Authored by Bondugulapati LNR
The prevalence of type 2 diabetes mellitus (T2DM) has reached epidemic proportions. The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014 [1]. Approximately 90% of these patients are expected to have T2DM based on the population-based surveys in developed countries [2]. The latest estimates by the international diabetes federation project that 592 million adults (1 in 10 persons) worldwide will have DM by 2035 [3]. Patients with T2DM are at significantly higher risk for cardiovascular disease (CVD) and as such, CVD represents the most prevalent cause of mortality and morbidity in this group [4]. In addition to the standard risk factors for CVD like obesity, dyslipidaemia and hypertension, which are common comorbidities seen in majority of T2DM patients, there are studies reporting of additional risk factors in these patients including hypercoagulability, endothelial dysfunction, chronic kidney disease, autonomic neuropathy and enhanced oxidative stress which may directly contribute to the development of CVD [5].
There has been a colossal change in the T2DM treatment options in the last decade with several new classes of drugs emerging including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 agonists and sodium glucose cotransporter-2 inhibitors (SGLT-2i). Further to United States Food & Drug Administration (US FDA) recommendations, all the new drugs now need to go through cardiovascular (CV) safety studies and prove non-inferiority. Surprisingly, SGLT-2i not only demonstrated CV safety but in fact were shown to reduce heart failure admissions and improve major adverse cardiac event (MACE) outcomes in patients with established cardiovascular disease. This mini-review is focussed on summarising the cardiovascular benefits of this exciting class of new drugs.
SGLT-2 inhibitors and their Pharmacodynamics
Three main drugs that are approved for usage in T2DM patients by the US FDA from this class are canagliflozin, dapagliflozin and empagliflozin (approved in March 2013, Jan 2014 and Aug 2014 respectively). SGLT-2i act by inhibiting the reabsorption of filtered glucose in the proximal convoluted tubule (PCT) of the kidneys, a mechanism that is independent of insulin pathway and therefore not affected by beta cell decline. Thus, they can be prescribed at any stage of T2DM. Apart from the basic function of antihyperglycemic effect, these drugs also help improve other metabolic parameters including hypertension, obesity and to some extent dyslipidaemia too. This makes them the preferred drug in patients with these comorbidities.The entire blood volume is filtered by the kidneys about 40-50 times/day in an average healthy adult with daily filtration rate of 160–180 grams of glucose. This filtered glucose is absorbed back almost completely in the kidneys through the proximal tubules via sodium-dependent transmembrane protein family called sodium glucose cotransporters (SGLT1 and SGLT2) preventing glycosuria. While SGLT1 is a low-capacity high-affinity transporter that is responsible for reabsorption of 10% of glucose, SGLT2 is a highcapacity low-affinity transporter and reabsorbs the rest of the glucose (90%). The SGLT-2i inhibit SGLT2 in the PCT and leading to increased urinary glucose excretion and reduction in blood glucose levels [6]. They are also shown to preserve beta cell function [7].
The common side effects include thrush, balanitis and urinary tract infections. In view of osmotic diuresis, volume depletion is a potential risk especially in patients who are on diuretics. Hypoglycaemia is rare except when these drugs are used concurrently with either insulin or insulin secretagogues. There are few case reports of diabetic ketoacidosis (DKA) especially when used in patients with type 1 diabetes mellitus (unlicensed usage). Very rarely, Fournier’s gangrene has also been reported.
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