Use Of Canagliflozin Research Articles

Bidirectional relationship between kidney disease progression and cardiovascular events in type 2 diabetes: new Insights from the CANVAS Program and CREDENCE trial

Abstract Background The extent to which chronic kidney disease (CKD) progression increases cardiovascular risk, and whether different types of cardiovascular events affect risk of CKD progression, is incompletely understood. Purpose We sought to explore risk of cardiovascular events before and after CKD progression, and CKD progression before and after different cardiovascular events in patients with type 2 diabetes. Methods We conducted a pooled individual participant data analysis of the CANVAS Program and CREDENCE trial. Using Poisson regression, we assessed the incidence of major adverse cardiovascular events ([MACE] stroke, myocardial infarction, or cardiovascular death) and hospitalised heart failure (HHF) or cardiovascular death before and after CKD progression (defined as 40% decline in estimated glomerular filtration rate [eGFR] or kidney failure), and CKD progression before and after nonfatal cardiovascular events, with no adjustment for confounding related to subgroups defined by post-randomization variables. We estimated the cumulative incidence of all-cause mortality after different nonfatal cardiovascular and kidney outcomes, including different thresholds of CKD progression (kidney failure, 40% or 50% decline in eGFR or doubling of serum creatine) using Cox regression models. Results Among 14,464 participants (mean age 63.7 years, 35.3% female, mean eGFR 55mL/min/1.73m2 and median urinary albumin:creatinine ratio 34mg/g) over a median follow-up of 2.5 years, 1,482, 1,076 and 1,020 experienced MACE, HHF or cardiovascular death, and CKD progression, respectively. After (vs. before) CKD progression, there was an approximate 3-fold increase in incidence of MACE (30.2 vs. 93.8 per 1000-patient-years) and 4-fold increase in HHF or cardiovascular death (21.0 vs. 79.3 per 1000-patient-years). Conversely, the incidence of CKD progression was approximately 1.5-fold higher after (vs. before) nonfatal myocardial infarction or stroke (21.7 vs. 34.1 per 1000-patient-years) and 5-fold higher after HHF (21.2 vs. 108.2 per 1000-patient-years). These patterns were consistent in both treatment arms, with unadjusted incidence rates for clinical events appearing numerically lower in canagliflozin compared to placebo-treated participants (Figure 1). Of all non-fatal cardio-kidney outcomes, HHF and doubling of serum creatine or kidney failure conferred the highest risk of death (Figure 2). Conclusion Atherosclerotic and heart failure risk increases substantially after CKD progression. CKD progression was accelerated after cardiovascular events, particularly HHF. Treatment with canagliflozin was associated with lower event rates before and after a serious cardio-kidney outcome, suggesting continued use of canagliflozin may be beneficial even after cardiovascular events and CKD progression.Figure 1.Figure 2.

The effect of antidiabetic drugs on bone metabolism: a concise review.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, which derives from either insufficient insulin production [type 1 diabetes mellitus (T1DM)] or both impaired insulin sensitivity along with inadequate insulin production [type 2 diabetes mellitus (T2DM)] and affects millions of people worldwide. In addition to the adverse effects of DM on classical target organs and tissues, skeletal health can also be adversely affected. There is considerable evidence linking DM with osteoporosis. The fracture risk in patients with DM differs upon the type of diabetes, and it appears to be related to the type of anti-diabetic treatment. Antidiabetic drugs may have various effects on bone health. Most of them have neutral or even favorable effects on bone metabolism with the exception of thiazolidinediones (TZDs). Some studies suggest that TZDs may have negative impact on bone health by decreasing bone formation and increasing the fracture risk. There are also limited studies linking the use of canagliflozin, a Sodium-glucose contransporter-2 inhibitor (SGLT2i), with increased fracture risk. On the other hand, therapies that are based on incretin effect, like Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like peptide-1 receptor agonizts (GLP-1RAs) might have positive effects on bone health by promoting bone formation. Herein we review the impact of antidiabetic drugs on bone health, highlighting the potential benefits and risks associated with these medications in an attempt to contribute to the development of personalized treatment strategies for individuals with DM.

The Use of Canagliflozin in Diabetes Mellitus Type 2 on Renal Outcome: A Systematic Review

Introduction: One of the leading causes of death in patients with diabetes mellitus is Diabetic Kidney Disease (DKD). Canagliflozin is one of the therapeutic options that can be used to mitigate the progression of DKD. However, the limited existing studies have left the data regarding the effects of canagliflozin on the progression of DKD still unclear. Therefore, a comprehensive study on the efficacy and safety of using canagliflozin in patients with DKD is warranted.Methods: We performed a systematic search in the PubMed, Cochrane Library, ResearchGate, and Springer for randomized, placebo-controlled trials of the treatment of type 2 diabetes mellitus (T2DM) with canagliflozin that were published. A total of 25 journals were identified, and after excluding irrelevant studies, eighteen studies were ultimately included in this systematic review with total participants of 20,047.Results: Canagliflozin reduces the rate of estimated glomerular filtration rate (eGFR) decline in patients with diabetes mellitus. The reduction of urinary albumin-to-creatinine ratio (UACR) level was greater in canagliflozin group than in the control group, and the progression of albuminuria was slower in the canagliflozin group than in the control group.Conclusion: The use of Canagliflozin is considered to be one of the effective therapeutic options for kidney protection in patients with diabetes mellitus who are at risk of chronic kidney disease (CKD).

Abstract 12011: A Case of Emphysematous Pyelonephritis With Use of Empagliflozin

Background: SGLT2i improve cardiovascular (CV) outcome in patients with HFrEF with or without diabetes (DM). Although recent trials and metanalysis have showed improve renal outcomes with SGLT-2i, one should be aware of the potential serious adverse effects with this group of medications including life threatening UTI. Case: 50-year-old female with history of type 2 DM presented with septic shock due to bilateral (B/L) pyelonephritis, with no associated renal calculi. CT of the abdomen also revealed emphysematous pyelonephritis of the left kidney. Few days later, patient went into PEA requiring intubation with return of spontaneous circulation within 4 minutes of advanced cardiac life support. Patient was extubated subsequently later on during her hospitalization. Work up for PEA revealed depressed left ventricular systolic function with an EF of 25-29% with no wall motion abnormality. Patient also developed decompensated HFrEF with development of b/l pleural effusion and generalized anasarca. Cardiology was consulted for management of her cardiomyopathy. She was recommended coronary angiography but she declined. Therefore, Patient was started on guideline direct medical therapy for HF with metoprolol succinate, lisinopril and spironolactone. Due to recent evidence of SGLT-2i improving CV outcomes in patients with HFrEF, it was also recommended to start SGLT-2i. Discussion: On further reviewing regarding use of SGLT-2i and association with UTI, we found a case report causing emphysematous pyelonephritis with use of canagliflozin. Medication reconciliation done at the time of discharge revealed that patient was recently initiated on empagliflozin three months prior to her admission. Therefore, it was speculated that her emphysematous pyelonephritis could be one of the rare complications of SGLT-2i since no other etiologies was noted per urological workup and we decided not to continue SGLT-2i. A search of FAERS from March 2013 through October 2014 identified 19 cases of urosepsis reported with the SGLT2 inhibitors (canagliflozin [n=10] and dapagliflozin [n=9]). All cases resulted in hospitalization. No deaths were reported. Clinicians should be aware of potential life-threatening UTI which may occur with SGLT-2i use.

Sodium-glucose co-transporter-2 inhibitor (SGLT2i) treatment and risk of osteomyelitis: A pharmacovigilance study of the FAERS database.

Background and purpose: Several clinical trials have indicated that the use of canagliflozin increases the risk of lower extremity amputation. Although the US Food and Drug Administration (FDA) has withdrawn its black box warning about amputation risk for canagliflozin, the risk still exists. We sought to estimate the association between hypoglycemic medications, especially sodium-glucose co-transporter-2 inhibitors (SGLT2is), and adverse events (AEs) before the irreversible outcome of amputation as a promising early warning, based on the FDA Adverse Event Reporting System (FAERS) data. Methods: Publicly available FAERS data were analyzed using a reporting odds ratio (ROR) method and validated by a Bayesian confidence propagation neural network (BCPNN) method. The developing trend of the ROR was investigated by a series of calculations based on the accumulation of data in the FAERS database quarter by quarter. Results: Ketoacidosis, infection, peripheral ischemia, renal impairment, and inflammation including osteomyelitis might be more likely to occur among users of SGLT2is, especially canagliflozin. Osteomyelitis and cellulitis are AEs unique to canagliflozin. Among 2,888 osteomyelitis-related reports referring to hypoglycemic medications, 2,333 cases were associated with SGLT2is, with canagliflozin accounting for 2,283 of these cases and generating an ROR value of 360.89 and a lower limit of information component (IC025) of 7.79. No BCPNN-positive signal could be generated for drugs other than insulin and canagliflozin. Reports suggesting that insulin could generate BCPNN-positive signals span from 2004 to 2021, whereas reports with BCPNN-positive signals emerged only since the second quarter (Q2) of 2017, 4years since the approval of SGLT2is in Q2 of 2013, for canagliflozin and drug groups containing canagliflozin. Conclusion: This data-mining investigation revealed a strong association between canagliflozin treatment and developing osteomyelitis that might be a crucial forewarning to lower extremity amputation. Further studies with updated data are needed to better characterize the risk of osteomyelitis associated with SGLT2is.

Influence of left ventricular ejection fraction on the reduction in N-terminal pro-brain natriuretic peptide by canagliflozin in patients with heart failure and type 2 diabetes: A sub analysis of the CANDLE trial

AimTo investigate the effect of left ventricular ejection fraction (LVEF) on the behavior of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with heart failure and type 2 diabetes mellitus with the use of canagliflozin compared to glimepiride. MethodsPatients (n = 233) from the CANDLE trial were randomly assigned to either the add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The patients were followed-up for 24 weeks. The NT-proBNP levels were measured at baseline and after 24 weeks. The LVEF was determined at baseline. ResultsThere was a significant relationship between the baseline NT-proBNP level (X1) and the change in NT-proBNP levels from baseline to 24 weeks (Y) in the canagliflozin group (Y = −0.533 × X1 + 178; r = −0.860, p < 0.001). However, this relationship was not observed in the glimepiride group (p = 0.428). The baseline LVEF (X2) correlated with Y with a marginal significance in the canagliflozin group (Y = 7.72 × X2–549; r = 0.192, p = 0.054), but no relationship was observed in the glimepiride group. In the canagliflozin group, bivariate regression analysis showed a significant correlation between Y, X1, and X2; Y = −0.567 × X1–6.04 × X2 + 542 (R = 0.871, p < 0.001). The partial regression coefficients of X1 (p < 0.001) and X2 (p = 0.006) significantly explained the variance in Y. The correlation coefficient for X2 was negative. There was a significant relationship between the logarithmically transformed NT-proBNP [ln(NT-proBNP)] at baseline (X1′) and the change in ln(NT-proBNP) values from baseline to 24 weeks (Y′), a surrogate of the rate of change in NT-proBNP levels, in the canagliflozin group (Y′ = −0.18 × X1′ + 0.93; r = 0.450, p = 0.001). ConclusionsThe baseline NT-proBNP level significantly affected the extent and the rate of its decrease by canagliflozin. The reduction in NT-proBNP levels by canagliflozin was prominent in patients with a higher LVEF at baseline. However, its confounding effect of LVEF on canagliflozin treatment was not recognized without adjusting for the NT-proBNP level at baseline.

A Network Pharmacology to Explore the Potential Targets of Canagliflozin and Dapagliflozin in Treating Atherosclerosis

Background: Atherosclerosis (AS) is an important pathological basis of many cardiovascular diseases. Canagliflozin and dapagliflozin have yielded impressive results in the treatment of cardiovascular disease in both diabetic and non-diabetic patients. In this study, we investigated their targets and mechanism involved in the treatment of atherosclerosis using network pharmacology. Methods: The potential targets of canagliflozin and dapagliflozin were gathered from the database PharmMapper. Targets associated with AS were derived from the GeneCards, Drugbank, DisGeNet, and therapeutic target databases (TTD) by searching for keywords on atherosclerosis and coronary artery disease. Overlap targets were collected by uploading drug and disease targets into jvenn. The cross-targets of the Venny plots were uploaded to the STRING database, and a protein–protein interaction (PPI) was constructed with their calculated features, aiming to reveal several key targets. Key targets were selected by using a plug-in of the Cytoscape software. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the database Metascape. Cytoscape was used to set up the pathways-genes network. Molecular docking with core targets and drugs was performed with AutoDock. Results: A total of 288 canagliflozin targets, 287 dapagliflozin targets and 4939 AS-related targets were obtained. A total of 191 overlapping targets were found after intersecting. Five core targets, including protein kinase B (Akt1), Mitogen-activated protein kinase 1 (MAPK1), Mitogen-activated protein kinase 14 (MAPK14), Proto-oncogene tyrosine-protein kinase SRC (SRC) and Epidermal growth factor receptor (EGFR) were collected. Pathways, biological processes, molecular functions and cellular components of canagliflozin and dapagliflozin were found. Conclusion: Canagliflozin and dapagliflozin play a role in atherosclerosis by regulating Akt1, MAPK1, MAPK14, SRC and EGFR. Our research provides further insights into the use of canagliflozin and dapagliflozin in the treatment of atherosclerosis.

Why can the use of Canagliflozin, the SGLT1/SGLT2 inhibitor, have additional glycemic and non-glycemic benefits in patients with type 2 diabetes mellitus?

Why can the use of Canagliflozin, the SGLT1/SGLT2 inhibitor, have additional glycemic and non-glycemic benefits in patients with type 2 diabetes mellitus?

An investigation on the association between sodium glucose co-transporter 2 inhibitors use and acute pancreatitis: A VigiBase study.

To characterize acute pancreatitis (AP) related to sodium glucose co-transporter 2 inhibitors and to investigate this relationship through disproportionality analysis in an international pharmacovigilance database. We analyzed all AP reports for canagliflozin, dapagliflozin and/or empagliflozin from the WHOs Global adverse drug reactions database VigiBase® up to July 2019. We characterized the patients, reporters, and reactions, and we present the proportional reporting ratio (PRR) and information component (IC) for each of the gliflozins. AP cases were reports containing at least one of 11 previously selected preferred terms. Gliflozin exposure was considered for all reports with at least one gliflozin as suspected/ interacting drug. Of the 19 834 180 individual case safety reports in VigiBase, in 600 reports containing 618 AP group reactions, gliflozins were suspected/ interacting drugs. Men were affected in 52.3% of the cases and 59.6% of the patients were in the 45-64 years age group. The reporters were in 417 cases healthcare professionals. Most of the reactions were reported for canagliflozin (59.7%), followed by empagliflozin (21%) and dapagliflozin (19.2%) and were serious (98.6%). Most of the reactions' outcomes (84% of the patients) were favorable. Ketoacidosis was frequently associated with the AP (21.3%). Significant PRR and IC were found for pancreatitis and pancreatitis acute for all three gliflozins, pancreatitis necrotizing for canagliflozin and empagliflozin and pancreatitis relapsing for empagliflozin. Most of the AP cases were serious and with favorable outcome. We identified possible alternative causes for AP, like concomitant medication, hypertriglyceridemia, and cholelithiasis and a frequent association with ketoacidosis. We found a significant association between AP and the use of canagliflozin, dapagliflozin, and empagliflozin that would need further investigation.

SGLT2 Inhibitor Induced Euglycemic DKA (EDKA) With Proximal Renal Tubular Acidosis (RTA) as a Rare Fatal Complication in a Non-Insulin Dependent Diabetic Patient: A Challenging Dilemma

Abstract Introduction: Diabetic Ketoacidosis (DKA) is characterized by a triad of hyperglycemia, acidemia, and ketonemia. Rarely, it would present with normal glucose levels making its diagnosis very challenging. The incidence of euglycemic DKA (eDKA) has increased with the introduction of the novel sodium-glucose cotransporter-2 inhibitors (SGLT2i). Currently, the reported incidence of SGLT2i induced DKA is 0.16–0.76 events per 1000 patient-years. We present a rare case of SGLT2i induced eDKA with proximal renal tubular acidosis (RTA). Case Presentation A 69 year-old male with type 2 diabetes mellitus presented to the hospital with severe respiratory distress, nausea and vomiting for 2 days. His home medications include metformin and canagliflozin. He was afebrile with respiratory rate 60 breaths/min. Arterial blood gas: pH 7.21, pCO2 9.2, pO2 223, HCO3 6. Blood glucose level was 120 mg/dl. Urinalysis was positive for large ketonuria &amp;gt;160 mg/dl and glycosuria &amp;gt;500 mg/dl. Serum anion gap and urine anion gap were elevated 29 mEq/L and 105 mEq/L respectively. Serum osmolarity and urine osmolality were elevated 296 mosm/kg and 653 mosm/kg respectively. Lactic acid was 5.3. Acetone was detected in blood. No source of infection was identified. Hemoglobin A1C was 5% and c-peptide was within normal range. Insulin and Islet cells antibodies were negative. DKA protocol was initiated until the anion gap closed. However, non-anion gap metabolic acidosis was persistent with profound hypophosphatemia. Repeat urinalysis showed glycosuria with pH ≤ 5.5, phosphaturia and generalized aminoaciduria. Ultimately, the patient elected to receive hospice care. Discussion: SGLT2i are currently recommended as second-line medications for type 2 diabetes mellitus. Their unique mechanism of action prevents glucose reabsorption from the proximal renal tubules. SGLT2i use is growing significantly, especially after recent clinical trials that demonstrated favorable protective effects. EDKA is precipitated by sepsis, acute illness, dehydration, or starvation. Once the diagnosis is suspected, SGLT2i should be stopped immediately. SGLT2i induced eDKA should be treated in a similar fashion as DKA. It is worth to note that SGLT2i half-life ranges from 11–17 hours, and despite drug discontinuation, glycosuria may persist for several days. What made our case unique and made the diagnosis challenging, was the normal blood glucose level, as well as other differentials that could have easily explained the acidosis including starvation ketosis and lactic acidosis. Also, the state of proximal RTA resembling renal Fanconi syndrome that occurred in correlation with canagliflozin therapy. To the best of our knowledge, this is the fourth reported case of proximal RTA with the use of canagliflozin resulting in life-threatening complications. The diagnosis was very challenging due to lack of awareness of this severe adverse effect.

Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial.

People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61-0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59-0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.

Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes: A PostHoc Analysis from the CREDENCE Trial.

The association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR] >300 mg/g). This post hoc analysis assessed canagliflozin's effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death. Complete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR (odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P<0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P<0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P<0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm. In people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes.

34-OR: SGLT2 Inhibitors: A Comparison of Cardiovascular, Medical, and Cost Outcomes

Since 2016, empagliflozin (EFZ) has been known to reduce cardiovascular (CV) events in patients with type 2 diabetes; however, similar label expansions for dapagliflozin (DFZ) and canagliflozin (CFZ) are quite recent. To date, limited evidence has been published comparing these drugs in real-world practice. This retrospective cohort study address that gap, and used administrative claims data from a nationwide Medicare Advantage Prescription Drug and commercial health plan to compare CFZ, EFZ and DFZ on CV outcomes, treatment persistence, healthcare utilization and costs. Eligible patients naïve to the SGLT2 inhibitor drug class for 6 months from January 2015 to June 2017 were identified. Patients had at least 12 months of continuous enrollment pre- and post-index date (i.e., date of first new prescription). Propensity score method using inverse probability of treatment weighting was used to adjust outcomes. A total of 5,503, 2,052 and 587 patients used CFZ, EFZ and DFZ, respectively. Weighted comparisons showed no difference in the risk of primary composite CV outcome (myocardial infarction, stroke, or mortality) between treatments, but a lower risk of secondary CV outcome (heart failure or death) in the DFZ cohort (hazard ratio 0.82, 95% CI 0.75-0.88) compared to CFZ. Patients indexed to use EFZ were more likely to remain persistent to treatment (odds ratio [OR] 1.09, 95% CI 1.03-1.16), and patients who used DFZ had lower odds of an emergency department visit encounter (OR 0.85, 95% CI 0.79-0.92), relative to the use of CFZ. There were no differences in inpatient hospitalization stays and outpatient services between treatment groups. This population-based study showed minor differences in clinical and cost outcomes between CFZ, EFZ and DFZ, including a post-hoc analysis showing slight variations in use of adjuvant glucose lowering therapies across the SGLT2 inhibitor cohorts. With the ever-evolving landscape of treatment in the care of patients with diabetes, these findings may be helpful to providers. Disclosure P. Schwab: Employee; Self; Humana. Employee; Spouse/Partner; Humana. A. Bowe: Employee; Self; Humana. M. Tindal: None. Y.A. Meah: None. I. Poonawalla: None.

1111-P: Real-World Evidence of SGLT2 Inhibitor (SGLT2i) Use among Adults in the T1D Exchange Registry (T1DX)

Little is known about SGLT2i use in T1D outside a clinical trial setting. This cross-sectional analyses compares characteristics among T1DX registry participants using SGLT2i off-label compared with those not using SGLT2i and assess glycemic outcomes pre-post SGLT2i initiation. The analysis cohort included 204 SGLT2i users and 7124 non-users (n=7,328) in the T1DX registry aged ≥18 yrs with T1D for ≥1 yr. Demographic and clinical characteristics were compared between SGLT2i users and non-users. To assess the effect of SGLT2i use on glycemic outcomes, A1c pre and post-SGLTi initiation was compared. Of 7,328 participants analyzed, 2.8% reported using SGLT2i. Use of canagliflozin, dapagliflozin, and empagliflozin was reported by 50%, 27%, and 27% of SLGT2i users. SGLT2i use was associated with older age, longer T1D duration, higher BMI, and higher socioeconomic status. Glycemic outcomes for the cross-sectional comparison are shown in the Table. There was little difference in mean A1c pre- and post-SGLT2i initiation (8.1±1.0% vs. 8.0±1.1%, P=0.25), but % with A1c &amp;lt;7% nearly doubled (10% vs. 18%, P=0.02). Less than 3% of adults in the T1DX reported SGLT2i use and glycemic benefits were unclear. SGLT2i users reported similar incidence of DKA to non-users, but higher SH rates. While observational data must be interpreted with caution, these findings suggest a need for prospective evaluation of SGLT2i use in T1D. Disclosure M.S. Hughes: None. R. Bailey: None. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. S. Lyons: Other Relationship; Self; Springer Publishing Company. D. DeSalvo: Consultant; Self; Dexcom, Inc., Insulet Corporation. V.N. Shah: Research Support; Self; Dexcom, Inc., JDRF, Mylan, Novo Nordisk A/S, Sanofi, vTv Therapeutics. Other Relationship; Self; Dexcom, Inc., Sanofi US. Funding The Leona M. and Harry B. Helmsley Charitable Trust (G-2016PG-T1D053)

Is it Worth CANVASing for CREDENCE? A Benefit-risk Analysis.

A number of significant positive and negative signals emerged from the CANVAS Program and CREDENCE trial with the use of canagliflozin. These signals are confusing. A Likelihood of being Helped of Harmed (LHH) analysis was conducted to determine the risk, benefit ratio associated with canagliflozin use and address the signals as a continuum. LHH was calculated from the number needed to treat (NNT) and number needed to harm (NNH) available from the absolute risk reductions reported with the outcomes of interest, in these two trials. In the CANVAS Program, LHH for major adverse cardiovascular events (MACE) points at a significant benefit with canagliflozin use in comparison to amputation (1.65), fractures (1.65) and euglycaemic diabetic ketoacidosis (euDKA) (16.67) risks. Only genital fungal infections were significant more in both sexes (0.21-M and 0.1-F) when LHH was matched against the positive outcomes. In contrast, the hHF benefits were outweighed by amputation (0.95) and fracture risks (0.95). In CREDENCE trial, the LHH for Primary composite, Renal composite and MACE, all supported the benefits in comparison to any adverse events encountered in the trial. The LHH from pooled data (CANVAS Program and CREDENCE trial) was in favour of all the benefits (hHF and renal composites) except for MACE matched against amputation (0.66). The outcome benefits were in favour of canagliflozin in comparison to all reported adverse events, when hHF and renal composite were under consideration, in both the individual and pooled LHH analysis. However, the MACE benefits were overwhelmed by amputation risk in the pooled analysis.

Sodium-glucose cotransporter-2 inhibitors: current knowledge on the use of canagliflozin, dapagliflozin and empagliflozin in the treatment of type 2 diabetes mellitus

Sodium-glucose cotransporter-2 inhibitors are considered the newest class of medication developed for the treatment of type 2 diabetes mellitus. This class of drug reduces blood glucose levels by decreasing glucose absorption at the level of the kidneys. Through their mechanism of action, drugs within this class exhibit the ability to reduce blood pressure, fasting blood glucose and body weight. The common side effects observed with the use of sodium-glucose cotransporter-2 inhibitors include: genital mycotic infections, intravascular volume depletion and dehydration. To date, much is already known about Sodium-glucose cotransporter-2 inhibitors and their use in treating type 2 diabetes mellitus; however, continuous studies are currently being undertaken to further investigate the cardiovascular benefits and side effect profile of this class of drug. This review discusses sodium glucose cotransporter-2 inhibitors specifically focusing on what is currently known about the use of canagliflozin, dapagliflozin and empagliflozin in the treatment of type 2 diabetes mellitus.Â

Patient showing increased uric acid level due to long-term use of canagliflozin at normal does

Patient showing increased uric acid level due to long-term use of canagliflozin at normal does

Concurrent Use of Teneligliptin and Canagliflozin Improves Glycemic Control with Beneficial Effects on Plasma Glucagon and Glucagon-Like Peptide-1: A Single-Arm Study.

IntroductionWe investigated the mechanisms of the glucose-lowering effects of teneligliptin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, by monitoring several gastrointestinal peptides using the most appropriate measuring methods during multiple meal tolerance tests (MTTs) and flash glucose monitoring.MethodsTwelve Japanese patients with type 2 diabetes were enrolled in the 14-day study. Subjects were treated with teneligliptin 20 mg/day from day 4, followed by a combination tablet of teneligliptin 20 mg and canagliflozin 100 mg (T/C) per day from day 11. MTTs were conducted on days 3 (premedication; Pre), 10 (teneligliptin; T) and 13 (T/C) to evaluate plasma glucose, C-peptide, glucagon, active glucagon-like peptide-1 (GLP-1), active gastric inhibitory polypeptide (GIP), ghrelin and des-acyl ghrelin.ResultsPlasma glucose was significantly decreased with the progress of treatment intervention, and C-peptide was significantly decreased in T/C compared to the others. Plasma postprandial glucagon was increased for 90 min from fasting in Pre, but only for 30 min in T and T/C. Plasma postprandial active GLP-1 was significantly increased in T compared to Pre, and that of T/C was significantly higher than T. Plasma postprandial active GIP was increased in T and T/C compared to Pre. Plasma ghrelin and des-acyl ghrelin levels did not change during the treatment.ConclusionTeneligliptin increased incretin hormones and suppressed postprandial glucagon secretion as expected. Concurrent use of canagliflozin and teneligliptin improved glycemic control without increasing postprandial glucagon secretion, and increased postprandial GLP-1 secretion and decreased the required amount of postprandial insulin secretion. The underlying mechanisms may involve canagliflozin’s inhibitory activity against not only SGLT2 but also SGLT1.Trial RegistrationUMIN identifier, UMIN000030043.FundingMitsubishi Tanabe Pharma Corporation and a Grant for Clinical Research from Miyazaki University Hospital.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-0666-7) contains supplementary material, which is available to authorized users.

Annals for Educators - 5 February 2019.

Annals for Educators - 5 February 2019.

Fracture Risk After Initiation of Use of Canagliflozin: A Cohort Study.

Sodium-glucose cotransporter-2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral density and a potential increased risk for fracture. To estimate risk for nonvertebral fracture among new users of canagliflozin compared with a glucagon-like peptide-1 (GLP-1) agonist. Population-based new-user cohort study. Two U.S. commercial health care databases providing data on more than 70 million patients from March 2013 to October 2015. Persons with type 2 diabetes who initiated use of canagliflozin were propensity score-matched in a 1:1 ratio to those initiating use of a GLP-1 agonist. The primary outcome was a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention. Secondary outcomes included fractures at other sites. A fixed-effects meta-analysis that pooled results from the 2 databases provided an overall hazard ratio (HR). 79964 patients initiating use of canagliflozin were identified and matched to 79964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1000 person-years) and GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) (overall HR, 0.92 [CI, 0.83 to 1.02]). Unmeasured confounding, measurement error, and low fracture rate. In this study of middle-aged patients with type 2 diabetes and relatively low fracture risk, canagliflozin was not associated with increased risk for fracture compared with GLP-1 agonists. Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.