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Cardio Diabetes Medicine 2017 437

risk of death and readmission for HF. Among T2DM metformin. Most recently, a robust meta-analysis of
patients with documented coronary artery disease 115 trials was conducted in which patients with T2D
(CAD), metformin appears to be associated with low- who were treated with sulfonylureas for at least 24
er mortality and CV risk than secretagogues. Several weeks were compared with patients treated with a
studies are in progress evaluating the potential CV nonsulfonylurea agent for the incidence of major car-
benefits of metformin. The METformin in DIastolic diovascular events. (7). The investigators concluded
Dysfunction of MEtabolic syndrome (METDIME) trial that the use of sulfonylureas in patients with T2D
aims to evaluate if metformin added to the standard was associated with increased mortality and a higher
treatment of patients with metabolic syndrome (MS) risk for stroke, whereas the overall incidence of major
is able to improve diastolic dysfunction.(4) The Gly- cardiovascular events was unaffected; the difference
cometabolic Intervention as an adjunct to Primary was not statistically significant. Another review of 15
percutaneous intervention in ST elevation myocardi- randomized trials with at least 72 weeks of treatment
al infarction (GIPS)-III trial aims to provide confirma- with sulfonylureas compared sulfonylureas with ac-
tion that metformin is able to decrease infarct size, tive comparators and did not see a statistical differ-
prevent adverse remodeling and ultimately improve ence in cardiovascular outcomes. (8) Sulfonylureas
systolic function (5). The Glucose Lowering In Non are very inexpensive, and they are not going to dis-
diabetic hyperglycemia Trial (GLINT) was designed to appear. Many people need them. If one does not
establish the effectiveness and cost-effectiveness of want to use sulfonylureas because of hypoglycemia
metformin in preventing CV events in non-diabetic or weight gain that is okay; but the reason should not
individuals with high glucose levels (6) be the stigma of adverse cardiovascular effects asso-
ciated with these drugs. As the DPP-4 inhibitors are
Cardiovascular safety of SU: Evidence from often considered to be the second line agents, the
studies Cardiovascular outcome study of Linagliptin versus
Glimiperide in patients with type 2 diabetes (CARO-
Sulfonylureas (SU) act by stimulating insulin release LINA) will stand out which compares linagliptin with
from pancreatic β-cells. SU also have a number of an active SU comparator, glimiperide for CV safety.
extra-pancreatic effects, although their clinical signif- The results will help to address the inconsistencies
icance needs to be clarified. These drugs can reduce regarding CV safety of SU’s and will also aid in fu-
hepatic glucose production and hepatic insulin up- ture decision making process regarding the choice
take and increase glucagon secretion by pancreatic of second line agents as an add on to metformin if
α-cells. They increase insulin sensitivity in peripheral linagliptin is found to be superior to glimiperide [9].
tissues as well as stimulate glucose utilization by As CAROLINA has no placebo group to calibrate any
these tissues. No consistent evidence exists as to findings to the population being studied a second
the association between SU use and risk of CVD in study called Cardiovascular safety and Clinical Out-
patients with T2DM. A meta-analysis revealed an in- come with Linagliptin (CARMELINA) is being carried
creased risk of stroke and a significant increase in out by the same sponsors who will compare the CV
mortality, without affecting the overall incidence of and renal safety of linagliptin vs placebo when added
major adverse cardiac events (MACE) with SU treat- to standard care in type 2 diabetes. (10)
ment. Another study has shown an increase in CV
risk and mortality with all SU, except for gliclazide
which was associated with a lower risk. In addition, Cardiovascular safety of insulin: Evidence
in diabetic patients with documented CAD, glipizide from studies
and glyburide were associated with increased mortal- Several studies have reported an increase in CV risk
ity, the latter probably because of its ability to impair and higher mortality, whereas others have demon-
ischemic preconditioning. SU have also been report- strated a reduction in CV events, apart of their raise
ed to reduce resting myocardial blood flow, to in- in the incidence of hypoglycemia. An observational
crease infarct size and to elicit proarrhythmic effects. study of patients on insulin plus metformin reported
Glimepiride however may be safer in patients with a higher risk of a composite effect of nonfatal CV
CVD, since it has no detrimental effects on ischemic and all-cause mortality among insulin therapy users
preconditioning. SU seem to increase mortality when compared to those administered sulfonylureas (SU)
patients are submitted to elective or emergency cor- as an add-on therapy. A recently published post
onary angioplasty for acute MI. Globally, several ret- hoc analysis of the action to control cardiovascular
rospective studies have demonstrated that all-cause risk in diabetes (ACCORD) trial suggests that insulin
mortality. and CV events and death are significantly dose did not play a role in the greater CV mortality
increased in patients treated with SU compared with in patients randomized to intensive glycemic control.

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