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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
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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
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Insulin resistance
and -cell dysfunction
Obesity
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
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.
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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)
UKPDS (1998)38
New onset
3,867
Sulphonylurea or insulin
10.0
ADVANCE (2008)43
11,140
Gliclazide (90.5%)
5.0
ACCORD (2008
and 2010)41,42
10
10,251
3.5
VADT (2009
and2011)44,45
12
1,791
5.6
*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.
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
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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)
UKPDS (1998)49
2.6
1,148
Intensive versus
standard
8.4
ADVANCE (2007)51
8.0
11,140
Intensive versus
standard
4.3
1.1
4,733
Intensive versus
standard
4.7
11.0
3,577
Ramipril versus
placebo
4.5
BENEDICT (2004)61
8.0
1,204
Trandolapril versus
placebo
3.6
ROADMAP (2011)62
6.0
4,447
Olmesartan versus
placebo
3.2
IRMA2 (2001)63
10.0
590
Irbesartan versus
placebo
2.0
IDNT (2001)64
NR
1,715
Irbesartan versus
placebo
2.6
RENAAL (2001)65
NR
1,513
Losartan versus
placebo
3.4
TRANSCEND (2008)66
NR
5,926
Telmisartan versus
placebo
4.7
DIRECT-Protect 2
(2009)59
9.0
1,905
Candesartan versus
placebo
4.7
*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.
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
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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.
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.
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Table 3 | Pharmacokinetics and pharmacodynamics of incretin-based therapies
Agent
Dose
Halflife
(h)
DPP4
inhibition
Elimination
Severe (eGFR
<30ml/min)
GLP1R agonists
Exenatide
2.4
NA
Glomerular filtration,
proteolytic degradation
Caution
Not recommended
Exenatide
2.4*
NA
Glomerular filtration,
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
Glomerular filtration,
tubular reabsorption and
metabolic degradation
Caution
Not recommended
DPP4 inhibitors
Sitagliptin
100mg daily
8.0
24.0
Max. ~97%
(>80% 24h
post-dose)
Dose reduction
Dose reduction
Vildagliptin
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)
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)
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.
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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.
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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
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BNP/ANP
SP
NPY
PYY
SDF-1
Meprin
HMGB1
DPP-4
inhibitor
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.
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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.
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.
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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.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
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.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
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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.