JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO.

12, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2015.12.058

REVIEW TOPIC OF THE WEEK

Incretin-Based Therapy for Diabetes

What a Cardiologist Needs to Know

Greer Waldrop, MS, Jixin Zhong, MD, PHD, Matthew Peters, MD, Sanjay Rajagopalan, MD

ABSTRACT

Incretin-based therapies are effective glucose-lowering drugs that have an increasing role in the treatment of type 2
diabetes because of their efficacy, safety, and ease of use. Both glucagon-like peptide–1 receptor agonists and dipeptidyl
peptidase–4 inhibitors are commonly used for glycemic control as adjuncts to metformin, other oral antiglycemic agents,
or insulin. Glucagon-like peptide–1 receptor agonists may have additional effects, such as weight loss, that may be
advantageous in obese patients. There is a large body of evidence from randomized controlled clinical trials supporting
the cardiovascular safety of dipeptidyl peptidase–4 inhibitors and some glucagon-like peptide–1 receptor agonists, at
least in the short term. However, concerns have been raised, particularly regarding their safety in patients with heart
failure. In this review, the authors provide a brief but practical evidence-based analysis of the use of incretin-based
agents in patients with diabetes, their efficacy, and cardiovascular safety. (J Am Coll Cardiol 2016;67:1488–96)
© 2016 by the American College of Cardiology Foundation.

T ype 2 diabetes mellitus (T2DM) is character-

ized by progressive decline in beta cell func-
tion and increased risk for cardiovascular
(CV) complications (1). Although diet, exercise, and
[DPP-4i] and glucagon-like peptide–1
agonists [GLP-1Ra]) from randomized controlled trials
published from 2008 onward. The intent is to provide
a succinct overview of the use of these agents for CV
receptor

weight loss are considered central tenets in the practitioners.

management of T2DM, pharmacological approaches
are almost always required. The ease of use of incre-
tin agents, their glycemic efficacy, low to no risk for
hypoglycemia, and ancillary benefits may allow their
earlier incorporation with other evidence-based
therapies in the treatment of T2DM. However, recent
reports of these agents being associated with heart
failure (HF) have created considerable confusion
(2,3). In this review we critically evaluate the
evidence supporting the efficacy (glycemic control,
weight loss, lipoprotein effects, blood pressure [BP],
and CV events) and safety of currently available
incretin agents (dipeptidyl peptidase–4 inhibitors
INCRETINS AND RELEVANCE TO
TYPE 2 DIABETES MELLITUS
Incretins are gut-derived members of the glucagon
superfamily, released in response to nutrient inges-
tion (mainly glucose and fat). Glucagon-like peptide–1
(GLP-1) and gastric inhibitory peptide (GIP) are the
major physiological incretins (4). Secreted by the
small intestine, these peptides amplify the insulin
secretory response to nutrients through their cognate
G protein–coupled receptors in the pancreatic
beta cell (5). Together, GLP-1 and GIP account for

Listen to this manuscript’s

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the Division of Cardiovascular Medicine, University of Maryland Baltimore, Baltimore, Maryland. Dr. Zhong was supported
by grants from the National Institutes of Health (DK105108), the American Heart Association (15SDG25700381 and
13POST17210033), Boehringer Ingelheim (IIS2015-10485), and the Mid-Atlantic Nutrition Obesity Research Center (NORC Pilot &
Feasibility Program). Dr. Zhong has received funding support from Boehringer Ingelheim. Dr. Rajagopalan served as a consultant
to Takeda Pharmaceuticals, Boehringer Ingelheim, and Janssen during the conduct of the study; and has received other fees from
GlaxoSmithKline outside of the submitted work. All other authors have reported that they have no relationships relevant to the
contents of this paper to disclose. Ms. Waldrop and Dr. Zhong contributed equally to this work.

Manuscript received October 5, 2015; revised manuscript received December 11, 2015, accepted December 22, 2015.
JACC VOL. 67, NO. 12, 2016 Waldrop et al. 1489
MARCH 29, 2016:1488–96 Incretin-Based Therapy for Diabetes

50% to 70% of total insulin secreted following an oral These pharmacokinetic considerations may ABBREVIATIONS

glucose load and contribute to the control of post- in part explain effects, such as weight loss AND ACRONYMS

prandial hyperglycemia (4). The effects on insulin
secretion are maintained only until a “normal”
threshold level of plasma glucose is achieved, thus
minimizing risk for hypoglycemia. GLP-1 receptor
signaling involves the activation of adenylyl cyclase
and gastric slowing, with GLP-1Ra that are
BP = blood pressure
not seen with DPP-4i (Table 1). DPP-4 is also
CI = confidence interval
involved in the catalytic inactivation of a
CKD = chronic kidney disease
number of other peptides, which may exert
effects independent of GLP-1 and GIP levels CV = cardiovascular

and cyclic adenosine monophosphate–dependent (Central Illustration) (8). DPP-4 = dipeptidyl-

aminopeptidase-4
activation of protein kinase A, which promote insulin APPROVED INCRETINERGIC AGENTS. The
DPP-4i = dipeptidyl peptidase–
secretion. Recent evidence at physiologically relevant approved agents for the management of 4 inhibitors
concentrations of GLP-1 (picomolar range) provides T2DM and their pharmacology, dosing, FDA = U.S. Food and Drug
evidence of restoration of beta cell competence by adverse effects, and costs are outlined in Administration
these hormones through increased membrane excit- Online Table 1. Exenatide is the 39–amino GFR = glomerular filtration
ability mediated by ion channels (6). The incretin acid synthetic version of exendin-4 (origi- rate
effect is markedly diminished in T2DM because of nally isolated from the Gila monster, a spe- GIP = gastric inhibitory peptide
resistance at the level of the beta cell, except in late cies of venomous lizard native to the GLP-1 = glucagon-like
stages, when there may be a reduction in plasma GLP- southwestern United States) that is resistant peptide–1

1 and GIP levels. Incretins, such as GLP-1, also address to DPP-4 degradation. Exenatide long-acting GLP-1Ra = glucagon-like
hyperglucagonemia in T2DM by inhibiting glucagon release is a depot formulation of exendin-4,
peptide–1 receptor agonists

secretion and reducing hepatic gluconeogenesis. entrapped noncovalently into biodegradable HbA1c = glycated hemoglobin

Finally, pharmacological doses of GLP-1 are well poly- D,L -lactide-co-glycolide microspheres HF = heart failure

known to decrease gastric emptying and appetite from which the drug is gradually released, HR = hazard ratio
through central nervous system mechanisms, thus increasing the half-life to 6 days. Liraglutide OAD = oral antidiabetic drug
contributing to weight loss (Figure 1) (7). is a GLP-1 (7–37) analogue, containing a fatty SU = sulfonylurea

CATALYTIC DEGRADATION OF INCRETINS BY acid chain at a lysine residue in position T2DM = type 2 diabetes
DIPEPTIDYL-AMINOPEPTIDASE-4. Both GLP-1 and 26 through a gamma-glutamyl spacer, mellitus

GIP have short half-lives in vivo (approximately 1 to which facilitates binding to albumin, in- TZD = thiazolidinedione

2 min) and are rapidly degraded to their inactive
forms (GLP-1 [9-36] and GIP [3-42] in humans) by
the peptidase dipeptidyl-aminopeptidase-4 (DPP-4).
DPP-4 is a widely expressed serine peptidase that
inactivates peptides with an alanine, proline, or
serine residue in the penultimate position from the
N-terminus (5). DPP-4 catalytic inhibition elevates
GLP-1 and GIP levels, although the extent of elevation
(picomolar) is small compared with pharmacological
supplementation with GLP-1 analogues (nanomolar).
creasing its half-life. Albiglutide and dulaglutide are
synthetic fusion proteins composed of dimers of
degradation-resistant GLP-1 with a linker protein
that prolongs half-life. There are currently 4
DPP-4i (“gliptins”) approved by the U.S. Food and
Drug Administration (FDA) (Central Illustration). All
gliptins are orally available, low-nanomolar selective
inhibitors and do not interfere with other members
of the DPP family. The plasma half-lives of these
agents do not reflect tissue half-life, as most DPP-4

F I G U R E 1 Glucose-Lowering Effect of Dipeptidyl Peptidase–4 Inhibitors and Glucagon-Like Peptide–1 Analogs

Proglucagon Gastric emptying Glucose absorption

GLP-1[1-37]
Appetite Food intake
GLP-1[1-36-NH2] Glucagon
DPP-4 Inhibitor GLP-1[7-36-NH2] GLP-1R Signaling Insulin
β cell proliferation
Blood glucose
(t1/2 ~ 1 min)
β cell apoptosis

GLP-1 analog
(Resistant to DPP-4
Hepatic glucose production
degradation)

Dipeptidyl peptidase–4 (DPP-4) inhibition preserves gut-derived glucagon-like peptide–1 (GLP-1), resulting in enhanced GLP-1 receptor (GLP-1R) signaling.
DPP-4-resistant GLP-1 analogs directly enhance GLP-1R signaling in multiple organs and reduce glucose via multiple mechanisms. DPP-4 ¼ dipeptidyl
peptidase–4.
1490 Waldrop et al. JACC VOL. 67, NO. 12, 2016

Incretin-Based Therapy for Diabetes MARCH 29, 2016:1488–96

long-acting agents appear to be comparable (17).

T A B L E 1 Effects of Short-Acting Versus Long-Acting Glucagon-Like Peptide–1 Receptor
Agonist Formulations and Dipeptidyl Peptidase–4 Inhibitors on
It may be reasonable to recommend GLP-1Ra in
Key Physiological Parameters combination with metformin, or as an alternative to
other agents, depending on patient preferences, need
Long-Acting GLP-1Ra
Exenatide for weight loss, and potential for side effects (see later
Short-Acting GLP-1Ra Long-Acting, DPP4-i
discussion).
Exenatide Liraglutide, Dulaglutide, Sitagliptin, Saxagliptin,
Short-Acting, Taspoglutide, Linagliptin, Vildagliptin, DOES A GLP-1Ra RESULT IN IMPROVED GLYCEMIA
Effect Lixisenatide Albiglutide Alogliptin
CONTROL AND WEIGHT LOSS COMPARED WITH
HbA1c YY YYY Y
BASAL INSULIN? Patients who cannot manage an
Plasma GLP-1 levels Intermittently Continuously Not consistently
elevated elevated elevated insulin regimen and/or need additional weight loss
Fasting glucose YYY YYY YY may be excellent candidates for GLP-1Ra. In studies
Postprandial glucose YYY YYY YY conducted versus basal insulin (glargine, detemir) in
Gastric emptying Y YY Y No effects
patients receiving 1 or more oral antidiabetic drugs
Body weight YY YY No change
(OADs), GLP-1Ra significantly improved HbA 1c and
Heart rate [ [* No change
Blood pressure Y Y No change
reduced weight compared with insulin (18–22).
Post-prandial Apo48, Y Y Y Adjusted weight loss in the comparator group ranged
free fatty acids from 2 to 5 kg.
and VLDL remnants
CAN A GLP-1Ra BE ADDED TO BASAL INSULIN FOR
*Long-acting analogues tend to have a greater effect on heart rate compared with short-acting analogs. IMPROVED WEIGHT AND GLUCOSE CONTROL? The
DPP-4i ¼ dipeptidyl peptidase–4 inhibitors; GLP-1 ¼ glucagon-like peptide–1; GLP-1Ra ¼ glucagon-like
peptide–1 receptor agonists; HbA1c ¼ glycated hemoglobin; VLDL ¼ very low density lipoprotein.
rationale for combining GLP-1Ra with insulin is based
on complementary pharmacological effects on pran-
dial and fasting glycemia, additional benefits of
is tissue bound. Online Table 2 summarizes agents attenuating weight gain and hypoglycemia, and the
under clinical development, including once-weekly potential of replacing complex basal bolus regimens.
DPP-4i. Addition of GLP-1Ra to insulin (with or without
COMMON QUESTIONS FOR OAD) significantly improved glycemic control in
CARDIOVASCULAR PRACTITIONERS ABOUT placebo-controlled studies and attenuated weight
INCRETIN THERAPIES gain with insulin (23,24).
HOW MUCH HbA 1 C LOWERING CAN BE EXPECTED
WHAT IS THE COMPARATIVE EFFICACY OF GLP-1Ra WITH A DPP-4i? When used as monotherapy, as
ON GLYCEMIA LOWERING AND WEIGHT LOSS? initial combination therapy, or in conjunction with
Both short-acting and long-acting GLP-1Ra as mono- 1 or $2 OADs, DPP-4i provided incremental glycemic
therapy significantly reduce glycated hemoglobin lowering of 0.4% to 1.1%. A previous meta-analysis
(HbA1c) by 0.4% to 1.6%, improve fasting and post- showed that the degree of glycemia lowering is
prandial hyperglycemia, and increase the proportion similar with the various approved agents (25).
of participants reaching an HbA 1c target of #7%. Compared with metformin monotherapy, DPP-4i
When compared head to head against DPP-4i or were associated with a smaller decline in HbA 1c and
sulfonylurea (SU) in patients in whom metformin a lower chance of attaining the HbA1c goal of <7%
failed or when metformin was used as an adjunctive (26,27). When compared with SU (on metformin
therapy, GLP-1Ra achieved greater HbA1c lowering regimens), DPP-4i demonstrated inferior HbA1c
with additional weight loss (9–13). When compared lowering in short-term studies (28–31). In studies
against metformin or thiazolidinediones (TZDs), >52 weeks in duration, DPP-4i, although noninferior,
GLP-1Ra may provide 0.2% to 0.6% incremental HbA1c showed more HbA 1c lowering (32). One possible
lowering (10,14–16). Weight loss with both explanation is that over longer durations, DPP-4i may
short-acting and long-acting GLP-1Ra ranges from allow better glycemic control, in part because of
1.4 to 4 kg, at the end of 6 months compared with secondary failure of SU (33). In studies comparing
baseline weight (9–13). Weight loss is seen as early as DPP-4i with SU, DPP-4i have been associated with
4 weeks, with a plateau after 4 to 6 months (9). In modest weight loss and substantially lower risk for
a large meta-analysis of all GLP-1 trials up to 2011 hypoglycemia (28–32,34). Compared with TZDs,
(21 trials, 6,411 participants), the weighted mean DPP-4i may provide poorer glycemic control but
difference following GLP-1Ra therapy was 2.9 kg are weight neutral compared with weight gain with
(95% confidence interval [CI]: 3.6 to 2.2 kg). TZDs (10,15). In trials comparing DPP-4i versus so-
The weight-loss effects of short-acting versus dium glucose cotransporter 2 inhibitors, either alone
JACC VOL. 67, NO. 12, 2016 Waldrop et al. 1491
MARCH 29, 2016:1488–96 Incretin-Based Therapy for Diabetes

CENTRAL I LLU ST RAT ION Incretin-Based Therapy: GLP-1-Dependent and GLP-1-Independent Cardiovascular Effects of
Dipeptidyl Peptidase–4 Inhibitors

GLP-1R Preservation of
DPP-4 Inhibitor Independent Substrates
Actions (e.g., SDF-1, BNP,
NPY, PYY)
Proglycagon

GLP-1 [1-37]

GLP-1 [1-36-NH3]
Angiogenesis
No Change in Blood Pressure Reduction of
GLP-1[7-36-NH3] GLP-1R Signaling No Change in Body Weight CV Events?
Blood Glucose
Postprandial Lipoprotein

Body Weight
Blood Pressure
GLP-1R Analog GLP-1R Signaling Blood Glucose Reduction of
CV Events?
(Resistant to DPP-4 (Superphysiological) Postprandial Lipoprotein
Degradation) Heart Rate

Waldrop, G. et al. J Am Coll Cardiol. 2016; 67(12):1488–96.

Incretin-dependent cardiovascular (CV) effects of dipeptidyl peptidase–4 inhibitors (DPP-4i) and glucagon-like peptide–1 receptor agonists (GLP-1Ra) involve
modulation of body weight, blood pressure, blood glucose, heart rate, and postprandial lipoprotein level (5,8,66,67). Incretin-independent effects may be mediated by
multiple nonincretin substrates of dipeptidyl peptidase–4 (DPP-4). BNP ¼ B-type natriuretic peptide; EU ¼ European Union; FDA ¼ U.S. Food and Drug Administration;
GLP-1 ¼ glucagon-like peptide–1; GLP-1R ¼ glucagon-like peptide–1 receptor; NPY ¼ neuropeptide Y; PYY ¼ peptide YY; SDF-1 ¼ stromal cell–derived factor 1.

or on top of metformin with or without SU, sodium
glucose cotransporter 2 inhibitors were superior, with
more patients attaining the HbA 1c goal of <7% with
weight loss (35).
CAN DPP-4i BE ADDED TO INSULIN? When used in
conjunction with insulin with or without 1 OAD,
DPP-4i provide significant incremental glycemic
lowering, with attenuation of weight gain incurred
with insulin (36–39). Thus, these agents can be used
in conjunction with insulin, although there is
evidence that efficacy diminishes in patients on
multiple OADs with long duration of T2DM (40).
CAN DPP-4i OR GLP-1Ra BE USED IN PATIENTS WITH
CHRONIC KIDNEY DISEASE? DPP-4i are an accept-
able treatment option in the presence of chronic
kidney disease (CKD) for glycemic lowering, espe-
cially when other OADs are contraindicated. This is a
major advantage for this class of drugs. With the
exception of linagliptin, however, all other approved
DPP-4i require dosing adjustments. Exenatide and
exenatide long-acting release are contraindicated in
patients with CKD with glomerular filtration rates
(GFR) <30 ml/min (Online Table 1). Liraglutide is
hepatically metabolized and can be used in patients
with CKD, although there is limited evidence in those
with advanced CKD.
CARDIOVASCULAR SAFETY AND EFFICACY
OF INCRETINERGIC AGENTS
FDA regulatory guidance around the CV safety of
antidiabetic agents has necessitated CV outcomes
trials in T2DM (41). Prior to the FDA guidance, a
number of studies assessed surrogate markers, which
included lipoprotein measures, BP, heart rate, and
biomarkers of relevance, as ancillary measures in
glycemia-lowering trials.
1492 Waldrop et al. JACC VOL. 67, NO. 12, 2016

Incretin-Based Therapy for Diabetes MARCH 29, 2016:1488–96

DO INCRETIN THERAPIES REDUCE POSTPRANDIAL
LIPOPROTEINS? Prior reviews have also provided
detailed discussions of the lipoprotein effects of
GLP-1Ra and DPP-4i (5,8). Although earlier small, brief
studies have shown reductions in very low density and
remnant lipoproteins via GLP-1-mediated reduction in
absorption of triglycerides and synthesis of Apo48
lipoproteins, often even with 1 dose, there has been
only 1 double-blind study assessing postprandial lipids
conducted for >12 weeks. This showed a 43% reduction
in postprandial triglycerides and a 50% reduction in
postprandial chylomicrons (42). In the SCALE (Effect
of Liraglutide on Body Weight in Overweight or
Obese Subjects With Type 2 Diabetes) double-blind
randomized controlled trial, there were reductions in
triglycerides, along with lower C-reactive protein and
weight loss with liraglutide (43).
DO GLP-1Ra AND DPP-4i LOWER BP? Clinical trials
assessing the glycemic efficacy of GLP-1Ra have
observed a small decrease in office systolic BP of 2 to
4 mm Hg when compared with placebo (14,24,44).
This has been replicated in meta-analyses that have
shown 2 to 2.5 mm Hg reductions in systolic BP
(45,46). However, these findings have not always
been replicable (12,44,47). In the only ambulatory BP
trial to test the effect of GLP-1Ra, dulaglutide 1.5 mg
significantly reduced mean 24-h systolic BP by about
3 mm Hg. The decrease in BP was accompanied by an
increase in pulse rate of 2 to 3 beats/min (48). The
effects on pulse rate have been noted with both short-
and long-acting agents against placebo (14,24,43).
The mechanisms responsible for BP lowering with
GLP-1Ra may relate to increased
atrial natriuretic peptide, natriuresis, and vascular
relaxation (49). However, evidence of increases in
atrial natriuretic peptide in humans with GLP-1Ra
administration is lacking at this time (50). The
mechanisms for the increase in heart rate are
currently unclear (51,52).
DO INCRETINERGIC AGENTS ALTER CV OUTCOMES?
There have been 4 randomized, double-blind,
placebo-controlled clinical trials (3 for DPP-4i and
1 for GLP-1Ra) that have evaluated hard CV endpoints
with incretin agents (Table 2). All 4 trials were designed
not as glycemia-lowering studies but rather to estab-
lish CV safety. Optimization of the glycemic regimen
was allowed in the placebo arm. The SAVOR (Sax-
agliptin Assessment of Vascular Outcomes Recorded in
Patients With Diabetes Mellitus) trial tested sax-
agliptin (5 mg/day, 2.5 mg if GFR #50 ml/min) versus
placebo in patients with established CV disease or
major risk factors over approximately 25 months (53).
The study was designed as a superiority trial, with a
pre-specified noninferiority comparison. Saxagliptin
was not superior to placebo but met the noninferiority
criterion. The EXAMINE (Exploring the Cardio-
vascular Safety of Therapies for Type 2 Diabetes) trial
compared alogliptin (25 mg/day or 6.25 to 12.5 mg if
GFR <60 ml/min) versus placebo in acute coronary
syndrome (54). Major adverse CV events were similar
with alogliptin and placebo (54). TECOS (Trial to
Evaluate Cardiovascular Outcomes after Treatment
With Sitagliptin) assessed the effect of sitagliptin
(100 mg/day, or 50 mg if GFR ¼ 30 to 50 ml/min)
in established CV disease, whereas in ELIXA (Evalua-
synthesis of tion of Lixisenatide in Acute Coronary Syndrome),

T A B L E 2 Cardiovascular Outcome Trials of Incretin Therapies

Study Design/Duration
Study (Weeks) Background OAD Therapy Intervention Arms Dosage Outcome Parameters

Outcome: cardiovascular death, nonfatal myocardial infarction, or stroke (primary efficacy endpoint)
Scirica et al. (53), SAVOR-TIMI RCT/DB/104 MET, insulin, SU, alone Saxagliptin 5 or 2.5 mg† HR: 1.00 (95% CI: 0.89–1.12)
or in combination (n ¼ 8,280) (p ¼ 0.99)
Placebo (n ¼ 8,212)
White et al. (54), EXAMINE RCT/DB/160 MET, SU, insulin, or TZD alone Alogliptin 25/12.5/6.25 mg† HR: 0.96 (95% CI: 1.16*)
or in combination (n ¼ 2,701) (p ¼ 0.32)
Placebo (n ¼ 2,679)
Outcome: cardiovascular death, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina (primary efficacy endpoint)
TECOS (55) RCT/DB/156 MET, SU, insulin, or TZD alone Sitagliptin 100 or 50 mg† OR: 0.98 (95% CI: 0.88–1.09)
or in combination (n ¼ 7,332) (p < 0.0001)
Placebo (n ¼ 7,339)
ELIXA (56) RCT/DB/108 MET, TZD, insulin, Lixisenatide 10–20 mg OR: 1.02 (95% CI: 0.89–1.17)
glinide, or SU alone (n ¼ 3,034)
or in combination Placebo (n ¼ 3,034)

*Upper boundary of the 1-sided repeated CI at an alpha level of 0.01. †Dosage reduced on the basis of glomerular filtration rate.
CI ¼ confidence interval; DB ¼ double-blinded; ELIXA ¼ Evaluation of Lixisenatide in Acute Coronary Syndrome; EXAMINE ¼ Exploring the Cardiovascular Safety of Therapies for Type 2
Diabetes; HR ¼ hazard ratio; MET ¼ metformin; OAD ¼ oral antidiabetic drug; OR ¼ odds ratio; RCT ¼ randomized controlled trial; SAVOR-TIMI ¼ Saxagliptin Assessment of Vascular Outcomes
Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction; SU ¼ sulfonylurea; TECOS ¼ Trial to Evaluate Cardiovascular Outcomes After Treatment With Sitagliptin;
TZD ¼ thiazolidinedione.
JACC VOL. 67, NO. 12, 2016
MARCH 29, 2016:1488–96
lixisenatide (10 to 20 m g) was compared with placebo in
patients post–acute coronary syndrome (55,56). There
are 5 ongoing randomized controlled trials of incretin
therapies that will report in the near future (Online
Table 3).
IS HF WITH DPP-4i A CLASS EFFECT? An unex-
pected finding in SAVOR was an increased incidence
of HF hospitalization (a pre-specified endpoint)
with saxagliptin compared with placebo (3.5% vs.
2.8%; hazard ratio [HR]: 1.27; 95% CI: 1.07 to 1.51),
without excess HF-related mortality (53). Previous
HF, estimated GFR <60 ml/min, elevated B-type
natriuretic peptide, and albumin/creatinine ratio
were the strongest predictors of HF hospitalization.
This excess HF risk was not noted with alogliptin or
lixisenatide, both of which were in a high-risk acute
coronary syndrome patient population, assuaging
concerns that incretin agents, as a class, were caus-
ative. In EXAMINE, the first occurrence of hospitali-
zation for HF occurred in 3.1% and 2.9% of the
alogliptin and placebo groups, respectively (HR: 1.07;
95% CI: 0.79 to 1.46; p ¼ 0.68) (57). There was no
excess of CV death. In TECOS, the hospitalization
rate for HF was identical with sitagliptin and placebo
(3.1% vs. 3.1%; HR: 1.00; 95% CI: 0.83 to 1.20;
p ¼ 0.98) (55). Lixisenatide also showed similar
hospitalization for HF compared with placebo (HR:
0.96; 95% CI: 0.75 to 1.23) in ELIXA. On the basis of
these trials, it is safe to conclude that the HF risk is
small and is associated mainly with saxagliptin. The
risk for HF with other GLP-1Ra remains to be
determined.
ADVERSE EVENTS ASSOCIATED WITH
INCRETIN AGENTS
DOES HYPOGLYCEMIA OCCUR WITH INCRETIN
THERAPIES? The risk for hypoglycemia is low with
both GLP-1Ra and DPP-4i and comparable with pla-
cebo when used as monotherapy or in combination
with metformin or TZD. In the 3 large randomized
controlled clinical trials on a background of multiple
oral hypoglycemic agents, rates of serious hypogly-
cemia were comparable with placebo (53–55). The risk
for hypoglycemia with DPP-4i and GLP-1Ra is nearly
always with concomitant SU therapy and is higher in
older patients. Thus, dose reduction of SU must be
considered when initiating a GLP-1Ra or DPP-4i
regimen in older patients (58,59). The risk for severe
hypoglycemia when GLP1Ra are combined with
insulin is low (20,36).
WHAT GASTROINTESTINAL SIDE EFFECTS ARE
COMMON WITH GLP-1Ra? Nausea and vomiting,
presumably related to the effects of GLP-1Ra on
Waldrop et al. 1493
Incretin-Based Therapy for Diabetes
gastrointestinal slowing, are common, decrease over
time, and occur more frequently with the shorter
acting preparations (exenatide > liraglutide > exe-
natide long-acting release ¼ dulaglutide > albiglu-
tide) (52,60–62). The mechanism appears to be
related to GLP-1Ra pharmacokinetics, with abate-
ment when steady-state levels are attained. Gastro-
intestinal side effects are uncommon with DPP-4i
(Online Table 1).
HOW OFTEN DO INJECTION-SITE REACTIONS
OCCUR WITH GLP-1Ra? Reactions at the injection
site (nodules) are common with the longer acting
agents and typically subside by 3 to 4 weeks (10%
to 30% of patients with longer acting agents, such
as exenatide long-acting release vs. <5% with
short-acting analogs) (Online Table 1).
WHAT IS THE RISK FOR PANCREATITIS AND
MEDULLARY CARCINOMA OF THE THYROID? There
is no indication of excess risk with pancreatitis or
pancreatic cancer in the 3 large trials with DPP-4i
(53–55) and the single trial with GLP-1Ra, although
the duration of follow-up might not be long enough to
rule out a signal. According to a joint FDA–European
Medicines Agency statement, there was no evidence
that incretin therapy in humans is associated with C
medullary thyroid cancer in humans (63).
DISCUSSION
Incretin-based therapies have an increasing role in
the management of T2DM. The American Diabetes
Association and European Association for Study of
Diabetes, the American Association for Clinical
Endocrinology guidelines, and International Diabetes
Federation guidelines recommend that GLP1a or
DPP-4i be considered as alternatives to metformin or
as combination therapy with metformin when glyce-
mic targets are not reached (Online Table 4). An
excellent indication for these agents is when met-
formin, SU, or pioglitazone is contraindicated or not
tolerated or when avoidance of hypoglycemia and/or
weight gain is a priority. A GLP-1Ra may be recom-
mended over a DPP-4i when weight loss is a priority
(i.e., body mass index >30 kg/m 2) and if greater re-
ductions in HbA 1c are desired. A general approach
that may work well in many patients requiring com-
bination strategies is to include a DPP-4i or GLP1
agonist as part of the regimen on the basis of patient-
specific factors. In older patients at risk for hypogly-
cemia or in patients with CKD, a DPP-4i may be a good
choice, either alone or in combination with other
agents. A DPP-4i or GLP-1a may also be used effec-
tively in conjunction with TZDs, SUs, and sodium
glucose cotransporter 2 inhibitors. In addition, DPP-4i
1494 Waldrop et al. JACC VOL. 67, NO. 12, 2016

Incretin-Based Therapy for Diabetes MARCH 29, 2016:1488–96

or GLP-1Ra may be considered as adjunctive therapy
with basal insulin regimens in lieu of other, more
complicated regimens.
Although an important consideration for antidia-
betic agents is their CV benefit, this has not been seen
within the duration (2 to 4 years) of currently
designed studies (64). However, it is possible that
more delayed benefits may still occur (64). When
considering treatments with potential delayed bene-
fits, the costs, treatment burden, and adverse effects
become especially important. Treatment burden and
adverse effects can have an appreciable negative
impact on patient quality of life, with prior studies
showing that interventions with a high treatment
burden for treating glucose (“glycemic disutility”)
may substantially attenuate benefit, as measured by
quality-adjusted life-years (65). At the present time,
clinicians should focus the treatment approach
around the patient, with individual preferences, pa-
tient disease variables, and other factors (i.e., cost)
also being considered, once glucose management
targets are set.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Sanjay Rajagopalan, Division of Cardiovascular
Medicine, University of Maryland, 20 Penn Street,
Baltimore, Maryland 21201. E-mail: srajagopalan@
medicine.umaryland.edu.

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KEY WORDS cardiovascular outcomes,
dipeptidyl peptidase–4, glucagon-like
peptide–1 receptor agonist
A PPE NDI X For supplemental tables and
references, please see the online version of this
article.