduction in macro
vascular and microvascular end points (Table2 and
Supplementary Table2 online). Moreover, in the activetreatment arm of the ADVANCE study (in which patients
received either the angiotensin-converting enzyme [ACE]
inhibitor perindopril plus the diuretic indapamide, or two
Multifactorial intervention
The Steno2 trial compared the effect of an intensive
multifactorial intervention with that of conventional
treatment on cardiovascular and renal risk in patients
with T2DM and microalbuminuria (Supplementary
Table3 online).9 The intensive treatment, administered
by the Steno Diabetes Centre, consisted of a lifestyle inter
vention and pharmacotherapy to achieve strict control
of glycaemia, blood pressure and dyslipidaemia, as well
REVIEWS
as the addition of aspirin. Patients in the conventional
care group were treated by their general practitioners,
with less-strict targets for glycaemia, blood pressure and
lipid levels, according to the prevailing guidelines of the
Danish Medical Association. At 8years of follow-up,
a61% reduction in the risk of developing macroalbumin
uria and a 55% reduction in the cardiovascular composite end point was noted in the intensive treatment group,
as compared to the conventional care group.9 These risk
reductions were still present 5years after the study had
ended, indicating that the beneficial effects of this intensive multifactorial intervention were sustained.55 However,
25% of the patients with T2DM had developed nephro
pathy at this time point, suggesting that a residual risk of
microvascular complications remains despite meticulous
implementation of a targeted, intensive multifactorial
intervention. These results highlight the unmet need for
novel strategies to further prevent or delay p
rogression of
diabetic n
ephropathy in patients with T2DM.
Potential pleiotropic effects

Antihypertensive therapy
The choice of an antihypertensive drug is potentially
important in renoprotection. In 409 patients with
T1DM, captopril treatment for 3years reduced the risks
of d
oubling of serum creatinine levels and ESRD by 48%
and 50%, respectively, versus placebo.56 As the betweengroup differences in achieved blood pressure were not
statistically significant, the researchers concluded that
ACE inhibitors might confer benefits beyond blood
pressure controlthat is, have pleiotropic effects.
Although further studies showed that similar renal
benefits were associated with RAAS inhibition in
patients with T1DM and diabetic nephropathy, other
studies showed a lack of effect of this approach against
new-onset microalbuminuria in normotensive patients
with T1DM.5759 As diabetic nephropathy in patients with
T2DM, as compared to T1DM, is more heterogeneous
(with respect to the pathogenetic factors involved and the
clinical time course), whether RAAS interference would
have the same favourable effect in patients with T2DM
was unclear. Whereas the UKPDS data 49 showed no
superior effect of captopril when compared with ateno
lol, the MICRO-HOPE trial60 demonstrated beneficial
effects of ramipril compared to placebo with regard to
both cardiovascular and renal end points.59 This finding
led to a myriad of large-scale trials investigating the
effects of ACE inhibitors or angiotensinII receptor blockers (ARBs) on renal and cardiovascular end points and
mortality in patients with T2DM with varying levels of
renal impairment and cardiovascular risk (Table2 and
Supplementary Table2 online). Collectively, the results
of these studies suggest that even though ACE inhibitors and ARBs prevent the onset 61,62 and progression60,63
of albuminuria in patients with T2DM, their effects on
doubling of serum creatinine levels and development of
ESRD remain uncertain.62,6466 Additionally (and similar
to the situation in T1DM), high-risk patients with T2DM,
comorbidities and advanced renal disease, in particular,
seem to derive a renoprotective benefit from treatment
with RAAS-interfering agents.64,65 As a consequence, the

current National Kidney FoundationKidney Disease
Outcomes Quality Initiative guidelines advocate RAAS
inhibitor therapy for hypertensive patients with T2DM, as
well as normotensive patients with T2DM and albumin
uria 30mg daily, who are at high risk of development or
progression of diabetic nephropathy.29
Intensive inhibition of the RAAS, for the purpose
of delaying development of diabetic nephropathy, was
investigated by combining ACE inhibitors with ARB
treatment or by the use of direct renin inhibitors,
such as aliskiren. Although these strategies improved
surrogate biomarkers of diabetic nephropathy, such
as albuminu ria, 67 combination therapy was associated with increased renal and cardiovascular eventsin
ONTARGET. 67,68 Additionally, both ALTITUDE 69
(inwhich patients with T2DM received aliskiren on top
of an ACE inhibitor or ARB) and the VA NEPHROND70
study (which assessed a combination of lisinopril and
losartan) were terminated early, owing to lack of
(expected) efficacy and an observed excess risk or incidence of cardiovascular and renal adverse events, most
notably hyperkalaemia and hypotension.67 At present,
dual-agent RAAS inhibition is not recommended in
patients with T2DM.
Antihyperglycaemia therapy
As for RAAS-interfering agents in blood pressure manage
ment, novel glucose-lowering agents with potential pleiotropic effects beyond glucose control might reduce both
cardiovascular and renal risks in patients with T2DM.
In the UKPDS, at 10 years of follow-up, sulphonylurea,
insulin or metformin use had no additional drug-specific
benefit on renal end points, although metformin showed
favourable effects on all diabetes-related end points, as
well as on myocardial infarction and all-cause mortality.38 Interestingly, the thiazolidinediones (for example
rosiglitazone and pioglitazone) reduced microalbumin
uria beyond the effects of glycaemic control alone, possibly by improving dyslipidaemia, endothelial function
and inflammation, by reducing secretion of angiotensinI,
angiotensinII and ET1, or by reducing glomerular and
tubular cell proliferation.71,72 However, rosiglitazone
has been withdrawn from the European market and its
indications have been restricted in the USA, because of
an association with adverse cardiovascular outcomes.73
Pioglitazone remains available, but concerns persist about
an elevated risk of bone fractures and bladder cancer.74
Based on current evidence, the conventional antihyperglycaemic drugs, including metformin, sulphonylurea
agents and insulin, do not seem to have renoprotective
effects beyond their glucose-lowering actions.
The incretin system

The incretin hormones, glucagon-like peptide 1 (GLP1)
and gastric inhibitory polypeptide (GIP), are released
from intestinal L and K cells, respectively, following
nutrient ingestion. 75 Both incretins maintain glucose
homeostasis by stimulating meal-related insulin secretion in a glucose-dependent manner.76 GLP1 (but not

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Table 3 | Pharmacokinetics and pharmacodynamics of incretin-based therapies
Agent
Dose
Halflife
(h)
DPP4
inhibition
Elimination
Use in patients with renal insufficiency

Moderate (eGFR
3060ml/min)
Severe (eGFR
<30ml/min)
GLP1R agonists
Exenatide
510g twice daily
2.4
NA
Glomerular filtration,
proteolytic degradation
Caution
Not recommended
Exenatide
2mg once weekly
2.4*
NA
proteolytic degradation*
Not recommended
Not recommended
Liraglutide
1.21.8mg daily
13.0
NA
Generalized proteolysis,
Elimination: renal (6%);
faecal (5%)
Not recommended
Not recommended
Lixisenatide
20g daily
3.0
NA
tubular reabsorption and
metabolic degradation
Caution
Not recommended
DPP4 inhibitors
Sitagliptin
100mg daily
8.0
24.0
Max. ~97%
(>80% 24h
post-dose)
Renal excretion (80%

unchanged)
Dose reduction
Dose reduction
Vildagliptin
50mg twice daily or

50mg once daily
(plus sulphonylurea)
1.54.5
Max. ~95%
(>80% 24h
post-dose)
Metabolized to inactive
metabolite, renal excretion
(22% unchanged)
Dose reduction
Dose reduction
Linagliptin
5mg daily
10.0
40.0
Max. ~80%
(~70% 24h
post-dose)
Elimination: renal (5%);

faecal (85%)
No adjustment
No adjustment
Saxagliptin
5mg daily
2.23.8
Max. ~80%
(~70% 24h
post-dose)
Metabolized to active
metabolite, Elimination:
renal (1229% unchanged,
2152% metabolite)
Dose reduction
Dose reduction
Alogliptin
25mg daily
12.5
21.1
Max. ~90%
(~75% 24h
post-dose)
Elimination: renal (>70%

unchanged)
Dose reduction
Dose reduction
*The pharmacokinetic profile of exenatide once weekly is similar to that of exenatide twice daily, except that adsorption from the subcutaneous space is
prolonged with the once weekly formulation. Abbreviations: DPP4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; GLP1R, glucagon-like
peptide 1 receptor; NA, not applicable.
GIP) exerts glucoregulatory actions via slowing of gastric

emptying and glucose-dependent inhibition of glucagon
secretion. GLP1 also promotes satiety and weight loss.77
Oral glucose administration elicits a 5070% greater
increase in plasma insulin levels than does glucose given
intravenously, despite resulting in similar plasma glucose
concentrations.78,79 The differential response to an oral
versus intravenous glucose load is called the incretin
effect, and is mediated by the incretin hormones.80 The
incretin effect is reduced in patients with T2DM, owing
to a diminished action of the incretin hormones on
pancreatic cells.81 As the insulinotropic action of exo
genously administered GLP1 is relatively well-preserved
in patients with T2DM, GLP1 has been used for further
development of T2DM therapies.82 In a 6week proof-ofconcept study in patients with T2DM, continuous subcutaneous administration of pharmacological doses of
GLP1 lowered levels of HbA1c and fasting and postprandial glucose, improved cell function, delayed gastric
emptying and induced weight loss.83 However, GLP1
is rapidly degraded by the ubiquitous enzyme DPP4,84
resulting in a short half-life (~12min).
DPP4-resistant, injectable GLP1R agonists and oral
inhibitors of DPP4 have been developed for clinical
use (Table3).85 The first GLP1R agonist (exenatide)
was based on the lizard (Heloderma suspectum) peptide

exendin4.86 Exenatide was approved by the FDA in 2005
and by the EMA in 2006. The first DPP4 inhibitor, sita
gliptin, was approved in the USA in 2006 and in Europe
in 2007. Both GLP1R agonists and DPP4 inhibitors
improve glycaemic control in patients with T2DM and
have a low risk of hypoglycaemia.84,86 GLP1R agonists
reduce body weight, whereas DPP4 inhibitors do not
affect body weight.87
The GLP1 receptor

GLP1R, a member of the glucagon receptor family of
Gprotein-coupled receptors,88 was first cloned in 1992.89
Expression of this receptor has been reported in the pancreatic islets, central nervous system, lung, gastrointestinal tract, heart, vasculature, liver, muscle and adipose
tissue of many species.90 The wide distribution of GLP1R
expression could explain the observed extrapancreatic
effects of GLP1 and GLP1R agonists. Moreover, GLP1R
is expressed in the kidney. Indeed, GLP1R mRNA transcripts9194 and protein expression94 have been detected in
the rodent kidney and primary porcine proximal tubular
cells, respectively. In the human kidney, expression of
GLP1R mRNA was demonstrated by insitu hybrid
ization,95 and GLP1R expression was detected using
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GLP-1
Neural
pathways
ANP
GLP-1
Other gut-derived factors
Neural pathways
Fluid and
solute
Intake
GLP-1
Neural
pathways
Fluid and
solute
Homeostasis
Neural
pathways
Figure 2 | The gutrenal axis. Potential regulatory links between the gastrointestinal
tract and the kidney involve neurohormonal interactions (simplified, feedback loops
not shown). Several gut-derived factors (including GLP1, guanylin, uroguanylin,
secretin, vasoactive intestinal peptide, ghrelin, gastrin and cholecystokinin) and
neural signals related to dietary intake and composition are thought to affect renal
function. These gastrointestinal hormones and neuropeptides might directly
influence the kidney, whereas indirect effects of GLP1, via neural pathways or
cardiac-derived ANP, are also suggested to increase postprandial natriuresis.
Abbreviations: ANP, atrial natriuretic peptide; GLP1, glucagon-like peptide 1.
I-labelled GLP1736 amide receptor autoradiography,

albeit only in hilar and intralobular arteries, and not in
arterioles, veins, glomeruli or tubules.96 Interspecies differences and methodological issues might hamper exact
mapping of the distribution of functional GLP1R. In a
study that characterized the sensitivity and specificity of
three commercially available GLP1R antisera, although
all three antibodies detected immunoreactive proteins
of a size consistent with GLP1R, they also detected a
protein of a comparable size in extracts from GLP1R/
mice.97 Surprisingly, none of these antibodies could definitively detect GLP1R in state-of-the-art Western blotting
and immunohistochemical studies.96 The exact cellular
localization of GLP1R in the kidney, both in humans and
animal species, requires further study.
125
Renal effect of GLP1 and incretin-based agents

The gutrenal axis
From an evolutionary perspective, intestinal regulation
of renal functions, especially following a meal that disturbs water and ion homeostasis, seems crucial. An incretin effect on sodium handling seems to exist, as dietary
intake of sodium induces more marked natriuresis than
does intravenously administered sodium,98,99 suggesting a role for gut-derived factors. Indeed, in addition
to pancreatic hormones, such as insulin and glucagon,
several gut hormones (including guanylin, uroguanylin,
secretin, vasoactive intestinal peptide, ghrelin, gastrin
and cholecystokinin) seem to be implicated in regulation
of renal function (Figure2).100 However, the underlying
mechanisms, their interactions, and the contribution of
nervous system signals to the gutrenal connection are
uncertain, and discussion of these areas is beyond the
scope of this Review.
In 1996, the involvement of GLP1 in the gutrenal axis
was first demonstrated by the increase in natriuresis in
rats in response to administration of exogenous GLP1.101

This finding was subsequently confirmed in humans
and in numerous nondiabetic and diabetic animal
models.102105 GLP1 promotes natriuresis by acting on
the proximal tubule, thereby also increasing the fractional
excretion of lithium.102,106 The involvement of NHE3
(which is bound to a complex that also contains DPP4) in
this process has also been demonstrated.106,107 Decreased
NHE3 activity augments natriu resis and decreases
hydrogen excretion.104,105 Thus, GLP1 administration
increases urinary pH levels in rats104 and in humans.105
Both GLP1R agonists and DPP4 inhibitors induce
natriuresis.108111 An indirect natriuretic or diuretic effect
of GLP1R activation, mediated by secretion of ANP,
has been reported in mouse cardiac atria.112 However,
GLP1 infusion in healthy humans did not affect circu
lating levels of either ANP or its propeptide, despite
a marked increase in sodium excretion.113 In hyper
hydrated rats110,114 and humans (including patients with
T2DM),115 exenatide increased solute-free water clearance, potentially through enhanced urinary excretion
of prostaglandin E2.114 As prostaglandin E2 antagonizes
the hydrosmotic effect of vasopressin, the subsequent
cascade might lead to increased solute-free water excretion via the following mechanisms: GLP1-induced proximal natriuresis; increased influx of isotonic tubular fluid
into the distal segment of the nephron; distal sodium
reabsorption and decreased water permeability of the
collecting ducts. However, GLP1-induced changes in
RPF might reduce the renal osmotic gradient, owing
to washout of solutes, thereby possibly contributing to
water impermeability of the collecting duct. GLP1 also
reduces water and salt intake in rats,101 healthy men,105
and obese individuals.105
Interference with pathways of renal damage

Apart from GLP1-induced effects on sodium and
fluid homeostasis, pharmacological levels of GLP1
confer renoprotection. Initial studies in hypertensionprone rats showed that GLP1 prevented the development of hypertension, ameliorated histologically
verified renal damage and reduced albuminuria.103,116
Subsequently, in various animal models of diabetes,
long-term treatment withGLP1R agonists (in Leprdb/db
mice108,111,117 and ratswith streptozotocin-induced diabetes118120) and DPP4 inhibitors (in Lepr db/db mice,111
rats with streptozotocin-i nduced diabetes 121123 and
Zucker diabetic fatty rats124,125) gave similar findings
(Supplementary Table4 online). Although in most of
these studies no control group using other antihyper
glycaemic agents was included to establish effects beyond
glucose control, the current evidence suggests that at
least some of the renoprotective effects of incretin-based
therapies are glucose-independent (Figure3).
Mechanisms of incretin-based therapies
Systemic and renal haemodynamics
In phaseIII trials included in meta-analyses,126128 GLP1R
agonists decreased systolic blood pressure by 25mmHg,
depending on the comparator drug (placebo or an active

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Hyperglycaemia
GLP-1R agonist
DPP-4 inhibitor
Metformin, sulphonylurea,
thiazolidinedione, insulin
GLP-1R agonist
DPP-4 inhibitor
GLP-1R agonist
DPP-4 inhibitor
Diabetic
kidney
disease
Glomerular
hypertension
Cytokines and
growth factors
Thiazolidinedione
GLP-1R agonist
DPP-4 inhibitor
Systemic
hypertension
Metabolic
syndrome
Figure 3 | Effects of incretin-based therapies on renal risk factors in T2DM. The

beneficial effects of incretin-based therapies on renal risk factors in T2DM seem to
go beyond glucose control and might thereby confer renoprotection. GLP1R agonists
and DPP4 inhibitors improve glucose control without significantly increasing the risk
of hypoglycaemia. These drugs also ameliorate several components of the metabolic
syndrome (obesity, hypertension and dyslipidaemia), reduce glomerular hypertension
(through their effects on renal haemodynamics), and reduce levels of proinflammatory
cytokines and growth factors. Interestingly, the thiazolidinediones (for example
pioglitazone) have favourable pleotropic effects on endothelial function, inflammatory
markers and lipid profile. However, the clinical use of thiazolidinediones is limited by
adverse events, including weight gain, congestive heart failure, bone fractures,
macular oedema and possibly bladder cancer. Green boxes with dotted lines indicate
proven actions of GLP-1R agonists and DPP-4 inhibitors, whereas green boxes without
dotted lines indicate proposed actions of GLP-1R agonists and DPP-4 inhibitors.
Abbreviations: DPP4, dipeptidyl peptidase 4; GLP1R, glucagon-like peptide 1
receptor; T2DM, type2 diabetes mellitus.
control, such as insulin, pioglitazone and sulphonylureas).

The lowering effects of GLP1R agonists on diastolic blood
pressure were more modest, ranging from 0.52.0mmHg,
and did not reach statistical significance.126128 Few studies
have investigated the antihypertensive effects of DPP4
inhibitors. Although modest reductions in systolic blood
pressure were observed in some studies,129131 a metaanalysis failed to show significant effects.132 The decrease
in blood pressure associated with the DPP4 inhibitor
linagliptin, was similar to that associated with placebo
in a pooled analysis of six phaseIII clinical trials.133
Interestingly, two head-to-head randomized comparison
studies (examining exenatide, sitagliptin and pioglitazone,
and liraglutide and sitagliptin) showed a slight decrease
in diastolic blood pressure for sitagliptin compared to
liraglutide, but not for sitagliptin compared to exenatide.
Furthermore, only exenatide significantly lowered systolic
blood pressure.134,135
The antihypertensive action of GLP1R agonists
might be partly attributable to a combination of GLP1mediated natriuresis and diuresis, but could also involve
improved endothelial function, increased release of vasoactive factors (such as NO and ANP), a decrease in ET1
levels and alteration in the balance of the autonomic
nervous system .112,136,137 In the context of these actions,
the small but consistent increase in heart rate (24bpm)
observed in phaseIII trials of GLP1R agonists, but
not those of DPP4 inhibitors, needs to be mentioned,
although the clinical significance of this observation is
unclear.138 Finally, although the weight loss induced by
GLP1R agonists could also result in lowering of blood
pressure, the antihypertensive effects occur early during

treatment, before any weight change.139
GLP1, GLP1R agonists and DPP4 inhibitors also
affect renal haemodynamics. 140 The GLP1-related
increase in sodium delivery to the macula densa restores
disrupted tubuloglomerular feedback associated with
diabetes, resulting in relative vasoconstriction of the
afferent renal arteriole and, consequently, a decrease
inP GC. However, pathways that affect renal haemo
dynamics independently of tubuloglomerular feedback
also seem to be present, suggesting an interaction with
vasoactive factors.141 The evidence suggests that both
GLP1R agonists and DPP4 inhibitors interact with
the RAAS (see below). Given the serial arrangement of
afferent and efferent arterioles in the kidneys, changes in
resistance to blood flow could lead to opposing actions
on PGC and GFR, which would complicate assessment
of the net effect of vasoactive factors on renal haemo
dynamics. For example, a GLP1-induced increase in NO
bioavailability 120 would not only promote vasodilatation
of both afferent and efferent arterioles, 142 but also
influence sodium excretion. These mechanisms could
potentially differentially affect renal haemodynamics.
Systemic metabolism and inflammation
Agonists of GLP1R and inhibitors of DPP4, used
either alone or in combination, reduce blood glucose
and HbA1c levels in patients with T2DM. 87 However,
GLP1R agonists have more marked antihyperglycaemic
effects than do DPP4 inhibitors.135,143 Both drug classes
lower postprandial (and to a lesser extent, fasting) hyper
glycaemia, although the long-acting GLP1R agonists
also significantly reduce fasting blood glucose levels.
As postprandial glucose excursions in particular are
associated with oxidative stress,144 exenatide therapy also
decreased postprandial markers of oxidative stress (such
as serum oxidised-LDL and malondialdehyde) in associ
ation with the decrease in postprandial glucose levels,
in patients with T2DM.145 Additionally, GLP1146 and
DPP4 inhibitors147 reduce expression of RAGE, thereby
decreasing AGE and other ligand-induced cell death and
oxidative stress markers, both invitro148 and in patients
with T2DM. 149 In rodents, incretin-based therapies
decrease levels of inflammatory and profibrotic markers
(such as transforming growth factor [TGF], fibronectin
and 8Oxo2-deoxyguanosine) and urinary markers of
oxidative stress, as well as reducing glomerular leucocyte infiltration, indicating a decrease in renal inflammation.117,122 Human studies show that GLP1R agonists
and DPP4 inhibitors reduce levels of circulating pro
inflammatory factors, both in an acute setting and after
long-term treatment.145,150152
GLP1R agonists reduce body weight in patients with
T2DM153 and in obese nondiabetic individuals,154 possibly as a consequence of inducing satiety and reduced
caloric intake,138 whereas DPP4 inhibitors are body
weight neutral. 155 GLP1R agonists might, therefore,
ameliorate kidney disease to a greater extent than do
DPP4 inhibitors, by improving weight-related risk
factors, including body fat content and distribution,
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BNP/ANP
SP
NPY
PYY
SDF-1
Meprin
HMGB1
DPP-4
inhibitor
Degradation by DPP-4 enzyme
BNP/ANP
SP
NPY
PYY
SDF-1
Meprin
HMGB1
Natriuresis?
Renal cell
protection
Inflammation
Inflammation
Natriuresis
Natriuresis
Natriuresis
Inflammation
Inflammation
Inflammation
Sympathetic
activity
Sympathetic
activity
Sympathetic
activity
RAAS
Vascular
effects
Vascular
effects
Vascular
effects
Tubular cell
protection
Angiogenesis
RAAS
Vascular
effects
Figure 4 | Potential GLP1-independent effects of DPP4 inhibitors on renal outcome. In addition to GLP1 and GIP, DPP4
cleaves a number of peptides and hormones, especially during ACE inhibitor therapy. Since inhibition of DPP4 leads to altered
levels and activity of these substrates, DPP4 inhibitors are thought to have GLP1-independent renal effects. Whether these
effects, which were mainly demonstrated in preclinical models and invitro, have a role in patients with T2DM remains to be
demonstrated. Upper row of blue boxes (dotted line) represents inactivated or degraded peptides. Boxes without dotted line
indicate active form of peptides with subsequent renal effects. Abbreviations: ACE, angiotensin-converting enzyme; ANP, atrial
natriuretic peptide; BNP, brain natriuretic peptide; DPP4, dipeptidyl peptidase 4; GIP, gastric inhibitory polypeptide; GLP1,
glucagon-like peptide 1; HMGB1, high mobility group protein B1; meprin , meprin A subunit ; NPY, neuropeptide Y; PYY,
peptide YY; RAAS, reninangiotensinaldosterone system; SDF1, stromal cell-derived factor 1; SP, substance P; T2DM,
type2 diabetes mellitus.
liver steatosis, insulin sensitivity and levels of circulating biomarkers (including Creactive protein and adiponectin).138 Additionally, weight loss could, at least
in part, explain the improvements in lipid profiles
reported in patients receiving incretin-based therapies:
in patients with T2DM who were treated with exenatide
for 3years, triglyceride levels decreased by 12%, whereas
HDL-cholesterol levels increased by 24%. 152 DPP4
inhibitors also improve dyslipidaemia in patients with
T2DM.156 However, whether the rather modest lipidlowering effects of incretin-based therapies contribute
to improved renal and cardiovascular risk remains to
bedemonstrated.
GLP1-independent effects of DPP4 inhibition
Besides GLP1 and GIP, DPP4 cleaves multiple substrates, such as brain natriuretic peptide (BNP), ANP,
substance P, neuropeptide Y (NPY), peptide YY (PYY),
stromal-cell-derived factor 1 (SDF1), meprin A
subunit (meprin ) and high mobility group proteinB1
(HMGB1), many of which are vasoactive (Figure4). As
DPP4 is also expressed at the apical brush border surface
of renal proximal tubular cells, 157 DPP4-inhibitormediated actions on the renal and cardiovascular system
might, in part, be GLP1-independent.158160 To illustrate this point, although GLP1R-agonist-mediated
renal effects are dependent on the presence of GLP1R
in mice, the effects of the DPP4 inhibitor alogliptin are
also evident in GLP1R/ mice.111 To date, no studies
have examined the relative effects of the different DPP4cleaved substrates on the kidney invivo, but preclinical
(pharmacological) studies demonstrate renal effects of
the various above-mentioned peptides. In these studies,
several DPP4 substrates increased natriuresis, 161,162
decreased RAAS activity, 163 had anti-inflammatory
effects161 and reduced sympathetic nervous system activity.164 Direct vascular effects of these substrates have also
been described (Figure4).161,165 Interestingly, SDF1,
a chemokine that is increased in ischaemic tissue and
has a major role in attracting stem cells to these sites for
the purposes of tissue repair, also seems to be involved
in murine kidney repair.166 Preclinical studies in mice167
and in rats168 have shown that DPP4 inhibition decreases
infarct size after myocardial ischaemia by preventing
thedegradation of SDF1. Sitagliptin also prevented
SDF1 degradation and increased circulating endothelial
progenitor cells in patients with T2DM without ischaemia.169 Whether SDF1 might also favourably affect the
kidney in humans remains to bedemonstrated.
Increased levels of DPP4 substrates resulting from
the action of DPP4 inhibitors might be harmful, in
terms of increased activation of the sympathetic nervous
system170 or inflammation.171 HMGB1, a known ligand
for Toll-like receptors and RAGE, is cleaved by DPP4
invitro, and affects angiogenesis in mouse vascular
cells.158 Additionally, HMGB1 leads to the production and
secretion of proinflammatory cytokines, and contributes
to renal injury in mice172 and rats with streptozotocininduced diabetes. 173 To date, most of the substrate-
modifying effects of DPP4 have only been demonstrated
invitro and in rodents. Whether these effects occur in and
have clinical relevance for humans remains to be shown.
Detailed mechanistic studies are needed to unravel the
individual and combined effects of DPP4-degraded
substrates during DPP4 inhibition invivo.
Renal effects in T2DM

Currently, the results of only a few studies suggest that
incretin-based therapies can provide renoprotection
in humans. In phaseIII trials, GLP1R agonist use was

REVIEWS
associated with a reduction in albuminuria in patients
with T2DM; however, this effect was not statistically
significant compared to that of the other agents used,
sitagliptin and pioglitazone.134 Furthermore, in small,
uncontrolled studies, 6months of treatment with sita
gliptin,174 or 12weeks of treatment with alogliptin,149
reduced albuminuria in patients with T2DM. These data
were confirmed and expanded in a pooled analysis of
phaseIII trials of linagliptin, which showed a significant
reduction in albuminuria after a mean of 24weeks of
treatment.175 Interestingly, 16weeks of treatment with
exenatide reduced both albuminuria and urinary levels
of TGF and typeIV collagen (versus glimepiride) in
patients with T2DM.176
After the association between rosiglitazone use and
increased cardiovascular risk was reported, 73 the FDA
issued recommendations for cardiovascular outcome
studies to be performed, in addition to assessing the
overall safety of glucose-lowering agents.177 Two such
trials for DPP-4 inhibitors have been published.177,178
These placebo-controlled studies, involving a median
2years of treatment with alogliptin178 and saxagliptin,179
respectively, demonstrated no cardiovascular harm and
a modest reduction in albuminuria progression in highrisk patients with T2DM, most of whom had a history
of cardiovascular disease. Post hoc analyses of these
trials did not detect any effects of DPP4 inhibitors on
clinically relevant renal end points. However, these data
should be interpreted with caution, as the trials were
not adequately powered to study the effects of DPP4
inhibitors on these outcomes.
Tolerability and safety

In phaseIII trials and in clinical practice, incretin-based
therapies are generally well tolerated; however, use of
GLP1R agonists, but not DPP4 inhibitors, is associated
with (usually transient) gastrointestinal adverse effects,
most notably nausea, and occasionally vomiting.85 Other
adverse effects, only reported after introduction to the
market, include sporadic cases of acute renal failure. All
affected patients had T2DM and used RAAS-inhibiting
agents and diuretics, which, together with nausea,
might have caused dehydration leading to renal failure.
However, a retrospective analysis of insurance claim
data did not find any association between incretin-based
therapy and renal failure.180 Several pathophysiological
mechanisms, identified mainly in preclinical or invitro
studies, could potentially explain the reported renal
adverse effects of incretin-based therapies. As discussed
above, DPP4 cleaves multiple substrates that might
have renal and vascular effects invivo. For example,
inhibition of DPP4 enhanced the renovascular effects
of angiotensinII in hypertensive rats, an observation
that was explained by an increase in the levels of active
forms of substance P, NPY and PYY.181,182 Additionally,
as ACE inhibitors and DPP4 inhibitors inhibit enzymes
with overlapping substrates, interactions between these
agents can occur. Drug interactions are especially likely
when the RAAS is maximally inhibited by ACE inhibitors, as the aforementioned substrates then become highly
dependent on DPP4 degradation. In healthy humans,

sitagliptin attenuated the acute systemic hypotensive
response to a high (but not a low) dose of an ACE inhibitor,183 in parallel with an increase in sympathetic nervous
system activity, possibly resulting from increased levels of
substance P, NPY and PYY.183,184 By contrast, as ARBs do
not affect the substrates of either ACE or DPP4, GLP1independent drug interactions resulting from combined
ARB and DPP4 inhibitor use are highly unlikely.185
Exogenous GLP1 reduced circulating angiotensinII
levels in healthy humans,105,113 although renin and aldo
sterone concentrations remained unchanged.113 In addition, GLP1R agonists inhibited angiotensinII-induced
hypertension in salt-sensitive mice.108,186 Specifically,
GLP1R-mediated increases in intracellular cAMP in
the glomerular endothelium inhibit phosphorylation and
subsequent (post-receptor) actions of the intracellular
mediators of angiotensinII, mitogen-activated protein
kinase (MAPK) 3 and MAPK1 (also known as ERK1
and ERK2, respectively).108,187 These preclinical, singledose human studies should be repeated in patients with
T2DM who are chronically exposed to RAAS-inhibiting
agents and incretin-based drugs, since dual inhibition
or intensive inhibition of the RAAS increases the risk
of adverse renal and cardiovascular events.6770 To date,
however, data from phaseIII studies have not given rise
to such concerns, although the reader should note that
these studies included a high proportion of relatively
low-risk patients.175
Additionally, GLP1R agonist and DPP4 inhibitor use
is associated with the occurrence of pancreatitis and pancreatic cancer,188,189 although no causal relationship has
yet been demonstrated in animal studies or published
outcome trials.178,179,190,191 Although present evidence suggests that incretin-based agents are safe,191 as for all new
drugs, data from ongoing trials, postmarketing surveillance and active research, including the SAFEGUARD
project,192 should provide clarity on long-term safety.
Future perspectives
Whether incretin-based therapies truly improve renal
outcomes in patients with diabetic nephropathy remains
to be demonstrated. The ongoing outcome studies of
GLP1R agonists and DPP4 inhibitors are designed to
examine the cardiovascular and overall safety of incretinbased therapies in patients with T2DM.193-198 Only one
ongoing trial is focused on the effect of DPP4 inhibitors on albuminuria.199 However, not only the incidence
or progression of microalbuminuria, but also clinically
significant renal end points should be included in these
studies, to establish the added value of incretin-based
treatment for diabetic nephropathy. Of special interest is an ongoing randomized, placebo-controlled trial
that seems to be adequately powered to evaluate the
cardiovascular and renal outcomes associated with linagliptin use in patients with T2DM.200 Further studies of
incretin-based drugs that are sufficiently powered, of an
appropriate duration, use relevant antihyperglycaemic
comparator therapies, and have the primary aim of
investigating renal outcomes, might also be needed.
REVIEWS
Conclusions
As the global incidence of T2DM and diabetic nephro
pathy is increasing, and current regimens to treat hyperglycaemia do not adequately prevent diabetes-related
complications, new interventions that could confer
benefits beyond glucose control are eagerly awaited. The
incretin-based therapies, with their various pleiotropic
effects, might represent one such approach to improve
renal and perhaps cardiovascular outcomes. In preclinical
studies, GLP1 and GLP1R agonists improve metabolic
parameters and have beneficial effects on systemicand
renal haemodynamics, as well as on the prevention
andprogression of renal dysfunction and kidney damage.
Interestingly, GLP1R agonists in particular interfere with
multiple metabolic, haemodynamic and proinflammatory
pathways, most of which have a role in the development
of diabetic nephropathy. The DPP4 inhibitors, besides
blocking the degradation of GLP1, also modify levels of
other (vasoactive) peptides that might act on the kidney.
Initial findings in healthy humans and in patients with
1.
2.
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4.
5.
6.
7.
8.
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12.
13.
14.
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T2DM have confirmed some of the potentially beneficial effects of both incretin classes. However, the added
value and true benefit of incretin-based therapies on renal
and cardiovascular end points, as well as their long-term
safety and tolerability, can only be established by the
results of ongoing large, prospective, long-term outcome
trials, which are eagerly anticipated.
Review criteria
The PubMed database was searched for abstracts and
full-text articles published in the English language before
October 2013, using the following keywords: incretin
hormones, incretins, glucagon-like peptide 1,
GLP1RA, dipeptidyl-peptidase IV inhibitors, DPP4,
type2 diabetes mellitus, diabetic nephropathy,
renal and kidney, alone and in combination. We also
searched MEDLINE and PubMed for review articles on
diabetic nephropathy and its current treatment. The
reference lists of identified articles were also searched
for further relevant material.
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Author contributions
M. Diamant, M.H.A. Muskiet and M.M. Smits
researched the data for the article, made a substantial
contribution to discussions of the content, wrote the
article, and reviewed and/or edited the manuscript
before submission. L.M. Morsink made a substantial
contribution to discussions of the content and reviewed
and/or edited the manuscript before submission.
Supplementary information is linked to the online

version of the paper at www.nature.com/nrneph.


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The gutrenal axis: do incretin-based agents

Over the past four decades, the global prevalence of

88 | FEBRUARY 2014 | VOLUME 10

multifactorial strategies for managing T2DM, a residual

Pathophysiology and clinical signs

development of hyperglycaemia. Below we summarize

Early phase of diabetic nephropathy

sodiumglucose co-transporters 1 and 2,14 and sodium

NATURE REVIEWS | NEPHROLOGY

VOLUME 10 | FEBRUARY 2014 | 89

Vasoconstrictors Ang II, ET-1

Macula densa signals

diabetic nephropathy;23 thus, diabetes and hypertension

Late phase of diabetic nephropathy

Outcome parameters (risk)

Microalbuminuria (RR 0.76)

Microalbuminuria (HR 0.91)

Metformin (86.9%) and

Microalbuminuria (HR 0.79)

Rosiglitazone plus metformin

Microalbuminuria (RR 0.74)

The late clinical phase of diabetic nephropathy is charac

Renoprotective strategies for T2DM

participants, the risk of having an impaired estimated GFR

NATURE REVIEWS | NEPHROLOGY

VOLUME 10 | FEBRUARY 2014 | 91

Outcome parameters (renal risk)

Microalbuminuria (RR 0.87)

Microalbuminuria (RRR 21%)*

ACCORD (2010 and

Microalbuminuria (HR 0.84)*

HOPE and MICRO-HOPE

Microalbuminuria (RRR 9%)

Microalbuminuria (AF 0.47)*

Microalbuminuria (HR 0.77)*

Restore albuminuria (RRR 34%||)*

Doubling of SCr (RR 0.67)*

Composite end point (RRR 16%)*

Renal abnormalities (RR 1.86)

Microalbuminuria (HR 1.01 and 0.76#)

death from renal disease).46 Interestingly, a posthoc

placebos), a decrease in blood pressure of 5.6/2.2mmHg

Blood pressure control

92 | FEBRUARY 2014 | VOLUME 10

Potential pleiotropic effects

with RAAS-interfering agents.64,65 As a consequence, the

The incretin system

NATURE REVIEWS | NEPHROLOGY

VOLUME 10 | FEBRUARY 2014 | 93

Use in patients with renal insufficiency

510g twice daily

2mg once weekly

Renal excretion (80%

50mg twice daily or

Elimination: renal (5%);

Elimination: renal (>70%

GIP) exerts glucoregulatory actions via slowing of gastric

was based on the lizard (Heloderma suspectum) peptide

The GLP1 receptor

I-labelled GLP1736 amide receptor autoradiography,

Renal effect of GLP1 and incretin-based agents

rats in response to administration of exogenous GLP1.101