Dapagliflozin (developed by Bristol – Myers Squibb and AstraZeneca) is the furthest advanced compound in clinical development belonging to the SGLT2 inhibitor class. It has favourable pharmacokinetic profile as compared to earlier agents. The C-aryl glycosidic linkage present in dapagliflozin confers resistance to degradation by intestinal β-glucosidase enzymes. Consequently, it is orally effective and has a long duration of action that suppresses both postprandial and fasting hyperglycemia for 24 h on once-daily dosing.[42,46] It also has approximately 1200 times more selectivity for SGLT2 than SGLT1.
Dapagliflozin has shown promising results in various preclinical and clinical studies of T2DM. Administration of a single dose of dapagliflozin induced renal glucose excretion in normal and diabetic rats without causing hypoglycemia. It also improved glucose tolerance in normal rats, and reduced hyperglycemia in Zucker diabetic fatty (ZDF) rats. Chronic treatment with dapagliflozin for 2 weeks significantly lowered fasting and fed glucose levels in ZDF rats and resulted in a significant increase in glucose utilization rate, accompanied by a significant reduction in hepatic glucose production. This promising evidence of efficacy in animal models led to further clinical investigations in humans.
In clinical studies, treatment with oral dapagliflozin (either as monotherapy or in combination with other antidiabetic drugs) significantly reduced fasting plasma glucose levels, improved glycemic control and decreased weight in T2DM patients (Table 2[30–35,47–50]). There was also a reduction in mean systolic and diastolic blood pressure due to its diuretic action.[30–32,35] This reduction in blood pressure was seen without an increased incidence of orthostatic hypotension.[30–32,35] In a few studies, dapagliflozin treatment also increased plasma high density lipoprotein (HDL) cholesterol levels and decreased plasma triglyceride levels.[30,32]
Clinical trials of dapagliflozin
Dapagliflozin was well tolerated in clinical trials. The most common side effect of dapagliflozin was an increased incidence of genital infections and urinary tract infections (UTI).[30–35,47–50] Genital infections were dose dependent. The incidence rates of genital infections with dapagliflozin dose 2.5, 5 and 10 mg were 5.8%, 7% and 7%, respectively, as compared to only 2.3% with placebo. These were more common in females in the form of vulvovaginal mycotic infection. Genital infections responded satisfactorily to standard treatment and led to discontinuation of study medication only in a few patients. More patients in the dapagliflozin group reported events suggestive of UTI as compared to those treated with placebo. The risk of UTI was not related to dose and duration of the treatment. The incidence rates of UTI with dapagliflozin dose 2.5, 5 and 10 mg were 4.2%, 7.3% and 6.5%, respectively, as compared to 4.5% with placebo. Like genital infections, UTIs were also more common in females. Most cases were mild to moderate in intensity and resolved with standard medication. Pyelonephritis was an uncommon event and occurred at equal rates in both placebo and dapagliflozin-treated groups (0.1% in both groups). Although these common side effects of dapagliflozin were not serious in nature, their long-term effect on renal function and reproduction remains to be investigated.
Serious but rare side effects of dapagliflozin include cancer development and hepatotoxicity. The safety data pooled from T2DM patients enrolled in phase 2b and 3 clinical trials revealed an increased incidence of bladder and breast cancer. A total of 9 cases of bladder cancer were reported out of 5478 patients in the study group, as compared to 1 case out of 3156 patients in the control group (0.3% of patients in dapagliflozin group as compared to 0.05% of patients in the control group). Also, there were 9 cases of breast cancer out of 2223 women in the study group as compared to 1 case in 1053 women in the control group (0.4% of women on dapagliflozin as compared to 0.1% of women in the control group). Given the lack of statistical significance of the breast and bladder cancer observation (P = 0.15 and P = 0.27, respectively) at this time, it is still unclear whether this is due to the carcinogenic potential of the drug or an imbalance of some baseline risk factor between the study and control groups. These findings require further investigation as neither bladder nor breast tissue express SGLT2 transporters. Moreover, rigorous 2-year carcinogenic studies in animals failed to demonstrate any neoplastic activity. Breast and especially bladder cancers take many years to develop, whereas the exposure to dapagliflozin was short (generally ≤1 year). In addition, there could have been a detection bias for bladder cancer, as frequent urine analyses in the treatment group (due to increased incidence of UTI) may have led to the discovery of microscopic hematuria. Similarly, weight loss in the treatment group may have lead to a relatively easier location of breast lump, thus increasing the rate of diagnosis of carcinoma breast.
Five cases in the Phase 2b and 3 clinical trial data pool were found to have elevated values of liver enzymes suggesting liver injury (laboratory values of aspartate aminotransferase or alanine aminotransferase more than three times the upper limit of normal in addition to elevation of total bilirubin greater than twice the upper limit of normal). An adequate explanation for these biochemical abnormalities could be identified in only one case. This was classified as a ‘probable diagnosis of mild to moderately severe dapagliflozin-induced liver injury’.
In clinical trials of dapagliflozin, a low risk of hypoglycemic episodes has been reported since this group of drugs acts selectively targeting the renal glucose transporters without affecting the counter regulatory hormones.[30–35,50] In a meta-analysis of randomized controlled trials of dapagliflozin, it was found that the overall incidence of major hypoglycemic events did not exceed 1% and was not significantly increased by dapagliflozin treatment. However, the risk of mild hypoglycemic events, generally not leading to the discontinuation of the drug, was reported more frequently with dapagliflozin compared to placebo. Further analysis of data revealed that this increased risk was not dose related and could only be explained by co-administration of insulin.[48,53] These results imply that although the risk of hypoglycemia with use of these drugs is low, it is important to investigate this risk when these drugs are administered in combination with other antidiabetic agents.
Dapagliflozin treatment was associated with a dose-dependent increase in hematocrit and blood urea nitrogen levels, suggesting volume depletion.[30,35,47] Dehydration and hypovolemia might put the patients at increased risk of thromoembolic events. The clinical relevance of this side effect is yet to be established, especially in elderly patients and patients on antihypertensive therapy and diuretics. There was also a dose-dependent decrease in serum uric acid levels with dapagliflozin treatment reported in few clinical trials.[30,35,47] The clinical relevance of this finding is unknown, although an association between glucosuria and increased renal uric acid clearance has been reported in some studies.
The finding of increased trabecular bone mass by dapagliflozin in animal studies led to a more critical assessment of the risk of fractures in clinical trials. The data gathered from phase 2b and 3 clinical trials demonstrated no significant effect on bone loss or increased risk of fracture.[36,38] In a few studies, an increase in levels of serum magnesium, phosphate and parathyroid hormone was found.[30,35,47] These electrolyte changes were statistically insignificant. The long-term effect of dapagliflozin on bone health remains to be investigated.
Dapagliflozin has completed phase 3 clinical trials as a once-daily oral treatment for T2DM. Its New Drug Application (NDA) has recently been reviewed by the US Food and Drug Administration (FDA). Citing fears of cancer development, the Endocrinologic and Metabolic Drugs Advisory Committee of FDA has voted against the approval of the drug. The FDA panel stated that ‘based on evaluation of the Surveillance Epidemiology and End Results (SEER) database and review of the literature on the incidence of these cancers in T2DM, it was determined that the number of observed breast and bladder cancers in the dapagliflozin-treated group exceeded the expected number of cases in the general T2DM population’. Other safety issues reviewed by the FDA panel included a possible hepatotoxicity risk and increased incidence of genitourinary infections by the drug.
The FDA advisory panel also questioned the efficacy of the drug in renal impairment. Patients with severe renal impairment (GFR<30 ml/min/1.73 m2) were excluded from large controlled clinical trials. Hence, the efficacy and safety data could not be extracted from these patients. Clinical trials conducted to assess the efficacy of dapagliflozin in patients with moderate renal impairment (GFR = 30 ml/min/1.73 m2 to 59 l/min/1.73 m2) demonstrated no statistical significant difference in attaining glycemic control by either placebo or dapagliflozin at the end of the treatment period.[36,38] These observations restrict the use of dapagliflozin to diabetic patients with normal renal function or patients with mild renal impairment. The FDA panel discussed the need for monitoring the renal function prior to or during the course of therapy. They also argued that as T2DM patients are at risk of worsening renal function over the course of their disease, the secondary failure of glycemic control might reflect a failure of dapagliflozin efficacy and require discontinuation of drug. This would be in contrast to the common practice of adding drugs with complementary effects in uncontrolled diabetes.
Based on these safety and efficacy concerns, the FDA advisory panel has delayed the approval of the drug, asking the manufacturers to submit the additional clinical data of dapagliflozin to allow a better assessment of its benefit–risk profile.
Despite a setback from the FDA, dapagliflozin has received a positive opinion from the Committee for Medicinal Products (CHMP) of the European Medicine Agency (EMEA), which will now be reviewed by the European commission. Dapagliflozin (Forxiga 5 mg/10 mg once daily) is intended to be approved for adult patients with type 2 diabetes to improve glycaemic control, as a monotherapy in metformin-intolerant patients as an adjunct to diet and exercise, and in combination with other glucose-lowering drugs, including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.
Other SGLT 2 inhibitors in clinical trials
A number of SGLT2 inhibitors are currently in phase 2/3 clinical trials, including canagliflozin, empagliflozin (BI 10773), ipragliflozin (ASP 1941), luseogliflozin (TS 071), LX4211, tofogliflozin (CSG 452), ertugliflozin (PF04971729) and EGT 1474 (Tables 3 and 4).[15,58–75] LX4211 is a dual SGLT2/ SGLT1 inhibitor (lesser extent of SGLT1 inhibition as compared to SGLT2). It inhibits both glucose reabsorption by the kidney and glucose absorption by the small intestine. It thus produces rapid and robust decreases in fasting plasma glucose, improvements in postprandial glycemic control and reductions in haemoglobin A1c (HbA1c). The HbA1c reductions achieved with LX4211 after 4 weeks of treatment were comparable to those achieved by other SGLT2 inhibitors at 12 weeks of treatment.[15,52] In this short-term clinical trial there were no reports of severe gastrointestinal adverse effects due to SGLT1 inhibition.
Table 3. SGLT2 inhibitors currently in clinical development (58–66)
|Canagliflozin||Johnson & Johnson||NDA submitted to US-FDA|
|Empagliflozin (BI 10773)||Boehringer Ingelheim||Phase 3|
|Ipragliflozin (ASP 1941)||Astella Pharma. Inc.||Phase 2/3|
|LX 4211*||Lexicon Pharmaceuticals||Phase 2|
|Luseogliflozin (TS071)||Taisho Pharmaceuticals Co. Ltd||Phase 3|
|Tofogliflozin (CSG452)||Chugai Pharmaceuticals||Phase 3|
|Ertugliflozin (PF 04971729)||Pfizer||Phase 2|
|EGT1474||Theracos Inc.||Phase 1|
|ISIS 388626||Isis Pharmaceuticals||Phase 1|Table 4.
Effects of the SGLT2 inhibitors (currently in phase 2/3 clinical trials) on HbA1c, fasting plasma glucose and body weight in patients of T2DM
SGLT 2 antisense oligonucleotide
ISIS – 388626 (developed by Isis Pharmaceuticals) represents a novel approach to SGLT2 inhibition. It is an antisense oligonucleotide (ASO) designed to block the expression of the SGLT2 gene in vivo. Administration of ISIS – 388626 once weekly yielded an approximately 80% reduction of renal SGLT2 mRNA expression without affecting SGLT1 expression. It was safe and effective during 6-week studies in dogs, 3-month studies in Sprague–Dawley (SD) rats and 6-month studies in ZDF rats. In ZDF rats a marked decrease in plasma glucose was attained after once-a-week injection for 4 weeks and this effect was maintained throughout the 6-month study (saline: 695 ± 46 mg/dl; ASO-treated: 382 ± 48 mg/dl), with a significant reduction in HbA1c (saline: 10.9 ± 0.3%; ASO-treated: 6.3 ± 0.8%). ISIS 388626 also slowed progression of ocular cataract formation, glomerular kidney and pancreatic islet cell deterioration.[10,76] This drug is in the early phase of clinical testing. The current clinical development of ISIS 388626 is not known.