Pharmacodynamics, Efficacy and Safety of Sodium–Glucose Co-Transporter Type 2 (SGLT2) Inhibitors for the Treatment of Type 2 Diabetes Mellitus

Abstract

Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment, and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population. The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebo-controlled trials with cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy als...

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

“…Taken together, these findings suggest that the combination of a DPP-4i with a SGLT2i would potentially provide additional help to individuals with T2D in reaching their glycaemic goal. Beyond a glucose-lowering effect, SGLT2i have some added value with reductions in body weight (including abdominal adiposity), blood pressure and serum uric acid, all markers considered as independent cardiovascular risk factors (Table 1) [8]. In EMPA-REG OUTCOME trial, empagliflozin, a selective SGLT2i, was associated with a remarkable reduction in cardiovascular and all-cause mortality in T2D patients with antecedents of cardiovascular disease [11,12].…”

“…SGLT2i, which target the kidney and promote glucosuria, belong to the newest pharmacological class of glucose-lowering agents [8]. Both their efficacy and safety have been recently reviewed [9,10].…”

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

“…SGLT2i (also known as gliflozins), which target the kidney and promote glucosuria, belong to the newest pharmacological class of glucose-lowering agents [3] . Both their efficacy and safety have been recently reviewed [4,5] .…”

“…Beyond a glucose-lowering effect, SGLT2i have some added value with reductions in body weight (including abdominal adiposity), blood pressure and serum uric acid, all markers considered as independent cardiovascular risk factors [3] . In EMPA-REG OUTCOME trial, empagliflozin was associated not only with a remarkable reduction in cardiovascular and allcause mortality in T2D patients with antecedents of cardiovascular disease [6,9] but also with a marked reduction in the incidence rate of hospitalisation for heart failure [16] .…”

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

“…Thus, there is little potential for pharmacokinetic interaction,11 but this has yet to be tested 5, 12…”