Tolerability Of Dapagliflozin Research Articles

FRI649 ADMIRE: Assessing Dapagliflozin And Metformin As An Initial Regimen In Diabetes Mellitus For Enhanced Glucose Control

Abstract Disclosure: D. Phadke: None. D. Gopal: None. D. Biswas: None. D. Birla: None. A. Prasad: None. P. Joshi: None. Introduction: Early aggressive glucose lowering in type 2 diabetes mellitus (T2DM) has shown improved outcomes, and combination oral antidiabetic agents (OAAs) on top of lifestyle therapy are necessary. In India, most T2DM patients receive combination therapy with two or more OAAs to achieve glycemic targets more rapidly. The fixed dose combination (FDC) of dapagliflozin and metformin is widely used in India, as it improves glycemia, reduces weight and blood pressure (BP), and has good tolerability. This study aimed to evaluate physician practices, efficacy, and tolerability of dapagliflozin and metformin FDC as initial therapy for T2DM patients in a real-world setting. Methods: This multicenter, retrospective, observational study enrolled 481 T2DM patients across 49 clinical units for a period of 6 months. The study aimed to evaluate physician practices, efficacy, and tolerability of dapagliflozin and metformin FDC as the initial choice FDC in T2DM. The study was conducted in compliance with the principles of the Declaration of Helsinki, good clinical practice, and regulatory guidelines. Ethical approval for the study was obtained on August 6, 2022, and the study was conducted from August 15, 2022, to January 20, 2023. Results: The study demonstrated that dapagliflozin and metformin FDC significantly reduced weight by 4.2 kg (p < 0.0001), fasting plasma glucose by 21.4 mg/dL (p < 0.0001), and improved estimated glomerular filtration rate (eGFR) by 1.9 m²/1.73 ml/min (p < 0.0001). Additionally, systolic BP was reduced by 10.7 mmHg (p < 0.0001), and diastolic BP was reduced by 6.6 mmHg (p < 0.0001), which is in combination with the concomitant medications. Incidence of genito-urinary tract infection was 8.9%. Conclusion: In a real-world setting, dapagliflozin and metformin FDC can be used as initial therapy for T2DM with good efficacy, tolerability, and safety. Physicians preferred this combination due to its ability to promote weight loss, reduce cardiovascular events, and decline in renal function. The excellent safety and efficacy reported by physicians for this FDC of dapagliflozin and metformin has contributed to improved compliance with the treatment. Thus, in the Indian population, dapagliflozin and metformin FDC is effective, safe, and has good tolerability as an initial therapy for T2DM. Presentation: Friday, June 16, 2023

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC’s excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear.MethodsWe performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed.ResultsOf 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements.ConclusionsDapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

P288 TREATMENT OF HEART FAILURE IN CLINICAL PRACTICE: NON–INTERVENTIONAL OBSERVATIONAL STUDY ON PATIENTS WITH HEART FAILURE TREATED WITH DAPAGLIFLOZIN (EVOLUTION–HF ITALY)

Abstract Background Heart Failure (HF) is a relevant issue for public health issue: it affects more than 64 million people worldwide1, and its burden is anticipated to increase as the population ages. Dapagliflozin is an inhibitor of the sodium–glucose cotransporter–2 (SGLT2i). In the DAPA–HF trial, dapagliflozin reduced the risk of hospitalisation for HF and death in patients with HFrEF (with or without Type 2 Diabetes) compared to placebo2,3,4. Currently, there is a lack of data on characteristics, treatment profiles, and patient reported outcomes (PROs) of patients initiated on dapagliflozin for HFrEF in clinical practice: the EVOLUTION–HF programme is aimed at answering those questions by collecting real–world data in 13 European Countries, including Italy. The primary objective is to characterise patients initiated on dapagliflozin for the treatment of HFrEF and to estimate occurrence of treatment discontinuations. Secondary objectives include an assessment of Health–related Quality of Life (HR–QoL) by means of the Kansas City Cardiomyopathy Questionnaire (KCCQ), patient–reported adherence to prescriptions of pharmacological treatments for HF (Medication Adherence Report Scale – 5 Item), performance on 6–Minutes Walking Test. Methods The study has an observational, longitudinal, descriptive design. To be enrolled, patients must be 18 years old or older and have initiated treatment with dapagliflozin according to the approved HFrEF label. Patients with a diagnosis of Type 1 Diabetes or previously treated with any SGLT2i are excluded from the study. Follow–up lasts one year from start of treatment. Sample size has been estimated in 250 patients, that will be enrolled in 11 centres. Results The study is currently ongoing, and it will generate evidences on the use and tolerability of dapagliflozin, as well as on treatment patterns of other pharmacological therapies for HF and diabetes. Also, the study will generate data from PROs regarding change of KCCQ across time, adherence to HF therapies in clinical practice, and 6–Minutes Walking Tesst. Multivariate analyses will evaluate association between patients’ characteristics and interruption of treatment, adherence and HR–QoL. The interim analysis will be available in the first months of 2023. Conclusions The EVOLUTION–HF Italy study Il programma di studio EVOLUTION–HF supporterà la pratica clinica con dati originali sull‘uso nel mondo reale delle nuove terapie farmacologiche per l‘HFrEF.

Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure: A Prespecified Analysis of the DELIVER Trial.

Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death. Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI ≤0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI ≥0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P<0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; Pinteraction=0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class. In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty. URL: https://www. gov; Unique identifier: NCT03619213.

Effect of Dapagliflozin in Combination with Lobeglitazone and Metformin in Korean Patients with Type 2 Diabetes in Real-World Clinical Practice.

PurposeThis study aimed to evaluate the efficacy and tolerability of dapagliflozin as an add-on or a switch therapy to lobeglitazone plus metformin (MFM) in Korean patients with inadequately controlled type 2 diabetes mellitus (T2DM) in real-world clinical practice.Materials and MethodsThe study included 109 patients who started dapagliflozin as add-on or switch therapy to lobeglitazone plus MFM. The primary outcome was a change in glycated hemoglobin (HbA1c) level from baseline after 12 months of treatment. Secondary outcomes included changes in fasting plasma glucose (FPG), lipid profiles, body weight, visceral fat area (VFA), and blood pressure after 12 months of treatment.ResultsThe baseline HbA1c was 8.3±1.3% (8.7±1.5% in the add-on group and 8.1±1.0% in the switch group). After 12 months, mean HbA1c decreased (-0.91%) in all patients (p<0.05) (-1.39% in the add-on group and -0.63% in the switch group). Significant reductions in FPG were also observed in both the add-on and switch groups (-54.37 mg/dL and -24.68 mg/dL, respectively). Overall, there was a significant improvement in serum triglyceride (-24.74 mg/dL), low density lipoprotein cholesterol (-7.92 mg/dL), body weight (-2.98 kg), VFA (-9.00 cm2), and systolic blood pressure (-8.67 mm Hg). Approximately 35.8% of patients achieved HbA1c <7.0% after 12 months.ConclusionDapagliflozin, as an add-on or a switch therapy to lobeglitazone plus MFM, can be a suitable alternative for Korean patients with inadequately controlled T2DM. The combination therapy resulted in significant reductions in HbA1c levels, body weight, and blood pressure.

Effects of Dapagliflozin Compared with Sitagliptin and Metformin in Drug-Naïve Japanese Patients with Type 2 Diabetes: A 12-Week, Open-Label, Randomized, Active-Controlled Trial.

IntroductionTo compare the efficacy and tolerability of dapagliflozin with those of sitagliptin and metformin in patients with type 2 diabetes who have never received glucose-lowering agents.MethodsIn this randomized, 12-week, open-label, active-controlled trial, 32 patients were randomly assigned to receive dapagliflozin 5 mg, sitagliptin 50 mg, or metformin 1000 mg per day for 12 weeks. At baseline and at week 12, the patients underwent a meal tolerance test (MTT).ResultsAfter 12 weeks of treatment, the changes in fasting and postprandial plasma glucose and plasma glucose area under the curve (AUC)0–120 min levels during the MTT from baseline were significantly improved in the three study groups, and there were no significant differences among the three study groups (P < 0.05). The mean changes in glycated hemoglobin (HbA1c) from baseline to week 12 were − 0.96%, − 1.24%, and − 1.40% in the dapagliflozin, sitagliptin, and metformin groups, respectively. Although there was no significant difference among the three study groups, the lowering effect of HbA1c tended to be greater in the metformin group than in the dapagliflozin group. In contrast, the insulin AUC0–120 min levels at week 12 significantly decreased only in the dapagliflozin group (P = 0.049). Similarly, body weight was significantly reduced only in the dapagliflozin group (− 2.1 kg [− 2.7%], P = 0.047). Moreover, dapagliflozin significantly improved serum adiponectin levels (P = 0.003). However, there were no significant differences in the changes in these glycemic and metabolic parameters among the three study groups. No serious adverse events were documented in any group.ConclusionsDapagliflozin exerted beneficial effects similar to sitagliptin and metformin on glycemic parameters. In addition, dapagliflozin significantly reduced body weight and insulin AUC levels and improved serum adiponectin levels. Therefore, we suggest that these three hypoglycemic agents could be viable first-line medications for drug-naïve Japanese patients with type 2 diabetes.Trial RegistrationUniversity Hospital Medical Information Network (UMIN000024427).

Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.

In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo. We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms. Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization. The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Safety and tolerability of dapagliflozin, saxagliptin and metformin in combination: Post‐hoc analysis of concomitant add‐on versus sequential add‐on to metformin and of triple versus dual therapy with metformin

The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin versus dual therapy with dapagliflozin or saxagliptin plus metformin was compared in a post‐hoc analysis of 3 randomized trials of sequential or concomitant add‐on of dapagliflozin and saxagliptin to metformin. In the concomitant add‐on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus saxagliptin 5 mg/d. In sequential add‐on trials, patients on metformin plus either saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or saxagliptin 5 mg/d, respectively, as add‐on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add‐on regimens. Urinary tract infections were more common with sequential than with concomitant add‐on therapy; genital infections were reported only with sequential add‐on of dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, saxagliptin and metformin, as either concomitant or sequential add‐on, were similar to dual therapy with either agent added to metformin.

Efficacy of dapagliflozin as an adjunct therapy in patients with inadequately controlled type 1 diabetes mellitus

ABSTRACTIntroduction: There is a clear unmet clinical need in people with Type 1 diabetes (T1DM) considering present day insulin therapy. New insulin analogues and novel technologies allowing more tailored insulin administration have improved the quality of life of people with T1DM, but issues like hypoglycemia, weight gain and variability in glucose profiles remain problematic.Areas covered: In this review, the clinical efficacy, safety and tolerability of dapagliflozin, a sodium-glucose cotransporter type 2 inhibitor, in type 1 diabetes (T1DM) is described based on a review of phase 2 and 3 studies to date.Expert opinion: Dapagliflozin has shown promising results as an adjunct therapy in T1DM, resulting in better glucose control, weight loss and lower blood pressure. No increase in hypoglycemia risk, in particular severe hypoglycemia, was observed, but, in comparison with reports in Type 2 diabetes (T2DM), genital infections were more prevalent. Dapagliflozin use was accompanied with decreases in insulin doses, but, to date, only a low risk of diabetic ketoacidosis (DKA) was reported. However, caution is needed when interpreting this data, arising from well controlled clinical trials, with intensive education programs around ketone measurements and DKA prevention. Further studies will need to establish how high the DKA risk is and how to mitigate this in a real-world setting.

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

AimTo evaluate the safety and tolerability of 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, 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, 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 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 AEs, urinary tract 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 renal AE was decreased creatinine clearance: 1.1% vs 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 0.010‐0.089). 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 and placebo/control groups, including the incidence of hypoglycaemia, volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with dapagliflozin than placebo.

Dapagliflozin

Objective: To review clinical evidence for the efficacy, safety, and tolerability of dapagliflozin (Farxiga-AstraZeneca), a sodium glucose cotransporter 2 inhibitor, as monotherapy or in combination with other hypoglycemic agents for the treatment of type 2 diabetes. Data Sources: Literature was identified through a systematic MEDLINE search of clinical trial results for dapagliflozin. Data Synthesis: Multiple controlled clinical trials have established the efficacy, safety, and tolerability of dapagliflozin as monotherapy or in combination with other therapies for type 2 diabetes. Dapagliflozin is approved by Food and Drug Administration as monotherapy or as an add-on to other glucose lowering agents including insulin for the treatment of type 2 diabetes. Conclusion: Dapagliflozin is effective for the treatment of type 2 diabetes.

Dapagliflozin Versus Glipizide as Add-on Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin

OBJECTIVEAlthough initially effective, sulfonylureas are associated with poor glycemic durability, weight gain, and hypoglycemia. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia by increasing urinary glucose excretion independent of insulin and may cause fewer of these adverse effects. We compared the efficacy, safety, and tolerability of dapagliflozin with the sulfonylurea glipizide in patients with type 2 diabetes inadequately controlled with metformin monotherapy.RESEARCH DESIGN AND METHODSThis 52-week, double-blind, multicenter, active-controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA1c, 7.7%), who were receiving metformin monotherapy, to add-on dapagliflozin (n = 406) or glipizide (n = 408) up-titrated over 18 weeks, based on glycemic response and tolerability, to ≤10 or ≤20 mg/day, respectively.RESULTSThe primary end point, adjusted mean HbA1c reduction with dapagliflozin (−0.52%) compared with glipizide (−0.52%), was statistically noninferior at 52 weeks. Key secondary end points: dapagliflozin produced significant adjusted mean weight loss (−3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide, significantly increased the proportion of patients achieving ≥5% body weight reduction (33.3%) versus glipizide (2.5%; P < 0.0001), and significantly decreased the proportion experiencing hypoglycemia (3.5%) versus glipizide (40.8%; P < 0.0001). Events suggestive of genital infections and lower urinary tract infections were reported more frequently with dapagliflozin compared with glipizide but responded to standard treatment and rarely led to study discontinuation.CONCLUSIONSDespite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors.