Cardiovascular Effects of the

DPP-4 inhibitors

Journal Reading
Yunita Iskandar
 Abstract

Type 2 Diabetes continues to rise in prevalence throughout the

globe, and cardiovascular diseases remain the most common
cause of morbidity and mortality among patients.
Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a newer class of
oral anti-hyperglycemic agents whose effect is mediated
through the incretin hormones, GLP-1 and GIP.
In this review, we discuss the incretin system, DPP-4 inhibitors
and their mechanism of action and, principally, the potential
impact of DPP-4 inhibition on the cardiovascular system.
However, the relationship between DPP-4 inhibition and actual
cardiovascular outcomes remains unknown.
 Introduction

The global prevalence of type 2 diabetes mellitus (T2DM)

continues to increase at an alarming rate, with cardiovascular
disease being the most common cause of mortality and morbidity
in affected patients.
Regulatory agencies actually now mandate that all new glucose-
lowering medications undergo thorough cardiovascular safety
assessment before marketing approval.
In this review, we will discuss a newer class of incretin-based
therapy, the DPP-4 (dipeptidyl peptidase-4) inhibitors their
mechanism of action, expected results on glycaemic parameters
and potential impact on the cardiovascular system.
 The incretin system: An overview

Early studies showed that oral carbohydrate consumption was

associated with greater pancreatic insulin secretion when
compared with an equivalent amount of glucose administered
intravenously. This phenomenon was subsequently coined the
incretin effect and has been estimated to account for up to 50
70% of mealtime insulin output.
Thus far, two incretin hormones have been identified: glucagon-
like peptide-1 (GLP-1), derived from the L-cells of the distal small
intestine and large bowel, and glucose-dependent insulinotropic
polypeptide (GIP), derived from the K-cells of the proximal small
intestine.
 Effects of GLP-1 include suppression of post-prandial glucagon
secretion from pancreatic alpha-cells, slowing of gastric
emptying through effects on the vagus nerve, and
enhancement of satiety at a hypothalamic level leading to
reduced food intake.
G-protein coupled receptors for GLP-1 are present in several
tissues beyond the pancreas, gastrointestinal tract and
nervous system, including cardiac myocytes, although their
physiological purpose(s) at these other sites remains largely
unknown.
 The enzyme dipeptidyl peptidase-4 (DPP-4) rapidly degrades
both GLP-1 and GIP to their inactive metabolites.
Competitive inhibition of DPP-4 increases the half-life and
bioavailability of active incretin hormones.
Presently, the available incretin-based therapies for diabetes
mellitus include the GLP-1 receptor agonists and DPP-4
inhibitors; the mechanisms of action of both involve the
potentiation of the endogenous effects of GLP-1.
GLP-1 receptor agonists are injectable peptides whereas the
DPP-4 inhibitors are oral agents.
Physiology of the incretin system. After meal ingestion, as blood glucose levels rise, neuroendocrine cells of the intestine secrete
the incretin hormones GLP-1 and GIP. Both stimulate insulin secretion by pancreatic beta cells, in a glucose dependent fashion. GLP-1
additionally decreases glucagon secretion from pancreatic alpha-cells, slows gastric emptying and increases satiety, allowing for
reduced food intake. Physiologically, the enzyme dipeptidyl peptidase(DPP)-4 rapidly degrades both GLP-1 and GIP to their inactive
metabolites. Pharmacological competitive inhibition of DPP-4 increases the half-life and bioavailability of active incretin hormones.
 DPP-4 inhibitors: Mechanisms and
clinical effects

DPP-4 is a 766 amino acid transmembrane glycoprotein, also

known as adenosine deaminase complexing protein 2 or CD26.
DPP-4 is expressed on the surface of several cell types, including
monocytes and lymphocytes. It is a serine aminopeptidase
enzyme which inactivates GLP-1, GIP.
Protein dimerisation is needed for catalytic activity, and
physiological function of the enzyme depends on its glycosylation.
Importantly, DPP-4 substrates are extensive and include several
proline or alanine containing peptides, such as growth factors,
chemokines, neuropeptides and vasoactive peptides.
 The currently available DPP-4 inhibitors include sitagliptin,
saxagliptin, linagliptin, vildagliptin and alogliptin.
Saxagliptin, sitagliptin and vildagliptin are hepatically metabolised
and renally eliminated.
Linagliptin is primarily excreted via non-renal pathways with
minimal hepatic metabolism; therefore dose adjustments are not
needed in the setting of renal or liver disease.
With daily doses ranging from 100 mg for sitagliptin to 5 mg for
saxagliptin and linagliptin, the drugs are all similar in their efficacy
in lowering HbA1c levels, safety profiles and patient tolerance.
DPP-4 inhibitors result in a mean decrease in A1c ranging between
0.5% and 1%.
 In clinical trials, the most commonly reported adverse effects
associated with DPP-4 inhibitor therapy included nasopharyngitis,
upper respiratory tract infection, urinary tract infection and
headache. Urticarial dermatological reactions and angioedema have
also been reported.
Rarely, pancreatitis may occur, although it remains unclear whether
this is actually an adverse effect of the medications themselves,
since this condition is seen with increased frequency in patients
with T2DM.
Generally speaking, the DPP-4 inhibitors are well tolerated and in
contrast to certain other anti-diabetic agents, not associated with
hypoglycaemia, weight gain, gastrointestinal symptoms or
peripheral oedema.
 Currently, the drugs are predominately used as second- or
third-line agents, typically after metformin or the
combination of metformin-sulfonylurea or metformin-
thiazolidinedione.
Fixed-dose combination tablets with metformin are now
available for several of the aforementioned compounds.
They are also approved for use as monotherapy, mainly
used in this setting in those who cannot tolerate or have
active contraindications to metformin (e.g. chronic kidney
disease).
 Cardiovascular effects of GLP-1

GLP-1 has been found to be cardioprotective in experimental models of

heart failure and myocardial infarction (MI).
In a clinical study led by Nikolaidis, the investigators compared in-hospital
outcomes of 22 high-risk patients with recent acute MI, left ventricular (LV)
dysfunction and successful reperfusion. GLP-1 infusion was associated with
an improved LV ejection fraction and improved contractility, measured 6
12 hours post-infusion.
Several studies have also suggested that GLP-1 agonists ameliorate
cardiovascular risk factors, such as blood pressure and lipid profiles.
We would caution, however, that these effects have been proposed to be
secondary to the weight loss seen with GLP-1 agonists, an effect not
observed with DPP-4 inhibition.
 Cardiovascular effects of DPP-4
inhibition

Read et al. tested whether increasing the plasma concentrations of

GLP-1 by DPP-4 inhibition could protect the heart from ischaemic
left ventricular dysfunction during dobutamine stress
echocardiography (DSE) in patients with ischaemic heart disease.
In addition to potential cardiac benefits possibly mediated through
GLP-1, DPP-4 inhibitors may also possess direct effects on the heart
and on cardiovascular risk factors, independent of the incretin
system.
One such mechanism may involve improved signalling through the
bone marrow chemokine known as stromal cell-derived factor
(SDF)-1 alpha.
 Endothelial progenitor cells (EPCs), derived from the bone
marrow, are known to promote vascular repair and
neoangiogenesis.
Importantly, one of the regulators of EPCs is SDF-1 alpha,
which actually stimulates their mobilisation. Since SDF-1
alpha is a known substrate for DPP-4, DPP-4 inhibition will
increase SDF-1 alpha concentrations, potentially enhancing
the delivery of EPCs to injured endovascular sites.
 DPP-4 inhibition and effects on
cardiovascular risk factors
Several other clinical studies have studied the potential effect of DPP-4
inhibitors on cardiovascular risk factors, such as hypertension and
hyperlipidaemia.
Shah et al. have shown that inhibition of DPP-4 within the microcirculation
relaxes vascular tone through the direct mediation of the nitric oxide
system.
The investigators proposed that the effect of this drug class on vascular
relaxation might promote better control of blood pressure, an important
cardiovascular risk factor. Yet, in most DPP-4 trials in humans, no consistent
effect on blood pressure.
In general, no notable effects of the DPP-4 inhibitors have been
demonstrated on circulating lipid concentrations in human clinical trials.
Clearly, more studies will need to be done to elucidate the balance of effects
of DPP-4 inhibition on cardiovascular risk factors.
 DPP-4 inhibitors and cardiovascular
outcomes
Studies evaluating the effects of DPP-4 inhibitors on actual cardiovascular
events are even more limited, and their findings should be considered highly
preliminary.
A recent meta-analysis by Lamanna and colleagues, presented at the 2011
Annual Meeting of the European Association of the Study of Diabetes
(EASD), was conducted to assess cardiovascular safety of the DPP-4
inhibition as a treatment strategy.
DPP-4 inhibitors, compared with placebo or other treatment, were
associated with a relatively robust 31% reduced risk of major cardiovascular
events.
The numbers of events in these trials, which were designed primarily to
assess for antihyperglycaemic efficacy, are obviously small.
Yet, the consistent finding of HRs < 1.0 is provocative and suggests the need
for larger and longer-term trials.
 Conclusion
DPP-4 inhibitors are a newer class of oral anti-hyperglycaemic
agents with demonstrated efficacy in the treatment of T2DM.
Some pre-clinical data, small mechanistic studies and post-hoc
analyses of randomised clinical trials suggest a possible beneficial
effect on cardiovascular risk.
However, the actual relationship between DPP-4 inhibition and
actual cardiovascular outcomes remains unknown.
To address this uncertainty, and also to satisfy recent regulatory
requirements to ensure cardiovascular safety of all new diabetes
drugs, several large clinical trials involving several DPP-4 inhibitors
and cardiovascular outcomes are now underway. Together, these
trials will allow investigators to learn about the potential
cardiovascular impact of these newer glucose-lowering drugs.
Thank you..