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Cardio Diabetes Medicine 2017 151

metabolism (folate, vitamin B6 or B12) are known to a mortality multiplier; that is, at every decrease in the
cause elevation of the plasma homocysteine concen- hemoglobin concentrations below 12 g/dL, mortality
tration. Several investigators have demonstrated that increases in patients with either CKD or CVD, and
in patients with T2DM, the presence of DN is a ma- those with both. Treatment of anemia with exoge-
jor determinant of elevated plasma total homocys- nous erythropoietin in patients with cardiorenal dis-
teine concentrations because of the reduced renal ease has shown promise in reducing morbidity and
clearance of homocysteine. Several studies suggest in improving survival and quality of life. However, he-
that homocysteine may induce thrombus formation moglobin concentrations more than 12.0 g/dL are not
by disturbing the balance between coagulation and recommended for patients with overt nephropathy.
fibrinolysis. Homocysteine can downregulate the ex- Newer Drugs for Diabetes and their CV effects: In the
pression of thrombomodulin (TM) in endothelial cells, year 2008, the US FDA issued guidance for industry
resulting in inactivation of protein C, a natural an- insisting on evaluating CV risk in new antihypergly-
ticoagulant. Homocysteine also can upregulate the cemic therapies seeking approval for the treatment
expression of tissue factor, an initiator of the coag- of T2DM.Based on this data from several Cardio
ulation cascade. Thus, homocysteine is associated Vascular Outcome Trials (CVOT) involving DPP-4
with the increased generation of thrombin, resulting inhibitors have been reported. The Trial Evaluating
in hypercoagulation.
Cardiovascular Outcomes with Sitagliptin (TECOS ) 46
Two large-scale prospective studies, which tested showed that sitagliptin was noninferior to placebo
whether treatment with folate and vitamin B6 and for the primary composite CV outcome of CV death,
B12 supplementation improves vascular outcomes, nonfatal myocardial infarction, nonfatal stroke, or
have reported that treatment with B vitamins did not hospitalization for unstable angina. Likewise, the
reduce the risk of major cardiovascular events in Saxagliptin Assessment of Vascular Outcomes Re-
patients with vascular disease, although B vitamins corded in Patients with Diabetes Mellitus–Throm-
supplementation was associated with a reduction bolysis in Myocardial Infarction (SAVOR-TIMI ) Trial
in plasma homocysteine Taken together, although showed noninferiority for saxagliptin when compared
it has been demonstrated that moderate elevation with placebo on the primary composite outcome.
of plasma homocysteine is associated with an in- This trial was done to determine whether alogliptin is
creased risk for CVD, hyperhomocysteinemia may noninferior to placebo with respect to major cardio-
be a marker, rather than a cause, of CVD. vascular events in patients with type 2 diabetes who
are at very high cardiovascular risk — those with recent
Asymmetric Dimethylarginine: Asymmetric dimethy- acute coronary syndromes. In conclusion, among pa-
larginine (ADMA) is an endogenous inhibitor of NO tients with type 2 diabetes and a recent acute coro-
synthase (NOS). In addition to inhibition of NO pro- nary syndrome, treatment with alogliptin resulted in
duction, ADMA may promote uncoupling of eNOS rates of death from cardiovascular causes, nonfatal
and lead to the generation of superoxide, resulting myocardial infarction, and nonfatal stroke that were
in increased oxidative stress. Elevated plasma ADMA similar to those with placebo.
concentrations have been reported in patients with
chronic renal failure, hypercholesterolemia, diabetes,, GLP-1 ANALOGS: Two of the GLP-1 analogs, namely,
and coronoary artery disease. Since renal function is liraglutide and lixisenatide, currently have CVOT data
a main determinant of serum ADMA concentrations available. In the LIRAGLUTIDE Effect and and Action
in humans, circulating ADMA accumulates in pa- in Diabetes: Evaluation of Cardiovascular Outcome
tients with chronic kidney disease. Elevated plasma Results (LEADER) Study, fewer patients experienced
ADMA concentrations are associated not only with the primary composite CV outcome in the liraglutide
endothelial dysfunction but also predict mortality and group when compared with those receiving place-
CVD events in CKD and ESRD. Like CKD, elevated bo. Studies in patients with DKD have additionally
plasma ADMA is associated with the morbidity of shown that liraglutide lowered albuminuria levels in
CVD in early diabetic nephropathy in T1DM patients. patients with normal kidney function or early-stage
Thus, elevated circulating ADMA concentrations may CKD and that liraglutide treatment did not adversely
contribute to endothelial dysfunction, resulting in a affect eGFR and showed improved glycemic control
high incidence of CVD in the setting of DN or CKD. in patients with T2DM and CKD stage 3. Recently re-
leased data from the LEADER Study as well as clini-
Anemia is common in patients with DN as well as
CKD, and has been shown to have an independent cal trials of semaglutide and dulaglutide consistently
role in the genesis of left ventricular hypertrophy show reduced risk of albuminuria onset and progres-
(LVH) and subsequent CVD.Anemia seems to act as sion. The consistency of these data across GLP-1 RA

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