SGLT2 Inhibitors

The SGLT2 (Sodium-GLucose co-Transporter 2) inhibitors block the reabsorption of glucose in the renal tubular system and thus increase glucose loss in the urine. This is responsible for their modest glucose-lowering effect. The first agent in this class, phlorizin, attracted attention in the nineteenth century because it caused glycosuria and appeared a possible cause of diabetes. Evidence for their efficacy and safety is still lacking, and marketing of the first in this class, dapagliflozin, was stalled by the FDA because there are some concerns regarding side-effects: an increase in urinary tract infections (due to the increased presence of glucose in the urine) but more worryingly a possible increase in bladder cancer.

Background and History

Image 1: Click to enlarge
Image 1: Click to enlarge
Phlorizin is a 2'-glucoside of phloretin present in the bark of pear, apple and other fruit trees. Von Mering, who later collaborated with Oskar Minkowski in the discovery of the pancreatic origins of diabetes, reported in 1886 that administration of phlorizin produced glycosuria, without affecting the blood glucose level in healthy animals. Continued administration produced polyuria and weight loss similar to that seen in diabetes. Other investigators showed that glycosuria could be induced in the isolated perfused kidney, indicating a direct renal action.

Phlorizin (spelled phloridzin in the older literature) contains a glucose moiety with very high affinity for the binding site of the glucose transporter in the renal tubules, thus inhibiting glucose reabsorption by competitive inhibition. It is poorly absorbed from the gut, but a dose-response relationship with glycosuria was observed when the drug was injected. Early studies showed that calories lost in the urine were replaced by protein breakdown (causing weight loss), but that the agent was only weakly effective in lowering blood glucose[1][2].

Mechanism of action of SGLT2 Inhibitors

Glucose is a polar molecule that requires an active transport system in order to cross lipid-rich cell membranes. Glucose transporters fall into two classes: the sodium/glucose cotransporters SGLT1 and SGLT2, and the GLUT transporters.

As the name suggests, the sodium/glucose cotransporters move both glucose and sodium into the cells lining the renal tubule. In common with other cotransport systems one solute (glucose) is transported against a steep concentration gradient, whereas the other (sodium) is transported downhill along a negative gradient achieved by pumping sodium across the internal cell membrane.

SGLT1 is the principal glucose transporter across the intestinal surface, and SGLT2 is the principal transporter across the renal tubule.

The hepatic output of glucose is in excess of 100 grams of glucose daily. Glucose reaching the kidneys passes directly through the glomerulus into the renal tubule, and would be lost to the body were it not for an active transport system that passes glucose back into the circulation.

Reabsorption of glucose is achieved by two sodium/glucose transporters located in the membrane of the proximal convoluted tubule. The Sodium-Glucose co-Transporter-2 is located on the luminal side of the proximal renal tubule and is responsible for reabsorption of filtered glucose. Under normal circumstances about 90% of filtered glucose is reabsorbed through SGLT2; the more distally located SGLT1 takes care of reabsorption of the final 10%.

As a result, the urine is in health almost entirely glucose free. The main exception is a condition known as renal glycosuria. In this the maximal absorptive capacity of the renal tubule is exceeded at physiological levels of circulating glucose. Renal glycosuria is due to mutations in SLC5A2, the solute carrier 5 (sodium/glucose cotransporter) gene which codes for SGLT2. Renal glycosuria is present in about 1/400 of the population and has no known harmful consequences, apart from false positive urine tests for diabetes.

The maximal reabsorptive capacity of this transport system is otherwise saturated at supraphysiological levels of circulating glucose (e.g >11-14 mmol/l). This is known as the renal threshold for glucose. The renal threshold for glucose increases with increasing age and renal insufficiency.

SGLT2 is upregulated in diabetes, presumably as an adaptive mechanism to repetitive glucosuria. The SGLT2 inhibitors are competitive inhibitors of the co-transport system. By blocking re-uptake of glucose in the renal tubule, these induce glycosuria and the associated loss of fluid and calories from the body. The consequence is a modest reduction in circulating glucose and promotion of weight loss and a small reduction in blood pressure. The presence of excess glucose in the urine can however predispose to genital candidiasis and (potentially) urinary tract infections.

Clinical Efficacy of SGLT2 Inhibitors

The SGLT2 inhibitors are not very potent glucose lowering drugs, lowering HbA1c by about 0.3 to 0.8% (3-9 mmol/mol). Because of the increased urinary caloric loss, the SGLT2 Inhibitors are associated with a weight loss of 1-2.5 kgs compared to placebo or metformin. Data on hard endpoints such as microvascular damage and mortality are lacking.

Adverse events

Persons with familial renal glucosuria, who have loss-of-function mutations in the gene encoding SGLT2 have no major morbidity and a normal life expectancy. This has been used as an argument for the safety of SLGT2 inhibitors. It must however be noted that these people are not exposed to the same level of glucosuria as those with type 2 diabetes, let alone those with type 2 diabetes starting SGLT2 inhibitors. This is reflected in the clinical data: urinary tract infections and genital infections (vulvovaginitis, balanitis) occur about twice as frequent in users of SGLT2 Inhibitors compared to controls. Hypoglycaemia is not an intrinsic side-effect of SGLT2 inhibitors, but when combining these drugs with insulin these may possibly increase the risk of hypoglycaemia. Finally, a somewhat higher frequency of bladder cancer and breast cancer in users of SGLT2 inhibitors compared to controls was observed in the clinical studies, but at the moment there a not sufficient data to draw any firm conclusions regarding this topic. In reflection of the difficulty in assessing these data, the European Medicines Agencies has recommended that dapagliflozin be approved for use in type 2 diabetes whereas the American FDA has asked for further studies by the manufacturer.

References

  1. ^ Von Noorden C, Metabolism and Practical Medicine, Walker Hall trans, William Heinemann, London, 1907, Vol III, 1184-98

  2. ^ Ehrenkrantz J et al. Phlorizin: a review. Diabetes Metabolism Research and Reviews 2005;21:31-8

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