The Role of Kidney in Glucose Homeostasis — SGLT2 Inhibitors, a New Approach in Diabetes Treatment

Vasileios Andrianesis; John Doupis

Disclosures

Expert Rev Clin Pharmacol. 2013;6(5):519-539. 

In This Article

First SGLT2 Inhibitors

The SGLT2 inhibitors that follow Phlorizin are glycosides that adopt the basics of its molecular structure and they resist intestinal degradation including also SGLT2 selectivity in the same time. The first agent,T-1095,and its active metabolite T-1095A, was not released to the market due to its mild selectivity on SGLT2 transporters.[60,61] Sergliflozin etabonate and its active entity Sergliflozin was progressed to Phase I clinical testing. Although it reached maximum plasma concentration at ~30–45 min post dose, it had a plasma elimination half-life of 0.5–1 h limiting the duration of the glucosuric effect.[62] This pharmacokinetic profile of Sergliflozin is attributed to O-glycoside linkages of the drug that make it vulnerable to hydrolysis by intestinal b-glucosidase.[61]

Remogliflozin etabonate and its active form, Remogliflozin, is a benzylpyrazole glycosidewith different structure than the other O-glycoside SGLT2 inhibitors, representing a novel category of selective low-affinity SGLT2 inhibitors.[63] Remogliflozin exhibits a plasma half-life of 120 min and it presents a dose-dependent glucosuria.[64] Latest studies suggest that apart from plasma glucose reduction, remogliflozin administration resulted in a significant decreasein body weight and blood pressure in human subjects with T2DM.[65] It has been also reported that remogliflozin may be also safely administered in patients with type 1 diabetes providing significant plasma glucose reduction.[66] Based on recent data, remogliflozin is in Phase IIb development.[102]

AVE2268 is another O-glycoside SGLT2 inhibitor that is currently in Phase II of clinical development.[67] Interestingly, apart from SGLT2 inhibitors, ISIS-388626 (ISIS Pharmaceuticals, San Diego, CA, USA) represents a novel intervention on SGLT2 glucose regulation mechanism. This agent is an antisense oligonucleotide that blocks the expression of SGLT2 gene. Animal studies have shown that once weekly subcutaneous administration of ISIS-388626 induced an 80% reduction of SGLT2 mRNA expression.[68] This was accompanied by a more than 1000-fold increase in glucosuria that persisted for several weeks after the treatment cessation.[69]

Dapagliflozin

Dapagliflozin is a C-glycoside developed by Bristol-Myers Squibb and Astra Zeneca. It is the first agent of this class that has completed Phase III clinical trials as once-daily oral treatment for T2DM.Contrary to the O-glycosides, the C-aryl glycosidic linkage of its structure makes dapagliflozin resistant to degradation from intestinal β-glycosidase enzymes prolonging its bioavailability.[70] Therefore, a single daily dose is sufficient to suppress both postprandial and fasting hyperglycemia.[70] Dapagliflozin presents an approximately 1,200 times more selective action for human SGLT2 than hSGLT1 transporters (EC50 for hSGLT2: 1.12 and for hSGLT1: 1,391).[71] The main results of the clinical trials on dapagliflozin are summarized in Table 2.

Efficacy

Efficacy of dapagliflozin in patients with type 2 diabetes has been tested in many clinical studies, either as monotherapy or in combination with other antidiabetic agents. Administration of dapagliflozin resulted in a glucosuria-related urinary calories loss (200–300 calories/day)[72] and a significant decrease both in fasting[56,72–74] and postprandial plasma glucose levels.[56,74] Additionally, many studies presented a significant HbA1c reduction,[56,57,72–74] an improved glycemic control and an significantdecrease in body weight.[56,72–75] It appears also likely that weight reduction during the first week of the trials represents fluid loss, whereas weight loss during the following weeks of dapagliflozin administration represents decreased fat mass.[74] The increased osmotic dieresis and mild urinary sodium loss after dapagliflozin administration, may explain the reduction in mean systolic and diastolic blood pressure,[56,72,74,75] the modest rises in hematocrit level and the increase in blood urea nitrogen that was observed in many studies.[56,72,74,75] This diuretic effect of dapagliflozin administration did not appear to increase the incidence of orthostatic hypotension and did not cause any meaningful changes in blood electrolytes levels.[56,57,72,73] In some studies also, dapagliflozin produced a small increase in HDL cholesterol without changing radically patient's lipidemic profile.[57,73,75] Finally, given that the mechanism of dapagliflozin action is unrelated to insulin secretion, itminimizes the risk of hypoglycemic episodes.[56] Although in all studies, there were no major hypoglycemic episodes, the rate of moderate hypoglycemia in the dapagliflozin-treated group was increased versus the placebo,[56] but it was decreased versus glipizide[75] and almost similar with metformin.[74]

Safety Issues

Genital and urinary tract infectionsare the most frequent side effects reported after dapagliflozin administration. According to the briefing document of the FDA Advisory Committee Meeting on dapagliflozin,[103] the number of genital infections (GIs) was dose dependent (2.1% in placebo group, 5.8% in 2.5 mg, 7.0% in 5 mg and 7.0% in 10 mg dapagliflozin group).[72] They were more common in females[75] and the rate of GI recurrence did not differ between the placebo and the dapagliflozin treatment groups. In females, the most common GI was vulvovaginal mycotic infection and in males the pruritus. Urinary tract infections (UTIs) were more frequent in dapagliflozin groups compared to placebo (4.5% in placebo, 4.2% in 2.5 mg, 7.3% in 5 mg and 6.5% in 10 mg dapagliflozin groups).[72] Female subjects were more susceptible to both genital and UTI than male,[75] and most cases were mild to moderate in intensity. Pyelonephritis was a rare adverse event and was reported with no significant difference between dapagliflozin and placebo group.[103]

FDA concerns to dapagliflozin mainly derived from increased rates of bladder and breast cancer cases that observed in clinical studies. More specifically, there were nine cases of bladder cancer in dapagliflozin-treated male subjects versus one case in placebo groups. These cases were reported via both the Four Month Safety Update and the Investigational New Drug Safety Reports for dapagliflozin.[103] As for the breast cancer, there were nine cases in the dapagliflozin group and none in the controls group. All the nine cases were women.[103] However, the short duration of drug administration (generally <1 year) cannot support strong causative relation given that breast and bladder cancer take many years to develop.[76] Moreover, FDA advisory committee in the briefing document for the dapagliflozin suggests that frequent urinalysis to dapagliflozin-treated patients, as a result of glucosuria and genito-urinary adverse events, may promote a detection bias.[103] Post-baseline detection of hematuria due to often urinalysis in the dapagliflozin group versus controls and further investigation of this hematuria leaded to higher rate of bladder cancer diagnosis than the controls group. Finally, studies on the safety of SGLT2 inhibitors[76] present that there was not observed carcinogenic action of SGLT2 inhibitors in animal trials and breast and bladder tissues do not express SGLT2 transporter gene.[103]

In Phases IIb and III of clinical trials, there were five cases with elevated serum ALT and total bilirubin levels compatible with biochemical Hy's law (hepatocellular injury caused from drugs with greater than threefold elevation of alanine transaminase or aspartate transaminase and greater than twofold elevation of total bilirubin level and not relation with other causes of acute liver disease), but only one case was finally associated with dapagliflozin and defined as a probable drug-induced liver injury (DILI).[103] There were reported several cases with hepatic markers elevation that cannot be linked to the treatment and cases that the assessment of their cause was difficult due to lack of sufficient data.[103]

Regarding bone health, Advisory Committee of the FDA concluded that dapagliflozin has minimal effects on bone mineral density and it is not related to bone loss or fracture and as for the cardiovascular system, the cardiovascular events rate did not significantly differ between dapagliflozin-treated groups and controls.[103]

Renal impairment is acommon diabetic complication and its incidence increases along with the progress of the disease. The efficacy of dapagliflozin depends on the filtered load of glucose, which is related to GFR. Due to this fact, patients with severe renal impairment and estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 were excluded from large controlled clinical trials.[103] One of the clinical trials in Phases IIb and III, which submitted to FDA advisor committee, was a 24-week trial in diabetic subjects with moderate renal impairment (eGFR of 30–59 ml/min/1.73 m2). Data from this study showed that both 5 and 10 mg doses of dapagliflozin failed to show statistically significant reduction of HdA1c.[103] Similar results were reported from an 'adhoc' subgroup analysis in Stage 3A patients with eGFR of 45–59. Therefore, dapagliflozin effectiveness is restricted to subjects with normal renal function or mild impairment.[104] Regarding the renal-related adverse events of dapagliflozin, they appeared to be similar to the control group. However, in short-term groups, there were reported 23 (1.1%) cases with elevated blood creatinine levels in the dapagliflozin-treated group versus 4 (0.6%) in the placebo.[103] Volume depletion events (hypotension, hypovolemia and dehydration) were slightly more frequent in dapagliflozin-treated patients versus the placebo group and especially in subjects who had been treated with thiazides, ACE-I or ARBs as well.[103] For this reason, a lower dose of 5 mg dapagliflozin was proposed in patients at higher risk of volume depletion. Additionally, as expected, due to volume depletion, there were small increases in mean hematocrit and hemoglobin levels (at Week 24 hematocrit increase for 1.6, 1.8 and 2.1% in dapagliflozin 2.5, 5, 10 mg groups, respectively, and for −0.4 in placebo) and an increase of the risk for deep vein thrombosis and pulmonary embolism. However, the rates of these events were very similar both in dapagliflozin-treated groups and the placebo.[103]

Although dapagliflozin is the first drug of this class of agents that was submitted for approval, the Endocrinologic and Metabolic Drugs Advisory Committee of FDA due to numerical imbalance of cancer cases between dapagliflozin-treated groups and placebo voted against the approval of the drugasking for additional clinical data on dapagliflozin benefit risk profile.[105,106] From the other hand, the Committee for Medicinal Products of the European Medicine Agency (EMA) voted for dapagliflozin and the European commission gave the final approval for Forxiga 5 mg/10 mg (trade name for dapagliflozin) in November 2012.[107]

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