Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials.

Existing Reviews

Please note, new claims can take a short while to show up.

No claims yet.

Annotation Summary

Term Occurence Count Dictionary
type 2 diabetes mellitus 4 endocrinologydiseases
dapagliflozin 78 endocrinologydiseasesdrugs
diabetes mellitus 4 endocrinologydiseases
diabetic ketoacidosis 3 endocrinologydiseases
metformin 2 endocrinologydiseasesdrugs

Graph of close proximity drug and disease terms (within 200 characters).

Note: If this graph is empty, then there are no terms that meet the proximity constraint.

Review

Having read the paper, please pick a pair of statements from the paper to indicate that a drug and disease are related.

Select Drug Character Offset Drug Term Instance
dapagliflozin 936 (epub): 10/2017Publication date (ppub): 3/2018AbstractAimTo evaluate the safety and tolerability of dapagliflozin , a highly selective sodium‐glucose co‐transporter‐2 inhibitor, in patients with type 2 diabetes
dapagliflozin 1161 (T2DM).MethodsData were pooled from 13 placebo‐controlled trials of up to 24 weeks’ duration ( dapagliflozin , n = 2360; placebo, n = 2295). Larger placebo‐/comparator‐controlled pools of 21 (≤208 weeks;
dapagliflozin 1285 n = 2360; placebo, n = 2295). Larger placebo‐/comparator‐controlled pools of 21 (≤208 weeks; dapagliflozin , n = 5936; control, n = 3403) and 30 trials (≥12 weeks; dapagliflozin, n = 9195; control,
dapagliflozin 1367 (≤208 weeks; dapagliflozin, n = 5936; control, n = 3403) and 30 trials (≥12 weeks; dapagliflozin , n = 9195; control, n = 4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis
dapagliflozin 1621 respectively.ResultsOver 24 weeks, the overall incidence of AEs and serious AEs (SAEs) was similar for dapagliflozin and placebo: 60.0% vs 55.7% and 5.1% vs 5.4%, respectively. Rates of hypoglycaemia, volume depletion
dapagliflozin 1864 infections (UTIs) and fractures were balanced between the groups. Genital infections were more frequent with dapagliflozin (5.5%) vs placebo (0.6%) and renal function AEs occurred in 3.2% vs 1.8% of patients (the most common
dapagliflozin 2133 0.7%). In the 21‐study pool, 1 SAE of DKA and 3 AEs of ketonuria/metabolic acidosis occurred with dapagliflozin vs none with control; estimated combined incidence for these events was 0.03% (95% confidence interval
dapagliflozin 2365 In the 30‐study pool, lower limb amputation occurred in 8 (0.1%) and 7 (0.2%) patients receiving dapagliflozin and control, respectively.ConclusionThe overall incidence rates of AEs and SAEs were similar in the
dapagliflozin 2479 and control, respectively.ConclusionThe overall incidence rates of AEs and SAEs were similar in the dapagliflozin and placebo/control groups, including the incidence of hypoglycaemia, volume depletion, fractures, UTIs,
dapagliflozin 2662 volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with dapagliflozin than placebo.JabbourS, SeufertJ, ScheenA, BaileyCJ, KarupC, LangkildeAM. Dapagliflozin in patients with
dapagliflozin 4083 suppressing renal glucose reabsorption and increasing urinary glucose excretion.4, 5, 6 In phase III trials, dapagliflozin was efficacious and well tolerated in the early and late stages of T2DM, with no major imbalances in
dapagliflozin 4233 in the early and late stages of T2DM, with no major imbalances in safety events observed between the dapagliflozin and control arms.7, 8, 9, 10, 11Although the CV safety of SGLT2 inhibitors has been confirmed in recent
dapagliflozin 6512 interval [CI] 1.41 to 2.75).1The present analysis builds on a previous publication on the safety of dapagliflozin 19 by evaluating the safety and tolerability of dapagliflozin in a larger pool of studies and reporting
dapagliflozin 6573 previous publication on the safety of dapagliflozin19 by evaluating the safety and tolerability of dapagliflozin in a larger pool of studies and reporting the incidence of amputation and DKA, which were not included
dapagliflozin 7030 of up to 24 weeks’ duration (Figure S1), in which patients with T2DM were randomized to receive dapagliflozin 10 mg (N = 2360) or placebo (N = 2295). This included 3 phase IIb studies of 12 weeks’
dapagliflozin 7329 placebo‐controlled pool was analysed to better enable identification of any difference in the frequency of AEs with dapagliflozin vs placebo. (ClinicalTrials.gov identifiers: NCT00263276, NCT00357370, NCT00528372, NCT00528879, NCT00643851,
dapagliflozin 8086 observing these events. A pool of 21 placebo‐/active comparator‐controlled trials (≤208 weeks; dapagliflozin [N = 5936] and placebo/active comparator [N = 3403]) was used to assess DKA (Figure S2) and
dapagliflozin 8278 assess DKA (Figure S2) and a pool of 30 placebo‐/active comparator‐controlled trials (≥12 weeks; dapagliflozin [N = 9195] and placebo/active comparator [N = 4629]) was used to assess lower limb amputation
dapagliflozin 8552 for the 13‐study pool. Additional studies were analysed for amputations that were not part of the dapagliflozin clinical programme (such as those with a study group receiving saxagliptin plus dapagliflozin). In these
dapagliflozin 8646 of the dapagliflozin clinical programme (such as those with a study group receiving saxagliptin plus dapagliflozin ). In these two pools, the doses of dapagliflozin given across all studies were 2.5, 5, 10, 20 and 50 mg;
dapagliflozin 8695 those with a study group receiving saxagliptin plus dapagliflozin). In these two pools, the doses of dapagliflozin given across all studies were 2.5, 5, 10, 20 and 50 mg; however, dapagliflozin 5 and 10 mg were
dapagliflozin 8776 pools, the doses of dapagliflozin given across all studies were 2.5, 5, 10, 20 and 50 mg; however, dapagliflozin 5 and 10 mg were the most frequently used doses.Outcomes2.2The outcomes analysed in the 13‐study
dapagliflozin 11205 trial.RESULTS3Patient disposition3.1Patient baseline characteristics were generally similar in the dapagliflozin and control groups in the studies included in the 3 study pools (data for the 13‐ and 21‐study pools
dapagliflozin 11827 ≥60 mL/min/1.73 m2. Over 90% of patients had a body mass index ≥25 kg/m2. Overall, 10.0% and 11.6% of dapagliflozin ‐ and placebo‐treated patients, respectively, were treated with loop diuretics.Overall AEs: 13‐study
dapagliflozin 12078 AEs is shown in Table 1. The proportions of patients reporting ≥1 AE were 60.0% and 55.7% in the dapagliflozin and placebo groups, respectively. Most events were not serious, were considered not related to study
dapagliflozin 13074 13‐study pool3.3Hypoglycaemia3.3.1The overall incidence of hypoglycaemia was 13.7% and 12.4% with dapagliflozin and placebo, respectively (Table 2). Major hypoglycaemia occurred infrequently, with 3 and 2 events
dapagliflozin 13202 respectively (Table 2). Major hypoglycaemia occurred infrequently, with 3 and 2 events reported with dapagliflozin and placebo, respectively. Most of the events of major hypoglycaemia occurred in patients receiving
dapagliflozin 13369 major hypoglycaemia occurred in patients receiving insulin as background therapy. Only 1 patient in the dapagliflozin group discontinued treatment because of hypoglycaemia. This patient was receiving dapagliflozin added
dapagliflozin 13465 the dapagliflozin group discontinued treatment because of hypoglycaemia. This patient was receiving dapagliflozin added to insulin and metformin, and discontinued treatment after reporting major hypoglycaemia on day
dapagliflozin 15698 patient‐years)Patients with lower‐limb amputation, n (%)7 (0.2)8 (0.1)Dapagliflozin total includes dapagliflozin 2.5, 5, 10, 20 and 50 mg groups combined. Control includes placebo with/without background medications
dapagliflozin 16494 function3.3.2Overall, AEs of renal function were reported in 76 (3.2%) and 42 (1.8%) patients receiving dapagliflozin and placebo, respectively. A greater number of events of decreased renal creatinine clearance or renal
dapagliflozin 16641 greater number of events of decreased renal creatinine clearance or renal impairment were observed with dapagliflozin (Table 2; Table S2); however, most events were transient, of mild/moderate intensity, and not accompanied
dapagliflozin 17186 frequent in patients aged ≥65 years than in those aged <65 years (Table S2).In patients receiving dapagliflozin , there was an initial decline in eGFR at week 1 (Figure 1), followed by a return towards baseline levels
dapagliflozin 17398 levels over time (mean change from baseline at week 24: −1.45 and −0.67 mL/min/1.73 m2 with dapagliflozin and placebo, respectively). The change from baseline over time was consistent in the overall study population
dapagliflozin 17644 baseline eGFR ≥60 mL/min/1.73 m2; however, compared with patients with a higher baseline eGFR, dapagliflozin ‐treated patients with an eGFR of 30 to <60 mL/min/1.73 m2 had a smaller reduction in eGFR at week
dapagliflozin 18204 depletion3.3.3The incidence of AEs of volume depletion (hypotension/hypovolemia/dehydration) was 1.1% and 0.7% with dapagliflozin and placebo, respectively (Table 2). In both treatment groups, half of the AEs of volume depletion occurred
dapagliflozin 18429 week 8, with 18.5% (5/27) and 17.6% (3/17) occurring during the first 2 weeks of treatment in the dapagliflozin and placebo groups, respectively. When stratified by age, the frequency of AEs of volume depletion was
dapagliflozin 18630 volume depletion was similar in patients aged <65 and ≥65 years in the placebo group, whereas in the dapagliflozin group, patients aged ≥65 years were more likely to have an AE of volume depletion (Table S3). The
dapagliflozin 19596 treatment period (Table S4).Urinary tract infection3.3.4The occurrence of UTI was 4.7% and 3.5% with dapagliflozin and placebo, respectively (Table 2), and UTIs were more frequent in women than men in both treatment
dapagliflozin 19850 were mild/moderate in intensity, and UTI‐related discontinuations were infrequent and similar to dapagliflozin and placebo (5 [0.2%] and 2 [0.1%], respectively). Most patients in both treatment groups responded
dapagliflozin 20235 infections. Furthermore, of the patients who reported UTIs, 26 (23.6%) and 24 (29.6%) patients in the dapagliflozin and placebo groups, respectively, had a medical history of UTI (Table S5).Genital infection3.3.5Genital
dapagliflozin 20388 medical history of UTI (Table S5).Genital infection3.3.5Genital infections were more frequent with dapagliflozin vs placebo (5.5% vs 0.6%). More women than men experienced genital infections in both treatment groups
dapagliflozin 20660 and discontinuations because of genital infections were reported for 5 (0.2%) patients treated with dapagliflozin (vulvovaginal mycotic infection [3 patients], balanitis [1 patient] and vulvovaginal candidiasis [1
dapagliflozin 21063 treatment. Of the patients who reported genital infections, 8 (6.2%) and 2 (14.3%) patients in the dapagliflozin and placebo groups, respectively, had a medical history of recurrent yeast infection (Table S5).Fracture3.3.6The
dapagliflozin 21255 infection (Table S5).Fracture3.3.6The proportion of patients reporting fractures was small in both the dapagliflozin (8 [0.3%]) and placebo (17 [0.7%]) groups (Table 2). The most common fracture locations were the foot,
dapagliflozin 21868 21‐study pool3.4One SAE of DKA, 2 AEs of ketonuria and 1 AE of metabolic acidosis were reported in the dapagliflozin group and none in the control group (Table 2). The estimated incidence of DKA/metabolic acidosis with
dapagliflozin 21984 group and none in the control group (Table 2). The estimated incidence of DKA/metabolic acidosis with dapagliflozin was 0.03% (95% CI 0.010‐0.089) and the estimated incidence of DKA alone was 0.02% (95% CI 0.004‐0.059).
dapagliflozin 22161 DKA alone was 0.02% (95% CI 0.004‐0.059). The SAE of DKA occurred in a patient who was receiving dapagliflozin 10 mg added to metformin and insulin. An event of gastroenteritis was also recorded in this patient
dapagliflozin 22579 amputation (ie, leg and foot amputation, mostly affecting the toes) was reported for 8 (0.1%) and 7 (0.2%) dapagliflozin ‐ and control‐treated patients, respectively (Table 2). There were no apparent between‐group differences
dapagliflozin 22971 including neuropathy, CV disease, dyslipidaemia and nephropathy. Time to amputation was similar for dapagliflozin ‐ and control‐treated patients. In the dapagliflozin group, the onset of events occurred >150 days
dapagliflozin 23027 nephropathy. Time to amputation was similar for dapagliflozin‐ and control‐treated patients. In the dapagliflozin group, the onset of events occurred >150 days after initiation of study treatment in the majority
dapagliflozin 23223 treatment in the majority (5/8) of patients.DISCUSSION4This pooled analysis reports the safety findings for dapagliflozin , including the newer emergent safety issues of ketoacidosis and lower limb amputation, thereby adding
dapagliflozin 23458 the safety of this agent in patients with T2DM. This analysis identified no new safety signals for dapagliflozin .The risk of hypoglycaemia associated with SGLT2 inhibitors is low, as suggested by their mechanism of
dapagliflozin 23676 action and clinical experience to date, and a similar incidence of hypoglycaemia was observed between dapagliflozin and placebo in the analysis reported here. In a pooled analysis of empagliflozin trials, 23.1%, 22.7%
dapagliflozin 24274 who were also receiving background antihyperglycaemic drugs.14Renal function AEs were observed with dapagliflozin in the present analysis. AEs consistent with decreased renal function have also been shown with other
dapagliflozin 25059 discontinuation and reporting of AEs based on laboratory values.The AEs of renal function observed with dapagliflozin were primarily associated with transient changes in serum creatinine or renal creatinine clearance,
dapagliflozin 25322 failure or marked abnormalities of serum creatinine >2.5 g/dL (data not shown). Notably, some of the dapagliflozin studies had protocol‐specific discontinuation requirements for patients with confirmed calculated
dapagliflozin 26521 in eGFR, which subsequently returns to baseline once the initial transient natriuresis observed with dapagliflozin resolved.21, 22In our pooled analysis, eGFR did not return to baseline in the overall population treated
dapagliflozin 26645 resolved.21, 22In our pooled analysis, eGFR did not return to baseline in the overall population treated with dapagliflozin , possibly because of the relatively short duration of treatment; however, in longer‐term dapagliflozin
dapagliflozin 26750 dapagliflozin, possibly because of the relatively short duration of treatment; however, in longer‐term dapagliflozin studies, the initial decline in eGFR was observed to return to near‐ or above‐baseline levels by
dapagliflozin 28385 1000 patient‐years with canagliflozin vs placebo, respectively.1 While volume depletion was low with dapagliflozin and empagliflozin, there is need for caution when prescribing an SGLT2 inhibitor to the elderly and
dapagliflozin 28776 risk of UTIs are less consistent. In our analysis, no increase in the risk of UTIs was observed with dapagliflozin vs placebo. The proportions of patients reporting UTIs were 15.1%, 14.5% and 15.0% with empagliflozin
dapagliflozin 29125 canagliflozin 100 and 300 mg and placebo, respectively.14The incidence of genital infection was higher with dapagliflozin vs control in the present analysis, and this is consistent with other analyses of dapagliflozin, empagliflozin
dapagliflozin 29221 with dapagliflozin vs control in the present analysis, and this is consistent with other analyses of dapagliflozin , empagliflozin and canagliflozin.2, 12, 13, 14, 19, 27 A meta‐analysis comparing all SGLT2 inhibitors
dapagliflozin 29767 levels, which has been hypothesized to exert adverse effects on bone30; however, in this pooled analysis, dapagliflozin did not increase fracture risk vs control. Furthermore, no clinically meaningful changes in bone minerals
dapagliflozin 29977 minerals including calcium, inorganic phosphorus and 25‐hydroxyvitamin D have been reported with dapagliflozin vs placebo.31No increased incidence of fracture was observed in pooled analyses comparing empagliflozin
dapagliflozin 33075 of autoimmune diabetes (ie, type 1 diabetes, etc.).35A low frequency of amputation was observed in dapagliflozin ‐ and placebo‐/active comparator‐treated patients; however, the number of patients with amputation
dapagliflozin 33578 another safety issue that has been previously explored, owing to a numerical imbalance observed between dapagliflozin ‐ and control‐treated patients in the new drug application submitted to the US FDA in 2011.36 In
dapagliflozin 33751 application submitted to the US FDA in 2011.36 In an updated analysis of >9000 patients in the phase IIb/III dapagliflozin trials, 9/5936 and 1/3403 dapagliflozin‐ and comparator‐treated patients, respectively, reported
dapagliflozin 33791 an updated analysis of >9000 patients in the phase IIb/III dapagliflozin trials, 9/5936 and 1/3403 dapagliflozin ‐ and comparator‐treated patients, respectively, reported bladder cancer, with an incident rate ratio
dapagliflozin 34057 of the data, with a small number of bladder cancer cases and the lack of carcinogenic potential of dapagliflozin in preclinical studies, does not support a causal relationship between dapagliflozin and increased bladder
dapagliflozin 34142 carcinogenic potential of dapagliflozin in preclinical studies, does not support a causal relationship between dapagliflozin and increased bladder cancer risk. There was however, the possibility of ascertainment bias possibly
dapagliflozin 35197 experiencing AEs, including hypoglycaemia, volume depletion, UTI and fracture, was generally balanced in the dapagliflozin and placebo/active comparator treatment groups. AEs of renal function with dapagliflozin were related
dapagliflozin 35286 balanced in the dapagliflozin and placebo/active comparator treatment groups. AEs of renal function with dapagliflozin were related to transient changes in renal laboratory values. Genital infections were more frequent
dapagliflozin 35405 related to transient changes in renal laboratory values. Genital infections were more frequent with dapagliflozin vs placebo, and this finding is consistent with the previously reported data for SGLT2 inhibitors. A
dapagliflozin 35601 SGLT2 inhibitors. A very low frequency of lower limb amputations was observed in the patients in the dapagliflozin and control groups. AEs of DKA, ketonuria or metabolic acidosis were rare, with 1 event of DKA reported
dapagliflozin 35726 groups. AEs of DKA, ketonuria or metabolic acidosis were rare, with 1 event of DKA reported in the dapagliflozin group. No new safety signals for dapagliflozin were identified in this pooled analysis of a large number
dapagliflozin 35773 acidosis were rare, with 1 event of DKA reported in the dapagliflozin group. No new safety signals for dapagliflozin were identified in this pooled analysis of a large number of patients.Supporting informationFigure S1.
metformin 13500 discontinued treatment because of hypoglycaemia. This patient was receiving dapagliflozin added to insulin and metformin , and discontinued treatment after reporting major hypoglycaemia on day 107.Table 2Summary of AEs of
metformin 22192 0.004‐0.059). The SAE of DKA occurred in a patient who was receiving dapagliflozin 10 mg added to metformin and insulin. An event of gastroenteritis was also recorded in this patient on the same day (day 214),
Select Disease Character Offset Disease Term Instance
diabetes mellitus 75 Title: Diabetes, Obesity & MetabolismDapagliflozin in patients with type 2 diabetes mellitus : A pooled analysis of safety data from phase IIb/III clinical trialsSerge JabbourJochen SeufertAndre
diabetes mellitus 1043 dapagliflozin, a highly selective sodium‐glucose co‐transporter‐2 inhibitor, in patients with type 2 diabetes mellitus (T2DM).MethodsData were pooled from 13 placebo‐controlled trials of up to 24 weeks’ duration (dapagliflozin,
diabetes mellitus 2787 placebo.JabbourS, SeufertJ, ScheenA, BaileyCJ, KarupC, LangkildeAM. Dapagliflozin in patients with type 2 diabetes mellitus : A pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018;20:620–628.
diabetes mellitus 3672 safety.1, 2 The safety of these agents is of keen interest to physicians treating patients with type 2 diabetes mellitus (T2DM). Common adverse events (AEs) have been associated with the use of SGLT2 inhibitors such as genital
diabetic ketoacidosis 1461 (≥12 weeks; dapagliflozin, n = 9195; control, n = 4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis (DKA) and lower limb amputation, respectively.ResultsOver 24 weeks, the overall incidence of AEs and
diabetic ketoacidosis 4839 compared with placebo.12, 13 Low rates of bone fractures, AEs consistent with decreased renal function and diabetic ketoacidosis (DKA) were observed in the empagliflozin and placebo groups.12, 13 Small increases in serum creatinine
diabetic ketoacidosis 36028 included in the 13‐study pool.Figure S2. Studies included in the 21‐study pool for the assessment of diabetic ketoacidosis .Figure S3. Studies included in the 30‐study pool for the assessment of amputations.Figure S4. eGFR
type 2 diabetes mellitus 68 Title: Diabetes, Obesity & MetabolismDapagliflozin in patients with type 2 diabetes mellitus : A pooled analysis of safety data from phase IIb/III clinical trialsSerge JabbourJochen SeufertAndre
type 2 diabetes mellitus 1036 dapagliflozin, a highly selective sodium‐glucose co‐transporter‐2 inhibitor, in patients with type 2 diabetes mellitus (T2DM).MethodsData were pooled from 13 placebo‐controlled trials of up to 24 weeks’ duration (dapagliflozin,
type 2 diabetes mellitus 2780 placebo.JabbourS, SeufertJ, ScheenA, BaileyCJ, KarupC, LangkildeAM. Dapagliflozin in patients with type 2 diabetes mellitus : A pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018;20:620–628.
type 2 diabetes mellitus 3665 (CV) safety.1, 2 The safety of these agents is of keen interest to physicians treating patients with type 2 diabetes mellitus (T2DM). Common adverse events (AEs) have been associated with the use of SGLT2 inhibitors such as genital

You must be authorized to submit a review.