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440 Cardiovascular Outcomes With Antihyperglycemic Therapy:
Past , Present , and Future Impact on Practice

may have beneficial pleiotropic effects on the CV Trial Evaluating Cardiovascular Outcomes with Sita-
system. Some of these beneficial effects may be gliptin (TECOS) where patients had a median follow
through GLP-1–dependent mechanisms, while others up of three years and showed that sitagliptin was
are postulated to occur through other DPP-4 targets considered to be non-inferior to placebo for primary
independent of their effect on GLP-1. These targets composite CV outcomes (HR: 0.98; 95% CI, 0.88 to
include stromal-derived factor-1a whose prolongation 1.09; p<0.001) and the total number of primary out-
leads to stimulation of endothelial progenitor cells come that occurred were 11.4% (4.06 per 100 person
involved in endothelial homeostasis and vascular re- years) in sitagliptin group in comparison to 11.6% (4.17
pair. Animal studies also show a reduction in infarct per 100 person years) in the placebo group. Moreover
size and the activation of cardioprotective molecular the rate of hospitalization for heart failure did not
pathways with DPP-4 inhibitor use. These drugs are differ between the two groups (HR: 1.00; 95% CI, 0.83
shown to prevent atherosclerosis and myocardial in- to 1.20; p=0.98). The population that were studied in
jury, improve endothelial dysfunction and lipid pro- these three trials were very similar and the patients
file, lower blood pressure, and decrease arrhythmia had well managed cardiovascular and glycemic risk
after CABG surgery, There have been 3 large CV out- factors at baseline. These trials also suggested that
come trials that have been completed for the dipep- the catalytic inhibition of DPP-4 is basically safe for
tidyl peptidase 4 (DPP-4) inhibitors- SAVOR-TIMI on the CV standpoint but such inhibition alone is insuf-
Saxagliptin (22), EXAMINE on Alogliptin (23), TECOS ficient to improve CV outcomes in such short term
on Sitagliptin (24). In the Examination of Cardiovas- and longer follow up is necessary. Most of the CV
cular Outcomes with Alogliptin versus Standard of outcome trials with the DPP-4 inhibitors were con-
Care (EXAMINE) trial with a median follow up of 1.8 ducted in a placebo controlled setting with no active
years; Alogliptin was studied as an addition to exist- comparator. This leads to a limitation in clinical in-
ing anti-hyperglycaemic treatment in comparison to terpretation and does not allow an assessment of
a placebo in patients with type 2 diabetes who had comparative effectiveness. Currently there are other
an acute coronary event in the last 15-90 days prior ongoing randomized clinical trials comparing DPP-
to randomization. The study showed that a primary 4i versus placebo added to conventional therapy in
end point (composite death from CV disease, non-fa- patients with T2DM. The CArdiovascular safety and
tal MI, non-fatal stroke) was 11.3% in the Alogliptin renal microvascular outcome study with LINAgliptin
group compared to 11.8% in the placebo group (HR: in patients with T2DM (CARMELINA), lasting till 2018,
0.96, upper boundary of one sided repeated CI, 1.16: has been designed to assess the long-term impact
p<0.001 for non- inferiority) suggesting that the rates on CV morbidity, mortality and renal function of treat-
of major CV events were not raised with Alogliptin ment with linagliptin. The CARdiovascular outcome
in comparison to a placebo . This was followed by trial of LINAgliptin versus glimepiride in patients with
the results from the Saxagliptin Assessment of Vas- T2DM (CAROLINA) is a trial ongoing since 2010 com-
cular Outcomes recorded in Patients with Diabetes prising a comparison of a sulfonylurea with a DPP-4i.
Mellitus- Thrombolysis in Myocardial Infarction 53 This trial is expected to provide considerable insight
(SAVOR-TIMI 53) trial with a median follow up of 2.1 as it is unique in comparing head-to-head add-on
years which evaluated saxagliptin against a placebo therapy
showing similar results for a cardiovascular primary
endpoint (7.3% and 7.2% respectively, HR: 1.00; 95% Sodium-glucose transporter-2 inhibitor s
CI 0.89 to 1.12, p=0.99 for superiority and p<0.001 The sodium-glucose transporter-2 (SGLT-2) inhibitors
for non-inferiority). This suggested that saxagliptin (SGLT-2i) are a new class of antidiabetic agents that
did not increase or decrease rate of ischemic events inhibit glucose reabsorption from the kidney increas-
but an unexpected outcome showed patient in the ing urinary glucose excretion. The FDA and EMA have
saxagliptin group with an increased admission with approved three inhibitors, canagliflozin, dapagliflozin
heart failure compared to the placebo (3.5% Vs 2.8%, and empagliflozin, with several others being under
HR: 1.27; 95% CI 1.07-1.51, p<0.007) The possible ex- late-stage clinical development. Ipragliflozin, tofogli-
planation for this was shown in a later sub-analysis flozin and luseogliflozin have been approved for the
which concluded that subjects who had greater risk treatment of T2DM in Japan. Other compounds re-
of hospitalization with HF were those who had an main in development, as well as Lx4211, a dual so-
eGFR <60 mls/min, had previous history of heart fail- dium-glucose transporter 1 and 2 inhibitor and ISIS
ure and with elevated baseline levels of N terminal – 388626, an antisense oligonucleotide (ASO) de-
pro B type natriuretic peptide (NT-proBNP) . The latest signed to block the expression of the SGLT2 gene
published data reflecting a similar trend was in the
in vivo. SGLT-2i protect the proximal tubular cells,

GCDC 2017