A vexing aspect of the treatment of type 2 diabetes is the potential of both insulin and the sulfonylureas to cause hypoglycemia, with increasing recognition of the association of hypoglycemia with adverse outcome. It is hypoglycemia rather than normalization of glycemic control that appears (for certain individuals) to be undesirable. Although in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study intensive glycemic treatment was associated with an increase in mortality, there was actual reduction in mortality with excellent control, with the dilemma that those diabetic patients in worse control initially appeared to have greater risk of both hypoglycemia and mortality.[2-4] Thus, the appearance of a new therapeutic class not intrinsically associated with hypoglycemia should be greeted with cautious optimism.
Glucose is present in the glomerular filtrate and is, under usual circumstances, completely reabsorbed by a group of transport proteins in the renal tubular epithelium, with sodium glucose transporter (SGLT)-2 quantitatively the most important. Recent observations have shown that diabetic patients upregulate the expression of this and other renal glucose transporters, presumably to compensate for and reduce glycosuria. A number of orally absorbed small molecules can inhibit this transporter, leading to glycosuria at even modestly elevated glucose concentrations, a phenomenon that was used experimentally nearly three decades ago in studies demonstrating that glucose toxicity is a reversible contributor to both insulin resistance and impaired insulin secretion. Glucose excretion with administration of these SGLT2 inhibitors increases in degree as glucose levels rise, whereas the agents do not increase glycosuria to a major degree at eu- or hypoglycemic levels. In addition, by causing osmotic diuresis, these agents may have benefits in lowering blood pressure, and the glucose lost in the urine can lead to weight reduction.
What are the clinical data? A number of SGLT2 inhibitors are being studied, including dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin. A series of Phase 3 clinical trials of dapagliflozin presented to the US Food and Drug Administration showed dose-related glucose-lowering of similar efficacy to that of sulfonylureas and metformin, with a study of dapagliflozin added to metformin showing a glucose-lowering effect equal to that of glipizide, but with less than one-tenth as much hypoglycemia. In a meta-analysis of clinical studies, dapagliflozin was associated with significant weight loss and with a reduction in systolic blood pressure without increasing hypoglycemia. Dapagliflozin is approved for the treatment of type 2 diabetes in the European Union. Canagliflozin, which has recently been approved in the US, similarly lowers glucose, blood pressure, and body weight in a dose-related manner. In a study of type 2 diabetic patients treated with metformin plus sulfonylurea, canagliflozin at the highest dose lowered HbA1c to a greater extent than did sitagliptin. Empagliflozin and ipragliflozin have been less well studied, but appear to similarly lower glucose levels in monotherapy and in combination with metformin.
It was thought that inhibition of the major intestinal glucose transporter SGLT1 would lead to undesirable gastrointestinal side effects, but interesting preliminary evaluation of LX4211, which inhibits SGLT1 as well as SGLT2, showed that in addition to similar glucose-lowering efficacy to that of the SGLT2 inhibitors, LX4211increased levels of both glucagon-like peptide-1 (GLP-1) and peptide YY, suggesting that by increasing the delivery of glucose to the distal small intestine there may be L-cell stimulation. In fact, because of the higher drug concentrations in the gastrointestinal tract, the SGLT2 inhibitors may also act on gastrointestinal SGLT1, with studies of canagliflozin showing that it lowers postprandial glucose in association with a reduction in gastrointestinal glucose absorption, and reduces renal glucose reabsorption.
However, there are a number of potential adverse effects to be considered in the use of SGLT2 inhibitors. By increasing glycosuria, they can predispose to both urinary infection and fungal genital tract infection,[10, 18, 19] and concerns have been raised as to potential for the development of bladder and breast cancers with dapagliflozin; such effects did not appear to occur with canagliflozin. Although diuresis is beneficial in the treatment of hypertension, some treated patients may become dehydrated with the agent, which could lead to initial adverse cardiovascular effects, although there is no overall evidence of cardiac safety effects. Given the dependence of the glycosuria on glucose in the glomerular filtrate, there is limited benefit with renal insufficiency. Finally, a dose-related 4–8 mg/dL (0.1–0.2 mmol/L) elevation in low-density lipoprotein–cholesterol (LDL-C) was observed with canagliflozin.
We are left then with a fascinating group of agents exhibiting the benefits of glucose lowering without hypoglycemia risk, with weight loss and the potential for blood pressure lowering. Concerns include urinary infection, genital tract micotic infection, the potential for volume depletion, very limited evidence of increased malignancy with dapagliflozin, and with mild but definite LDL-C increases with canagliflozin, and the lesser efficacy of these agents with renal insufficiency. Just as we now routinely give combinations of multiple blood pressure-lowering agents in the treatment of hypertension, can we foresee a time when multiple oral agents can be given to type 2 diabetic patients, with a low risk of hypoglycemia and weight gain, allowing stable long-term glycemic control?