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556 Cardio Diabetes Medicine 2017

Sulfonylureas and Cardiovascular Mortality?

Dr. Vimala Paul, MD

Physician, Tuticorin

Abstract for the management of diabetes, there is a continued
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Prevalence of diabetes mellitus has shown a steep controversy about their cardiovascular safety. New-
increase worldwide. Sulfonylureas are recommended er sulfonylureas have been developed over the
by major guidelines for the management of diabetes. years. Sulfonylureas are classified as first-genera-
However, there is a controversy about cardiovascular tion (chlorpropamide, tolazamide, and tolbutamide),
safety of sulfonylureas. Sulfonylureas may cause car- second-generation (glipizide and glyburide), and
5
diovascular adverse effects by inhibiting extra-pan- third-generation agent (glimepiride). Fourth genera-
creatic K ATP channels and sulphonylurea receptors tion photo-switchable sulfonylurea JB253 has been
present in cardiac myocytesand smooth muscle cells. developed recently.First-generation Sulfonylureas
Impaired ischaemic preconditioning may be responsi- have longer half-lives and are associated with in-
ble for the excess cardiovascular mortality observed. creased incidence of hypoglycaemia, and drug in-
However, different sulfonylureas have different lev- teractions. The second- and third-generation agents
els of affinity towards sulphonylurea receptors. Large have more rapid onset of action, shorter half-lives,
number of studies have evaluated the cardiovascu- and lower incidence of hypoglycaemia. Different the
lar safety of sulfonylureas. Results of meta-analysis generations differ in their pharmacokinetic, efficacy,
5, 6
of RCTs(randomised controlled trial) suggest no in- and safety profiles.
creased risk of cardiovascular adverse effects with
sulfonylureas whereas results of meta-analysis of How do Sulfonylureas compromise
observational studies indicate increased risk of car- cardiovascular safety?
diovascular adverse effects.Gliclazide and glimepiride Sulfonylureas act by binding to the subunit of ade-
were associated with a lower risk of all-cause mor- nosine triphosphate (ATP)–sensitive potassium chan-
tality and cardiovascular-related mortality compared nels in the pancreatic β cells to keep the channels
with glibenclamide. closed. This leads to an influx of calcium ions into the
Key words: Sulfonylureas, cardiovascular mortality, cell that results in an increased release of insulin via
cardiovascular adverse effects,KATPchannels, ish- exocytosis of insulin-containing granules. The cause
emic preconditioning of increase in cardiovascular involvement may be di-
rectly related to the mechanism of action. The first
Introduction two generation of sulfonylurea drugs do not act only
on pancreatic β cells. They also bind to ATP-sensitive
Diabetes mellitus is a metabolic disorder that is an potassium channels in cardiomyocytes and vascular
epidemic in the world today. India has more than 62 smooth-muscle cells. This binding of sulfonylureas
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million diabetics today. Several groups of drugs tar- to potassium channel in cardiac tissues prevents 3
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geting glucose metabolism and regulation are being otherwise beneficial mechanisms:
developed.
• Vascular smooth-muscle cell relaxation that im-
Sulfonylureas are recommended by the guidelines proves coronary blood flow;
issued by American Diabetes Association, Europe-
an Association for the Study of Diabetes and Inter- • Limitation of myocardial damage during ischemia
2,3
national Diabetes Federation. The University Group • Protection of energy-generating mitochondria in
Diabetes Program (UGDP) trial results published in cardiomyocytes. 4
1970 questioned the cardiovascular safety of sulfo-
nylureas. Even after 50 years of using sulfonylureas

GCDC 2017