Evidence of the Month

Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.

Maria Rosa Gallego Vila Franca Xira Health Care Centre Vila Franca de Xira, Portugal	Click here to download PowerPoint slides of this commentary.
	Click here for the programme evaluation and post-test.

Background
The kidneys perform a role in blood glucose regulation that serves energy needs but works to the disadvantage of people with Type 2 diabetes. Through the action of sodium-glucose cotransporters (SGLTs), the proximal renal tubules reabsorb filtered glucose into the bloodstream so that all of it is available for energy and none of it is lost in the urine. In the presence of hyperglycaemia, this full recovery of glucose is counterproductive; the kidneys would better serve people with Type 2 diabetes by excreting instead of reabsorbing excess glucose. However, elevated glucose has been found to beget elevated SGLTs, giving the kidneys an even higher capacity for glucose reabsorption.

Research in recent years has focused on the treatment of Type 2 diabetes through selective inhibition of SGLT2, the transporter protein responsible for almost all renal glucose reabsorption. The goal of this strategy is to encourage urinary glucose excretion and thereby reduce hyperglycaemia and related complications. Therapeutic inhibitors of SGLT2 are being tested in animal studies and early clinical trials, which are reviewed by Abdul-Ghani and DeFronzo.

Methods and Key Results
The authors considered published data on renal filtration and reabsorption of glucose in normal and hyperglycaemic states; the effects of SGLT2 inhibition on glucose reabsorption, glucose levels, insulin resistance, and β-cell function; and the safety of SGLT2 inhibition in the treatment of Type 2 diabetes. Their report highlights the following findings:

Renal glucose reabsorption—SGLT2 acts in the convoluted segment of the proximal renal tubule to handle 90% of glucose reabsorption. SGLT1, a transporter protein located in the distal straight segment of the proximal tubule (as well as the gut), is responsible for 10% of glucose reabsorption. The maximal glucose reabsorptive capacity (Tm) of the proximal tubule averages 375 mg/min, well above the rate needed for normoglycaemic individuals. In the presence of hyperglycaemia, the filtered glucose load may exceed the Tm, resulting in glycosuria. However, in vitro and animal studies have shown that hyperglycaemia increases the gene expression and activity of SGLT2, which raises the Tm for glucose, minimizes glycosuria, and exacerbates hyperglycaemia. Though not systematically studied in individuals with Type 2 diabetes, an increased Tm has indeed been observed in individuals with Type 1 diabetes. Together these findings have given rise to the concept of selectively inhibiting SGLT2 to increase glycosuria and improve hyperglycaemic parameters.

Effects of SGLT2 inhibition—For proof of concept studies, a competitor of SGLT2 known as phlorizin was used in diabetic rats. It successfully induced glycosuria, normalized fasting and fed-state glucose levels, reversed insulin resistance, and improved β-cell function. Selective SGLT2 inhibitors including sergliflozin, dapagliflozin, and the phlorizin derivative T-1095 have since been developed and found to improve β-cell function and insulin sensitivity in the liver and muscle. Dapagliflozin has been shown to have the greatest selectivity for SGLT2 versus SGLT1 and to require the lowest concentration to achieve 50% inhibition (EC₅₀) of SGLT2.

In phase 1 and 2 clinical trials, dapagliflozin treatment has induced glycosuria and reduced fasting glucose and the area under the curve during oral glucose tolerance testing in individuals with Type 2 diabetes. It has also reduced glycated haemoglobin (HbA_1c) by 0.7 % over 12 weeks (without evidence of dose dependence) from baseline levels of 7.8 % to 8.0 %. Weight loss (about 2 to 3 kg) and blood pressure reduction have also been noted. Studies with sergliflozin have shown dose-dependent glycosuria and modest weight loss over 14 days in individuals with Type 2 diabetes.

Safety of SGLT2 inhibition—Despite increased glycosuria, excessive losses of fluid, sodium, or potassium have not emerged as major safety issues with SGLT2 inhibition. Nor has hypoglycaemia, because SGLT2 inhibition does not affect glucose counter-regulatory mechanisms. (The rate of hypoglycaemia associated with dapagliflozin, for example, has been similar to that associated with metformin.) However, an increase in urinary tract infections and vaginitis has been observed and may be a potential drawback of enhanced glycosuria.

Clinical Implications
The potential therapeutic value of SGLT2 inhibition for Type 2 diabetes seems exceptionally high at this point of research. As Abdul-Ghani and DeFronzo point out, the unique mode of action of SGLT2 inhibition—that is, its independence from insulin secretion or insulin resistance—suggests that it may continue to be effective despite β-cell dysfunction or severe insulin resistance. At the same time, these very problems may be ameliorated by the corrective effects on hyperglycaemia from SGLT2 inhibition. The unique mechanism of action also suggests an opportunity for effective combination therapy with existing anti-diabetic agents that target insulin secretion or glucose metabolism.

Much is yet to be learned about the safety of enhancing glycosuria. However, a genetic model of SGLT2 inhibition exists to offer insights. Individuals with familial renal glycosuria have a decreased Tm for glucose, reduced SGLT2 or SGLT2 activity, and chronic glycosuria (excreting up to 100 g or more of glucose per day), yet they evince normal blood glucose levels, normal renal function, rare hypoglycaemia, and no increases in urinary tract infections. In treating individuals with Type 2 diabetes, a similarly favourable side-effect profile may depend largely on the ability to selectivity inhibit SGLT2 over SGLT1, given that SGLT1 inhibition is associated with glucose malabsorption and diarrhea. If such side effects can be avoided, SGLT2 inhibition may offer a new and important opportunity for glycaemic control and prevention of long-term diabetic complications.

All over the world, diabetes is an increasing pandemic disease. Evidence that the course of this disease is determined by the prevention and reduction of its major macrovascular and microvascular complications and mortality, through lifestyle changes and pharmacological intervention strategies, has been leading research for many years now.

The growing knowledge about the causal pathophysiological changes observed in diabetes promoted a pipeline of drug development in the last decades. Because diabetes is a multifactorial disease, the use of several drugs to tackle the underlying suspected causes is a common fact in clinical practice, since lifestyle changes, though the more efficacious strategy, are difficult to maintain, and still not enough to achieve a near-normal glycaemic control throughout life.

Metformin is considered the first-line oral anti-hyperglycaemic agent for the treatment of Type 2 diabetes. Therefore, SGLT2 inhibitors would be considered as an add-on, second-line agent in individuals not adequately controlled on metformin monotherapy and as an alternative to other second-line treatment options, including sulfonylureas (with advantages in relation to weight gain and hypoglycaemic risk), thiazolidinediones (no oedema or weight gain), and dipeptidyl peptidase-4 inhibitors.

In this review, the authors point out that SGLT2 inhibitors appear to be safe in the phase 1, 2, and 3 studies, and generally well tolerated, and will potentially be a beneficial addition to the growing battery of oral anti-hyperglycaemic agents. Nevertheless, as with all agents, safety issues regarding long-term use and drug interactions must be a concern for all clinicians, especially in a chronic disease where the average number of drugs is more than 6.