Professor Carol PollockRoyal North Shore Hospital, University of Sydney
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Sodium-linked glucose transport -2 inhibitors were initially introduced as they effectively lower blood glucose in patients with Type 2 diabetes and relatively preserved renal function. Mandated cardiovascular end-point trials, EMPAReg, using empagliflozin and CANVAS using canagliflozin, in patients at high cardiovascular risk, demonstrated a significant reduction in macrovascular outcomes and in heart failure requiring hospitalisation. Subsequently the DECLARE study, using dapagliflozin, reported similar outcomes in a “primary care” population. Real World analyses of the CV outcomes demonstrate a consistent trend to reflect trial data. Secondary analyses in all studies demonstrated an approximate 40% reduction in the renal composite endpoint.
The benefits in CV, and secondary pre-specified secondary endpoints of heart failure and renal endpoints cannot be explained entirely by glycaemic control, weight loss and BP control. Hypothesised additional mechanisms of benefit include natriuresis (due to inhibition of sodium-linked glucose transport and also due to reduced sodium-hydrogen exchange) and contraction of the intravascular volume with associated reduction in left ventricular volume, a reduction in epicardial and peri-renal fat with positive effects of paracrine adipokine signalling, reduced glycotoxicity and hence a reduction in inflammation and fibrosis, a reduction in serum uric acid with potential vascular benefits and altered intrarenal haemodynamics to limit renal hyperfiltration. More recently, the beneficial effects of SGLT2 inhibitors in driving nocturnal catabolism brought about by a raised glucagon/insulin ratio initially depleting glycogen in the liver and ultimately activating gluconeogenesis utilizing circulating amino acids (AAs) has been recognised. Associated with this there is a general fuel switch from glucose to free fatty acids and ketones (accompanied by a change in mitochondrial morphology from a fission to a sustained fusion state driven by a decrease in AA levels); a decrease in circulating AAs and insulin driving inhibition of mammalian target of rapamycin complex 1 (mTORC1), which enhances autophagy/lysosomal degradation of dysfunctional organelles resulting in organ protection.
Resumption of eating in the morning restores anabolic biogenesis of new and fully functional organelles and proteins.
Many of these hypothesised mechanisms are clearly operational diabetic but also non-diabetic patients. Hence multiple studies are currently being undertaken to assess the likely mechanisms underpinning positive cardiovascular and renal outcomes. The CREDENCE study using canagliflozin in a diabetic population with chronic kidney disease with primary renal and CV endpoints was stopped early due to benefit in favour of the active drug. It is due to be reported in April 2009. End point trials are being conducted in patients with and without diabetes to assess diverse conditions including, but not limited to heart failure, non-diabetic renal failure, obesity, non-alcoholic steato-hepatitis (NASH), Syndrome of inappropriate ADH (SIADH) and exercise capacity. If results of these studies are positive the clinical indications for the use of SGLT2 inhibitors will significantly broaden.
About the speaker
Professor Carol Pollock is an academic nephrologist with basic and clinical interests in the mechanisms of progressive kidney disease.
During her PhD studies she defined, using micropuncture techniques, the physiological basis underpinning progressive renal pathology in a rat model of diabetes and a model of compensatory hypertrophy. She subsequently developed an interest in the cellular basis of progressive renal disease with a focus on diabetic nephropathy.
Professor Pollock has authored over 170 publications to date. She is currently Chairman of the Area Health Advisory Council for the Northern Sydney Central Coast Area Health Service (NSCCAHS), is Research Chairman of the NSCCAHS and Associate Director of the Kolling Institute.
She is Chairman of the Greater Metropolitan Task force in NSW (overseeing clinical networks in NSW), and Chairman of the Clinical Variation in Practice subcommittee of the Health Efficiency taskforce. She is a founding director of BioMed North, a company supporting the development of intellectual property out of Area Health Services, and sits on the Board of several philanthropic organizations supporting medical research.