New Data on Cardiovascular Effects of GlucagonLike Peptide-1 Receptor Agonists
CURRENT RESEARCH IN DIABETES & OBESITY JOURNAL JUNIPER PUBLISHER
Abstract
Cardiovascular disease (CV) is the leading cause of
morbidity and mortality in patients with type 2 diabetes. Glucagon-like
peptide-1 receptor agonists are new agents that are very promising
because they affect many cardiovascular risk factors, apart from
improving the glycemic control. Based on the published LEADER and
SUSTAIN-6 trials liraglutide and semaglutide have shown cardiovascular
benefit and could be reasonable options as second line agents for
patients with CV disease. Lixisenatide have been evaluated in one CV
safety trial and has neutral effects on CV outcomes. Individuals without
CV disease can be treated with any of the other classes of
anti-diabetic medication. However, in patients with established CV
disease medications with proven CV benefit should be preferred.
Keywords: Cardiovascular disease; Type 2 diabetes mellitus; Glucagon-like peptide-1 receptor agonists
Abbreviations: CV:
Cardiovascular; UKPDS: UK Prospective Diabetes Study; MI: Myocardial
Infarction; ACCORD: Action To Control Cardiovascular Risk in Diabetes
Study Group; HbAlc: Glycated Hemoglobin; FDA: Food and Drug
Administration; EMA: European Medicines Agency; GLP: Glucagon-Like
Peptide; SGLT: Sodium-Glucose Co-Transporters; ELIXA: Evaluation of
Lixisenatide in Acute Coronary Syndrome ;
HF: Heart Failure; LEADER: Liraglutide Effect and Action in Diabetes:
Evaluation of Cardiovascular Outcome results; SUSTAIN-6: Trial to
Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in
Subjects With Type 2 Diabetes; EXSCEL: Exenatide Study of
Cardiovascular Events Lowering Trial; FREEDOM-CVO: Study to Evaluate
Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated with
ITCA 650; REWIND: Researching Cardiovascular Events with Weekly Incretin
in Diabetes
Introduction
Diabetes mellitus is a metabolic disorder that is characterized by hyperglycemia. Cardiovascular disease (CV)
is the leading cause of morbidity and mortality in patients with
diabetes and hyperglycemia is the link between them [1-3]. The
worldwide rise of incidents of type 2 diabetes is following the
increase of the obesity and makes the prevention of CV disease a primary target [4-6].
Several studies in the past have shown that better glycemic control is
associated with reductions of micro angiopathic complications, but the
cardiovascular effect of strict diabetes control using the older
anti-diabetic medications was not clear [7,8].
The first study that showed that intensive blood
glucose control with sulfonylureas or insulin significantly reduces the
risk of microvascular complications, but has no effect on macrovascular
outcomes was The UK Prospective Diabetes Study (UKPDS) [7].
However, the 10-year follow-up of the UKPDS demonstrated that intensive
blood reduces significantly (by 15%) myocardial infarction (MI) and
therefore, provides macrovascular benefits [8].
On the other hand, the Action to Control Cardiovascular Risk in
Diabetes Study Group (ACCORD) trial reported that although intensive
blood glucose control reduced significantly the risk of MI, it resulted
in an increase of all-cause mortality [9].
However, in this study the HbA1c target was <6% and the arm with the
intensive treatment experienced more hypoglycemic episodes and
consequently, had increased risk of CV disease [10,11].
At the same time, a meta-analysis of the CV safety of
rosiglitazone was published and reported that patients had increased
risk of MI and borderline increased risk of CV death [12]. As a result, the US Food and Drug Administration (FDA) in 2008 [13] and the European Medicines Agency (EMA) in 2012 [14]
reported that new anti-diabetic agents have to perform clinical trials
in order to evaluate the CV safety and gain approval. These trials do
not evaluate the efficacy to the glycemic control, but assess
non-inferiority in lowering CV risk, while superiority is a secondary
endpoint. Generally, these trials recruit patients who are at high CV
risk or have established CV disease in order
to gather a sufficient number of CV events in a timely manner.
Consequently, it is not clear if the findings of CV safety trials can be
generalized to a healthier diabetic population.
Over the last decades the quiver of anti-diabetic
agents has increased significantly and currently we have 9 classes of
medications approved for the treatment of type 2 diabetes: metformin,
sulphonylureas, meglitinides, thiazolidinediones, alpha glucosidase
inhibitors, insulin, dipeptidyl peptidase -4 inhibitors, glucagon-like
peptide (GLP)-1 receptor agonists and sodium-glucose co-transporters
(SGLT-2) inhibitors. The first line agent for the treatment of type 2
diabetes is metformin according to the American Diabetes Association and
the European Association for the Study of Diabetes [15].
However, the choice of the second line agent when metformin fails to
achieve proper glycemic control is still challenging. We have to keep in
mind that the main target of patients with diabetes is the reduction of
diabetic complications and not just the reduction of blood glucose.
The aim of this mini-review is to identify the CV
risk profile of GLP-1 receptor agonists, based mostly on CV safety
trials. We performed a thorough search of MEDLINE and EMBASE between
January 1980 and February 2017 using the terms "antidiabetic agents",
"CV risk", "GLP-1 receptor agonists", alone and in combination to
retrieve available data.
GLP-1 Agonists
GLP-1 receptor agonists are newer anti-diabetic
agents that are administered subcutaneously and act by maintaining the
biological actions of endogenous GLP-1. GLP-1 is a gastrointestinal
hormone that promotes insulin release in a glucose-dependent manner and
inhibits glucagon secretion, thus lowering basal and postprandial blood
glucose. GLP-1 agonists, additionally, promote weight loss by enhancing
satiety, slow gastric emptying and have been found to lower systolic
blood pressure [16].
The main adverse events are gastrointestinal (nausea and vomiting). Due
to those favorable effects on several CV risk factors accompanied with
low hypoglycemia risk, the results of the GLP-1 receptor agonist CV
trial were expected to be exciting.
Lixisenatide was the first GLP-1 receptor agonist
that was evaluated about CV safety in The Evaluation of Lixisenatide in
Acute Coronary Syndrome (ELIXA) trial. The primary composite outcome
was: non-fatal MI, non-fatal stroke, hospitalization for unstable angina
and CV death in patients with type 2 diabetes and an acute coronary
syndrome (MI or unstable angina) within 180 days before randomization [17].
In the study 6.068 patients were randomized and had a median follow up
of 2.1 years. The results showed that treatment with lixisenatide had
neutral effect on the composite primary outcome and on hospitalization
for HF, which was a secondary outcome.
The second trial was the Liraglutide Effect and
Action in Diabetes: Evaluation of Cardiovascular Outcome results
(LEADER). Treatment with liraglutide showed superiority of an
anti-diabetic agent for the primary composite endpoint of CV death,
non-fatal MI or non-fatal stroke [18].
A total of 9.340 patients with type 2 diabetes at high risk of CV
disease were recruited. One arm was receiving placebo and the other was
receiving liraglutide. The median follow up was 3.8 years. Fewer
patients in the liraglutide group experienced any component of the
primary endpoint compared with patients in the placebo group (13%
reduction of the primary composite endpoint), including a significantly
22% lower risk of CV death, a nonsignificant 12% lower risk of non-fatal
MI and a non-significant 11% lower risk of non-fatal stroke.
Furthermore, treatment with liraglutide was also associated with a 15%
lower risk of death from any cause, while hospitalization for HF did not
differ between the two treatment arms of the trial.
Treatment with liraglutide was associated with
greater weight loss as expected. Liraglutide was also associated with a
lower rate of incidence nephropathy, which was a secondary outcome and
was defined as new onset microalbuminuria, doubling of serum creatinine,
need for continuous renal- replacement therapy of death from renal
disease. On the other hand, the incidence of retinopathy was
non-significantly higher in the liraglutide treatment group. The main
adverse events of liraglutide were gastrointestinal disorders and
increases in heart rate. Hypoglycemia was more common in participants
receiving placebo, while acute gallstone disease was more common in
patients receiving liraglutide. Acute pancreatitis, pancreatic cancer
and medullary thyroid carcinoma and did not differ between the two
treatment groups.
The positive effect of liraglutide to the CVD was
mainly attributed to modification of various CV risk factors such as
weight reduction and lowering of systolic blood pressure, apart from the
glucose lowering effect. However, the authors were not able to explain
the different results of the LEADER and the ELIXA trials and it is not
clear yet if the reduction of CV morbidity and mortality is drug
specific for liraglutide or a class effect of GLP- 1 agonists. It should
be taken into account that only subjects with acute coronary syndrome
in the previous three months were recruited in the ELIXA study, while in
the LEADER trial subjects with established CV disease or subjects at
high risk for CV disease were recruited.
The Trial to Evaluate Cardiovascular and Other
Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes
(SUSTAIN 6) was the CV safety trial of one weekly semaglutide and was
published recently. The trial consisted of 3.297 patients with type 2
diabetes and established CV disease, chronic HF, chronic kidney disease
of stage 3 or higher or an age of 60 years or more with at least one CVD
risk factor. The median follow up period was 2.1 years [19].
Patients in the semaglutide treatment arm had a 26% lower rate of the
primary composite endpoint (i.e. CV death, non-fatal MI or non-fatal
stroke) compared with those on placebo. The overall benefit was driven
mostly by a 39% reduction in the occurrence of non-fatal stroke, since
the 26% reduction in the occurrence of MI was not significant and the
rates of CV death were similar between the two treatment groups.
Treatment with semaglutide was not associated with
lower risk of death from any cause or hospitalization for HF, but was
associated with a 36% lower risk of new or worsening nephropathy.
However, diabetic retinopathy complications, such as need for retinal
photocoagulation or intravitreal medications, vitreous hemorrhage and
onset of diabetes related blindness, were more common in patients
receiving semaglutide. Mean heart rate was slightly but significantly
higher in the semaglutide groups compared with the placebo group, but
treatment with the active agent was associated with lower systolic blood
pressure and greater weight loss. The main adverse events of
semaglutide were gastrointestinal adverse effects (nausea and vomiting).
We are eagerly expecting within the next years the
results of several trials assessing the CV safety of different GLP-1
receptor agonists. The Exenatide Study of Cardiovascular Events Lowering
Trial (EXSCEL): A Trial To Evaluate Cardiovascular Outcome After
Treatment With Exenatide Once Weekly In Patients With Type 2 Diabetes
Mellitus [20] and the Study to Evaluate Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated With ITCA 650 (FREEDOM-CVO) [21]
are evaluating the CV safety of exenatide, while The Researching
Cardiovascular Events With Weekly Incretin in Diabetes (REWIND) trial [22] is evaluating the CV safety of once weekly dulaglutide.
Conclusion
Altogether, GLP-1 receptor agonists are promising
anti diabetic agents that effectively lower HbA1c, weight and systolic
blood pressure with low risk of hypoglycemia. Liraglutide and
semaglutide are the first GLP-1 analogs that had favorable effects on CV
outcomes and seem a reasonable second line treatment in patients that
do not reach HbA1c goals with metformin, while lixisenatide has been
shown to be neutral in terms of CV safety. However, the exciting
findings of the LEADER and the SUSTAIN 6 trials need confirmation by
further studies in different study populations in order to have more
robust data and with superiority as a primary outcome.
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