CV Risk in Diabetes

1. Looking Ahead at EASD 2015: CV Risk and T2DM
Faculty and Disclosures
Posted 11/09/2015
CPD accreditation is pending Faculty of Pharmaceutical Medicine Review.
This educational activity is intended for an international audience of non-US healthcare professionals, specifically
diabetologists, endocrinologists, general practitioners, primary care physicians, cardiologists, and other healthcare
professionals involved in the care of patients with type 2 diabetes mellitus (T2DM).
The goal of this activity is to recognize the scope of clinical research being presented at the European Association for
the Study of Diabetes (EASD) 2015 annual meeting regarding CV risk management in T2DM.
Upon completion of this activity, participants should be able to:
1. Appraise the landscape of cardiovascular (CV) outcomes trials in type 2 diabetes mellitus (T2DM)
2. Evaluate the latest evidence related to antihyperglycemic therapy and CV risk in patients with T2DM as
presented at the 2015 European Association for the Study of Diabetes annual meeting
Looking to EASD 2015
This year's Annual Meeting of the European Association for the Study of Diabetes (EASD), which will be held in
Stockholm, Sweden from September 14 to 18, takes place during an exciting time for diabetes research.[1] This is
reflected in the breadth and quality of scientific programs, with 1209 abstracts accepted from the more than 2000 that
were submitted. The EASD Annual Meeting has become the world's leading forum for diabetes research and
medicine; last year's meeting attracted more than 17,000 participants from 132 countries.[2] The Annual Meeting
program provides high-quality education and professional development opportunities for students, researchers,
clinicians, nurses and other healthcare professionals who care for people with diabetes. It includes 6 concurrent live
sessions, as well as poster sessions, symposia, and keynote lectures.[1] The Annual Meeting provides an excellent
opportunity to highlight key developments in diabetes research from around the world, across a variety of disciplines.
New data on the cardiovascular (CV) effects of antihyperglycemic agents will be presented, including the results
from the EMPA-REG OUTCOME study. It is an important part of the global effort to improve the diagnosis and
management of diabetes and improve the quality of life of the 382 million currently living with the disease.[3]
Risk for CVD in People With T2DM

2. The relationship between type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) is well established.
Multiple studies have demonstrated that T2DM is a major independent risk factor for CVD, including myocardial
infarction (MI), stroke, peripheral vascular disease, and heart failure.[4,5] Most people with T2DM are at a high risk
for future CV events. A 2010 meta-analysis of almost 700,000 people from 102 prospective studies found that people
with diabetes had a twofold increase in risk of developing coronary heart disease and stroke compared with those
without diabetes, and that this was independent of other conventional CVD risk factors.[6] CVD is the most common
cause of death among people with the disease, accounting for up to 70% of all deaths.[7]
For most patients, T2DM occurs in the context of the metabolic syndrome.[8,9] They commonly have abdominal
obesity, hypertension, elevated fasting plasma glucose, hyperlipidemia, and comorbidities, such as chronic kidney
disease. Strategies to treat T2DM must focus on these modifiable risk factors.[10]
Hyperglycemia is a significant contributor to CVD. In the Norfolk cohort of the European Prospective Investigation
into Cancer and Nutrition (EPIC-Norfolk), each 1% increase in glycated hemoglobin (HbA1c) was associated with a
40% increase in CV mortality in people with diabetes.[11]
CVD Prevention in T2DM
Glycemic control is a cornerstone of therapy for T2DM, aiming to reduce HbA1c levels without inducing
hypoglycemia.[12,13] However, its effect on CV outcomes has been the subject of much debate in recent decades. A
landmark CV outcomes trial was the UK Prospective Diabetes Study (UKPDS) which studied newly diagnosed
T2DM patient with a low risk for CVD, treated with different drugs, including metformin, sulfonylurea (SU) and
insulin. It concluded that intensive glycemic control was associated with a reduction in CV events, and a 10-year
follow-up study confirmed this finding.[14,15] Other recent CV outcomes trials have produced more controversial
results. The ADVANCE trial,[16] the ACCORD trial,[17] and the VADT[18] studied patients with a high risk for CVD,
but reported no significant decrease in primary CV endpoints with intensive glucose control. In fact the ACCORD
trial was terminated after an association was found between intensive glycemic control and an increase in all-cause
mortality. However, it is possible that rapidly attaining aggressive HbA1c targets (<6%) may have contributed to this
outcome. It also is possible that in these trials the potential benefits of intensive glucose-lowering therapy were offset
by the adverse consequences of hypoglycemia and the limitations of what are now considered older
antihyperglycemic agents. For example, SUs are associated with a high risk for hypoglycemia and, in the ACCORD
trial, the rate of severe hypoglycemia was threefold higher among patients in intensive therapy group compared with
the control group. Thiazolidinediones (TZD) are associated with an increased risk for heart failure, and links between
the TZD, rosiglitazone, and an increased risk for MI have been reported.[13] The long-term follow up of the VADT
trial was published in 2015, and reported a 17% (HR 0.83) reduction in the primary outcome of time to first major
CV event.[19]
The fact that the specific role of intensive glycemic control in reducing CV events is still poorly understood underlies
the importance of physicians adopting a patient-centered approach to the management of hyperglycemia in their
patients with T2DM.[12,13] Treatment strategies should take account of the patient's age, disease duration, co-
morbidities and lifestyle, as well as other patient-specific factors and the profiles of available antihyperglycemic
agents. The leading treatment guidelines recommend glycemic targets ranging from 6.0% to 7.0% for most patients,
provided they can be achieved without adverse outcomes such as hypoglycemia.[13,20] For example, in its 2015 update
the American Diabetes Association (ADA)/ EASD recommends an HbA1c target of <7% for the majority of patients,
and a more stringent one (6.0%-6.5%) in those with a short disease duration and no significant CVD. By contrast it

3. recommends less stringent targets (7.5% -8.0% or more) with a history of severe hypoglycemia and extensive co-
morbidities such as CVD.[13]
Most guidelines recommend a stepwise approach to managing T2DM, starting with lifestyle modifications and
progressing to anti-hyperglycemic agents, with treatment being intensified once it becomes clear that glycemic targets
are not being met.[13,20] A critical aspect of managing T2DM in patients with CVD or a high risk for it is the
avoidance of hypoglycemia. It is possible that in patients who have a history of CVD, hypoglycemia may exacerbate
MI or cause arrhythmias.[12,21,22] Careful selection of antihyperglycemic agents is important, in particular avoiding
those that are associated with CV events, as previously described. If possible, it may be advisable to avoid agents that
are associated with weight gain, such as TZDs and insulin, as weight gain and obesity are independent risk factors for
CVD.[12,13]
Newer Antihyperglycemic Agents and Recent CV Outcomes Trials
A range of antihyperglycemic agents has been developed in recent years that address some of the problems associated
with older agents. Insulin analogues, such as glargine, detemir, and the second-generation analogues, degludec and
peglispro, are highly effective in lowering HbA1c levels. They are also associated with lower rates of hypoglycemia,
in particular nocturnal hypoglycemia, than older insulins. The 2012 large, prospective outcomes trial, Outcome
Reduction with an Initial Glargine Intervention (ORIGIN), did not demonstrate an increased risk for adverse CV
events in patients in whom glargine was added to their glycemic-control regimen compared with those receiving
standard care.[23] However, insulin analogues are associated with weight gain, one of the risk factors for CVD.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, both of which
are GLP-1-based therapies, provide clinically relevant reductions in HbA1c and do not increase the risk for
hypoglycemia. GLP-1 RAs are associated with reductions in weight and have demonstrated CV risk factor benefits,
such as improvements in blood pressure (BP) and lipid profile.[24] DPP-4 inhibitors are weight neutral, and have
demonstrated a modest effect on BP and lipid concentrations.[25,26] Sodium-dependent glucose cotransporter 2
(SGLT2) inhibitors are a newer class of antihyperglycemic agent that use an insulin-independent mechanism to lower
blood glucose by inhibiting glucose reabsorption into the proximal renal tubules.[27,28] They have demonstrated
improvements in glycemic control, without increasing the risk for hypoglycemia, and are associated with a reduction
in BP and with weight loss. Their long-term effect on CV outcomes is being investigated.[29]
Following guidance from the US Food and Drug Administration in 2008,[30] new antihyperglycemic agents have been
assessed in CV outcomes trials to determine if their effect is neutral (Table 1).[31-35] The first 2 large CV outcomes
trials to report results involved the DPP-4 inhibitors saxagliptin and alogliptin.[31,32] The SAVOR-TIMI 53 study
involved more than 16,000 T2DM patients either with a history of or at risk for CV events.[31] They were treated with
either saxagliptin or placebo plus standard of care and followed up for 2.1 years. Saxagliptin had a neutral effect on
ischemic events, including MI, stroke, and CV death, but the rate of hospitalization for heart failure increased
compared to patients receiving placebo (3.5% vs 2.8%; HR 1.27).[31] In the EXAMINE study 5380 patients with a
recent acute coronary syndrome (ACS) event received either alogliptin or placebo plus standard of care and were
followed for up to 40 months. Alogliptin had a neutral effect on the primary endpoint of major adverse coronary
events (MACE) and there was no increase in heart failure rates.[32]
Table 1. Completed CV Outcomes Trials for New Antihyperglycemic Agents

4. Study Name Agent Enrollment Duration Major Inclusion
Criteria
Major Outcomes
DPP-4 Inhibitor
SAVOR-TIMI
53[31]
Saxagliptin 16,492 May 2010 -
May 2013
T2DM; HbA1c ≥6.5%;
high CV risk
(established CVD
and/or
multiple risk factors)
The primary endpoint event
(composite of CV death, MI,
ischemic stroke) occurred in 613
patients in the saxagliptin group
(7.3%) and in 609 patients in the
placebo group (7.2%) (HR with
saxagliptin 1.00; P<.001 for
noninferiority). More patients in
the saxagliptin group were
hospitalized for heart failure than
in the placebo group (3.5% vs
2.8%; HR 1.27).
EXAMINE[32] Alogliptin 5380 September
2009 - June
2013
T2DM; HbA1c 6.5–
11% on mono- or
combination
antihyperglycemic
therapy (noninsulin);
HbA1c of 7–11% if on
insulin regimen includes
insulin;
diagnosis of ACS 15-90
days prior to
randomization
The primary endpoint event
(composite of death from CV
causes, nonfatal MI, or nonfatal
stroke) occurred in 305 patients
assigned to alogliptin (11.3%) and
in 316 patients assigned to placebo
(11.8%) (HR 0.96; P<.001 for
noninferiority). Hospitalization
rates for heart failure were similar
between the groups (3.1%
alogliptin vs 2.9% placebo; HR
1.07)
TECOS[33] Sitagliptin 14,691 December
2008 -
March
2015
T2DM; HbA1c 6.5%-
8.0%; pre-existing CVD
The primary endpoint (composite
of CV death, nonfatal MI, nonfatal
stroke, or hospitalization for
unstable angina) occurred in
11.4% in the sitagliptin group and
11.6% in the placebo group (HR
1.00; P=.98). The rate of
hospitalization for heart failure did
not differ between the groups (HR
1.00).
GLP-1 RA
ELIXA[34] Lixisenatide 6068 June 2010 -
February
2015
T2DM; recent
spontaneous ACS event
(within 180 days)
The primary outcome (composite
of CV death, nonfatal MI, nonfatal
stroke, or hospitalization for
unstable angina) occurred in
13.5% of the 3034 patients
assigned to lixisenatide and 13.2%
of the 3034 patients in the placebo

5. group. (HR 1.02; 95% CI 0.89-
1.17).
SGLT2 Inhibitor
EMPA-REG
OUTCOME[35]
Empagliflozin 7034 July 2010-
April 2015
T2DM; HbA1c 7.0 -
10.0% if patients on
background therapy;
HbA1c 7.0%-9.0% if
treatment naive; high
CV risk
Primary outcome: Time to the first
occurrence of either CV death or
nonfatal MI or nonfatal stroke.
Preliminary information indicates
endpoint met and superiority
demonstrated when added to
standard of care. Results to be
announced at EASD 2015.
ACS = acute coronary syndrome; CI = confidence interval; CV = cardiovascular; CVD = cardiovascular disease;
DPP-4 = dipeptidyl peptidase-4; EASD = European Association for the Study of Diabetes; GLP-1 RA = glucagon-
like peptide-1 receptor agonist; HbA1c = glycated hemoglobin; HR = Hazard ratio; MI = myocardial infarction;
SGLT2 = sodium glucose cotransporter 2; T2DM = type 2 diabetes mellitus
The TECOS trial, which studied the effect of another DPP-4 inhibitor, sitagliptin, on more than 14,000 patients with
well-controlled T2DM who had pre-existing CVD, reported its results in June 2015.[33] Adding sitagliptin vs placebo
to standard of care did not appear to increase the risk for MACE, hospitalization for heart failure, or other events.[33]
Another DPP-4 inhibitor, linagliptin, is being evaluated in 2 other CV outcomes trials (Table 2).[36-43] The
CAROLINA study will evaluate linagliptin vs an SU in T2DM patients with a high risk for CV events.[36] In the
CARMELINA study, linagliptin will be compared with placebo in T2DM patients with a high risk for CV events
receiving standard of care.[37] Both studies are expected to complete in 2018.
The first CV outcomes trial involving a GLP-1 RA reported its results in June 2015. The ELIXA study evaluated
lixisenatide vs placebo for 2 years in 6068 T2DM patients who had experienced a recent ACS event, receiving
standard of care. It found that lixisenatide had a neutral effect on the primary outcome of CV death, nonfatal MI,
nonfatal stroke, or hospitalization for unstable angina. Furthermore, there was no increase in hospitalization for heart
failure.[34] Several ongoing CV outcomes trials are evaluating other GLP-1 RAs in patients with T2DM, most of
whom also have stable coronary artery disease: LEADER (liraglutide),[38] SUSTAIN 6 (semaglutide),[39] EXSCEL
(exenatide),[40] and REWIND (dulaglutide)[41] (Table 2).
Table 2. Ongoing CV Outcomes Trials for New Antihyperglycemic Agents
Study Name Agent Start Date Expected
Completion
Date
Number
of
patients
Trial Number
Clinicaltrials.gov
Inclusion Criteria
DPP-4 Inhibitor
CAROLINA[36] Linagliptin October
2010
September
2018
6000 NCT01243424 CV disease or age/CV
risk factors
CARMELINA[37] Linagliptin July 2013 January 2018 8300 NCT01897532 CV risk (macrovascular
disease and/or impaired
renal function)
GLP-1 RA

6. LEADER[38] Liraglutide August
2010
October 2015 9340 NCT01179048 CV disease or age/CV
risk factors
SUSTAIN 6[39] Semaglutide February
2013
January 2016 3260 NCT01720446 CV disease or age/CV
risk factors
EXSCEL[40] Exenatide June 2010 April 2018 14,000 NCT01144338 T2DM alone
REWIND[41] Dulaglutide July 2011 April 2019 9622 NCT01394952 CV disease or age/CV
risk factors
SGLT2 Inhibitor
DECLARE-TIMI
58[42]
Dapagliflozin April 2013 April 2019 17,150 NCT01730534 CV risk factors
CANVAS[43] Canagliflozin December
2009
June 2017 4411 NCT01032629 CV disease or CV risk
factors
CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; GLP-1 RA= glucagon-like peptide-1 receptor agonist; SGLT2
= sodium glucose cotransporter 2; T2DM = type 2 diabetes mellitus
SGLT2 inhibitors are being evaluated in 2 CV outcomes trials. The EMPA-REG OUTCOME study, involving more
than 7000 people with T2DM, assessed the effect of empagliflozin vs placebo in patients receiving standard of care
who were at high risk for CV events.[35] It was first designed to test for noninferiority then for superiority. The
primary endpoint was time to first occurrence of CV death, nonfatal MI, or nonfatal stroke. The study was completed
and results will be reported at this year's EASD Meeting, the first CV outcomes to be reported for an SGLT2 inhibitor
(see next section).[35]
Two other SGLT2 inhibitors are being evaluated in ongoing CV outcomes trials.[42,43] The DECLARE-TIMI 58 study
is assessing another SGLT2 inhibitor, dapagliflozin, vs placebo in more than 17,000 T2DM patients at high risk for
CV events receiving standard of care.[42] The CANVAS study is assessing canagliflozin vs placebo in more than 4000
patients with poorly controlled T2DM and either a history of or risk for CV events who are receiving standard of
care.[43]
CV Outcomes Results at EASD 2015
A number of studies to be presented at EASD 2015 are of relevance to the CV effects of antihyperglycemic therapy.
Three studies on SUs report an increased CV risk.[44-46] A meta-analysis of survival data found that SUs were
associated with a higher risk for all-cause mortality (HR 1.26) and CV mortality (HR 1.46) than other
antihyperglycemic agents, and that the risk increased over time. The risk for MI was significantly higher compared
with DPP-4 inhibitors (HR 2.54) and SGLT2 inhibitors (HR 41.80).[44] A German study of more than 35,000 people
receiving first-line treatment for T2DM found that those taking an SU monotherapy seemed to have a higher risk for
MACE and T2DM hospitalization compared with those receiving metformin monotherapy.[45] A study of more than
68,000 people being treated with metformin for T2DM found that those in whom SU was added to regimen, the risk
for fatal/nonfatal CVD and all-cause mortality was higher (HR 1.11 and 1.20, respectively) than those in whom a
DPP-4 inhibitor was added.[46] A study of more than 5000 people with diabetes (either type 1 or 2) found that the
novel insulin peglispro was not associated with an increased risk for MACE compared with other insulins (HR 0.82
for both).[47] A knockout mouse study found that the neuroprotective efficacy of linagliptin is mediated by a GLP-1
receptor-independent mechanism.[48] Previous studies by this group found that linagliptin is efficacious against stroke

7. in normal and obese mice, as well as those with T2DM, and the results presented at EASD may help to determine the
mechanism of protection against stroke.[48]
The problem of delays or failure to intensify antihyperglycemic therapy is highlighted by the results of a large
population-based study of more than 1 million people newly diagnosed with T2DM who had a minimal history of
CVD.[49] It found that therapeutic inertia for BP and glycemic control was associated with an increase in the risk for
MI, heart failure, and stroke. Patients with HbA1c >7.5% over 2 years had an 80% increased risk of composite CV
events compared with those <7.5%.[49]
Finally, as previously described, the results of the EMPA-REG OUTCOME study will be presented.[35] Preliminary
information, recently released, reported that the study met its primary endpoint -- time to first occurrence of either
CV death, nonfatal MI, or nonfatal stroke -- and demonstrated the superiority of empagliflozin when added to
standard of care. Although the trial data will not be available until the EASD meeting, it suggests that empagliflozin
is the only antihyperglycemic agent to have demonstrated a reduction in the risk for CV events in a CV outcomes
trial.[50]
The number of ongoing and recently completed CV outcomes trials with new and more traditional antihyperglycemic
agents, and the new findings on this topic that will be presented during EASD 2015, reflect the importance of
ensuring that glycemic control can be effectively achieved in patients with T2DM, while carefully managing their
risk for CV events.
 References
 Abbreviations