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4 August 2010

Nor Azmi Kamaruddin*
National University of Malaysia
Kuala Lumpur.

Aretaus, one of the most celebrated of the ancient Greek physicians coined the term "diabetes" when he derived the name for the wasting disease from the Greek word “siphon" (diabaino in Ionian Greek, meaning “passing through”). While the 17th century London physician, Dr Thomas Willis, diagnosed "honeyed" diabetes by sampling the urine of his patients. Since then the role of the kidneys in the pathogenesis of diabetes mellitus had been largely ignored.

In healthy individuals, nearly all of the glucose that passed through the kidneys is reabsorbed by the sodium-glucose transporter 2 (SGLT-2) which is mainly expressed in the proximal tubules. Only 10% is reabsorbed by the SGLT-1 which is found in the distal tubules. Hyperglycaemia that is a feature of uncontrolled diabetes saturates the SGLT receptors and exceeds the maximum threshold of glucose absorption, resulting in increased glycosuria. It has been shown that diabetic patients also expressed an increased number of SGLT-2 compared to healthy individuals based on preclinical study of cultured proximal convoluted tubule cells. As a result renal glucose reabsorption is also greatly enhanced in these PCT cells taken from the diabetic patients. The resultant hyperglycaemia worsens the already existing glucotoxicity brought about by insulin resistance and deficiency, the two main defects of type 2 diabetes mellitus (T2DM).

On the other hand in patients with familial renal glycosuria due to a mutation of the SLC5A2 gene that encodes SGLT-2, there is renal glycosuria ranging between 50 grams to 100 grams daily. Despite this marked glycosuria they remained asymptomatic without any significant electrolyte abnormalities nor any increase in urogenital infections. This suggested that inhibiting SGLT function did not cause any significant adverse renal effects. Based on this finding a new class of SGLT-2 inhibitors was developed.

The first combined SGLT-1/2 inhibitor, phlorizin was first isolated in 1835 from the root bark of the apple tree. It was shown to be beneficial in rats with diabetes. However its progress was marred by the low bioavailability from poor intestinal absorption. In addition there were serious gastro-intestinal side-effects due to the concomitant inhibition of SGLT-1 which were found in abundance in the gut.

Among the specific SGLT-2 inhibitors, dapaglifozin is the most developed agent currently in phase III clinical trials as a once-daily oral treatment for T2DM. The presence of the C-aryl glucoside linkage confers it resistance against degradation by the gastrointestinal tract β-glucosidase enzymes. It is also 1,200–times more selective for SGLT-2 compared to SGLT-1. As a result the renal glucose reabsorption is inhibited by approximately 16-50% in healthy individuals with no discernible hypoglycaemia.

In the first large scale trial of dapagliflozin involving 354 T2DM patients who were on Metformin, there was a dose –dependent reduction of A1c of 0.84% in those on maximum dose of 10 mg daily compared to 0.3% in the placebo group. Similarly there was a lost in body weight of 2.9 kg compared to 0.9 kg in the placebo group over the 24 week study period. Although previous phase 1 & 2 studies did not show any increase in genital infections there was a slightly increase in the incidence of UTIs with similar increase in serum urea and haematocrit probably attributed to the osmotic diuresis.

In terms of its anti-diabetic action, SGLT-2 inhibitors generally have a modest glycaemic effect as an add-on pharmacotherapy. However this may be compensated by its ability to reduce weight and blood pressure which in the long run may lead to favourable cardiovascular outcome.

*The author was a principal investigator of a phase II clinical trial involving canagliflozin, an SGLT-2 inhibitor belonging to Johnson & Johnson.

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