Canagliflozin Cardiovascular Assessment Study Research Articles

Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program.

This study compared initiation of insulin and other antihyperglycaemic agents (AHAs) with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year, fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs. 16%), insulin (3% vs. 9%) or any non‐insulin AHA (5% vs. 12%) (P < .001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31, 0.43; P < .001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about 2 years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (P < .001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes.

Prescribing Paradigm Shift? Damned If You Do, Damned If You Don't.

Over the last decade, large cardiovascular outcome trials (CVOTs) have provided a wealth of data on the reduction of cardiovascular (CV) events by glucose-lowering agents in patients with type 2 diabetes (T2D). These trial results have started to influence management recommendations, in particular, the 2019 European Society of Cardiology (ESC) guidelines on CV disease in diabetes, which for the first time recommended that sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) should be considered as first-line therapy in people with drug-naive T2D with CV disease (1). Colleagues in Glasgow, U.K., have responded to this recommendation by investigating the clinical implications and potential costs of implementing these guidelines (2). The background to this change in recommendations primarily relates to the results of placebo-controlled CVOTs with SGLT2i and GLP-1RA. In brief, four CVOTs examined the effect of SGLT2i on three-point major adverse cardiovascular events (3P-MACE). Empagliflozin (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME] trial) (3) and canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]) (4) significantly reduced 3P-MACE, and in a separate trial in patients with T2D with chronic kidney disease (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation [CREDENCE]), canagliflozin also significantly reduced 3P-MACE while ameliorating a decline in renal function (5). Dapagliflozin (Dapagliflozin Effect on Cardiovascular Events [DECLARE-TIMI 58] trial) had no effect on 3P-MACE (6), although all three SGLT2i showed a significant reduction in the combined end point of heart failure hospitalization or CV death. Seven placebo-controlled CVOTs examined the effect of GLP1-RA on CV events in patients with T2D at high CV risk. Two trials, ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) (7) and EXSCEL (Exenatide Study of Cardiovascular Event Lowering) (8), showed only noninferiority for the primary 3P-MACE end point. In contrast, four trials—LEADER (Liraglutide …

Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program.

Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes. To assess whether eGFR declines <57% could detect canagliflozin's effects on renal outcomes, we conducted a post hoc study comparing effects of canagliflozin versus placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with ESKD and renal death. Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, we made estimates using all eGFR values as well as estimates that excluded early measures of eGFR influenced by the acute hemodynamic effect. Among the 10,142 participants, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up of 188 weeks. Compared with a 57% eGFR reduction (risk ratio [RR], 0.51; 95% confidence interval [95% CI], 0.34 to 0.77), the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45 to 0.83), 40% (RR, 0.70; 95% CI, 0.57 to 0.86), or 30% (RR, 0.81; 95% CI, 0.71 to 0.93) eGFR reductions. In analyses that controlled for the acute hemodynamic fall in eGFR, effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reductions were much reduced by controlling for this early hemodynamic effect. Declines in eGFR <57% may provide robust estimates of canagliflozin's effects on renal outcomes if the analysis controls for the drug's acute hemodynamic effect. CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629 and CANVAS-R, NCT01989754.

Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: A systematic review and meta-analysis.

BackgroundThe association between sodium-glucose cotransporter 2 inhibitors (SGLT2i’s) and lower extremity amputation is unclear.PurposeTo systematically review randomized control trials (RCTs) and observational studies quantifying risk of lower extremity amputations associated with SGLT2i use.Data sources and study selectionWe searched PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from January 2011 to February 2020 for RCTs and observational studies including lower extremity amputation outcomes for individuals with type 2 diabetes mellitus treated with SGLT2i’s vs. alternative treatments or placebo.Data extraction and synthesisTwo reviewers independently extracted data.Main outcomes and measuresOur primary outcome was risk of lower limb amputation. Secondary outcomes included peripheral arterial disease, peripheral vascular disease, venous ulcerations, and diabetic foot infections. We also evaluated the risk of bias. We conducted random and fixed effects relative risk meta-analysis of RCTs.ResultsAfter screening 2,006 studies, 12 RCTs and 18 observational studies were included, of which 7 RCTs and 18 observational studies had at least one event. The random effects meta-analysis of 7 RCTs suggested the absence of a statistically significant association between SGLT2i exposure with evidence of substantial statistical heterogeneity (n = 424/23,716 vs n = 267/18,737 in controls; RR 1.28, CI’s 0.93–1.76; I2 = 62.0%; p = 0.12) whereas fixed effects analysis showed an increased risk with statistical heterogeneity (RR 1.27, 1.09–1.48; I2 = 62%; p = 0.003). Subgroup analysis of canagliflozin vs placebo showed a statistically significantly increased risk in a fixed effects meta-analysis (n = 2 RCTs, RR 1.59, 1.26–2.01; I2 = 88%; p = 0.0001) whereas the meta-analysis of dapagliflozin or empagliflozin (n = 2 RCTs each) and a single RCT for ertugliflozin did not show a significantly increased risk. The findings from observational studies were too heterogeneous to be pooled in a meta-analysis and draw meaningful conclusions. Both randomized and observational studies were of generally good methodological quality.ConclusionsOverall, there was no consistent evidence of SGLT2i exposure and increased risk of amputation. The increased risk of amputation seen in the large, long-term Canagliflozin Cardiovascular Assessment Study (CANVAS) trial for canagliflozin, and select observational studies, merits continued exploration.

1118-P: Validation of the PromarkerD Test for Predicting Renal Decline in Type 2 Diabetes in the Canagliflozin Cardiovascular Assessment Study (CANVAS)

Chronic kidney disease (CKD) develops in 1 in 3 people with type 2 diabetes (T2D) and is the leading cause of end-stage renal disease (ESRD). The ability of baseline urinary albumin: creatinine ratio or estimated glomerular filtration rate (eGFR) to predict onset and progression of CKD complicating diabetes is limited. PromarkerD is a novel blood test that can predict future renal function decline. This study sought to validate the prognostic utility of PromarkerD in individuals with T2D from CANVAS, a randomized controlled trial of INVOKANA® (canagliflozin). PromarkerD scores were measured at baseline in 3,570 CANVAS participants (n=1,196 placebo arm, n=2,375 canagliflozin arm). Biomarker concentrations (CD5L, ApoA4, IGFBP3) measured by mass spectrometry were combined with clinical data (age, serum HDL-cholesterol, eGFR) using previously defined algorithms to provide PromarkerD scores. The test score (predicted probability) ranges from 0 to 100% and is categorized as low-, moderate- or high-risk as determined by pre-specified cut-offs at 10% and 20%. Renal function decline was defined as incident DKD during the 4 years from randomization. At baseline, the participant sample (mean age 62.7 years, 67% males, median diabetes duration 12.4 years) had a median PromarkerD score of 2.88%, with 70.5% categorized as low-risk, 13.6% as moderate-risk and 15.9% as high-risk for renal function decline. There was no significant difference in baseline PromarkerD scores by allocated treatment (P=0.58). In a model adjusted for treatment, baseline PromarkerD moderate-risk and high-risk scores were increasingly prognostic for renal function decline (OR 5.29 [4.22, 6.64] and OR 13.52 [10.69, 17.11] versus low-risk, respectively; both P&amp;lt;0.001). These data provide further validation of the role of PromarkerD in predicting clinically significant renal function decline and thus to facilitate preventive management strategies. Disclosure K. Peters: Other Relationship; Self; Proteomics International Laboratories Ltd. J. Xu: Employee; Self; Janssen Research &amp; Development, LLC. S. Bringans: Other Relationship; Self; Proteomics International Laboratories Lt. W.A. Davis: Advisory Panel; Spouse/Partner; Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Spouse/Partner; Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Proteomics International. Other Relationship; Spouse/Partner; Proteomics International. T. Davis: Advisory Panel; Self; Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Spouse/Partner; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Protemics International. Other Relationship; Spouse/Partner; Protemics International. M.K. Hansen: Employee; Self; Janssen Research &amp; Development, LLC. R.J. Lipscombe: Other Relationship; Self; Proteomics International Laboratories Ltd. Funding Janssen Research &amp; Development, LLC

1120-P: Association between the Inflammatory Marker GDF-15 and Kidney Disease Progression: Results from the CANVAS Trial

Introduction: Growth differentiation factor 15 (GDF-15) is a marker of inflammation and cellular injury. Small clinical studies have suggested that SGLT2 inhibitors exert anti-inflammatory effects. We examined the association of baseline GDF-15 with kidney outcomes in patients with type 2 diabetes mellitus (T2DM) participating in the CANagliflozin cardioVascular Assessment Study (CANVAS) study. We also assessed the effect of the SGLT2 inhibitor canagliflozin (CANA) on GDF-15. Methods: The CANVAS trial randomized 4330 people with T2DM at high cardiovascular risk to CANA or placebo. Plasma GDF-15 concentration was measured with GDF-15 Roche Elecsys assay at baseline and follow-up. The association between GDF-15 and the primary kidney outcome (40% eGFR decline, end-stage kidney disease, or renal death) was assessed using multivariable adjusted Cox regression. Linear mixed effects models were used to assess the effect of CANA versus placebo on GDF-15 levels. Results: We included 3557 CANVAS participants with available plasma samples (mean age 62.8 years, 33.1% female, mean eGFR 76.9 ml/min/1.73 m2, median uACR 11.6 mg/g, median GDF-15 1776.0 pg/ml). During a mean follow-up of 5.7 years, 137 kidney outcomes occurred. Higher GDF-15 levels were independently associated with higher risk of kidney events (HR 1.98 [95% CI 1.40 to 2.81] per log increment GDF-15). Treatment with CANA modestly lowered GDF-15 compared to placebo (-2% [95% CI -5 to 0; p=0.046]). The effect of CANA on the kidney outcome (HR 0.56, 95% CI 0.40-0.79) was consistent regardless of baseline GDF-15 levels (p-interaction=0.75). GDF-15 did however not mediate the renal protective effect of CANA (percent mediation 3.9% [95% CI -3.6 to 14.0]). Conclusion: CANA modestly lowers GDF-15, which is independently associated with a higher risk of kidney disease progression in patients with T2DM at high cardiovascular risk. The modest reduction in GDF-15 with CANA did not mediate the renal protective effect of CANA. Disclosure J. Li: Employee; Self; George Institute. T. Sen: None. B. Neal: Research Support; Self; Janssen Research &amp; Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research &amp; Development, LLC. V. Perkovic: Other Relationship; Self; See Other Relationship field. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson &amp; Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. Y. Yavin: Employee; Self; Janssen Research &amp; Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research &amp; Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research &amp; Development, LLC

1123-P: Stress Cardiac Biomarkers and Adverse Cardiac Outcomes in the CANagliflozin CardioVascular Assessment Study (CANVAS)

SGLT2 inhibitors reduce risk of major adverse cardiovascular events (MACE) and hospitalization for heart failure (HHF) in patients with type 2 diabetes (T2D), but mechanisms remain unclear. We examined effects of canagliflozin vs. placebo on 3 prognostic biomarkers in CANVAS, as well as their predictive ability for outcomes of interest. High sensitivity cardiac troponin T (hs-cTnT; Roche Diagnostics), soluble (s)ST2 (Critical Diagnostics), and insulin-like growth factor binding protein 7 (IGFBP7; Roche Diagnostics) were measured in up to 3680 participants at baseline, 1 y, and for hs-cTnT and sST2, 6 y. Conventional statistical methods adjusting relevant covariates were used to relate biomarkers to risk for incident MACE or HHF. Higher concentration of all 3 biomarkers was associated with higher adjusted risk for incident MACE or HHF, with C-index improvements beyond covariates for MACE or HHF (Table). In terms of treatment effect, no biomarkers were differentially altered by 1 y but where data existed, both hs-cTnT (n=915; treatment coefficient [95% CI]: -0.064 [-0.121, -0.007]; p=0.027) and sST2 (n=828, treatment coefficient [95% CI]: -0.129 [-0.248, -0.010]; p=0.033) were reduced significantly at 6 y. Among patients with T2D, concentrations of hs-cTnT, sST2, and IGFBP7 were associated with risk for MACE and HHF. Canagliflozin slowed longer term (6 y) increases in hs-cTnT and sST2. Disclosure N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. J. Xu: Employee; Self; Janssen Research &amp; Development, LLC. J. Butler: Consultant; Self; Amgen, Array BioPharma, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, CVRx, G3 Pharmaceuticals, Innolife Co., Ltd., Janssen Pharmaceuticals, Inc., Luitpold Pharmaceuticals, Inc., Medtronic, Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Relypsa, Inc., VIfor. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson &amp; Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. W. Shaw: Employee; Self; Janssen Pharmaceuticals, Inc. N. Rosenthal: None. D.E. Gutstein: Employee; Self; Janssen Research &amp; Development, LLC. M.K. Hansen: Employee; Self; Janssen Research &amp; Development, LLC. J. Januzzi: Consultant; Self; Roche Diagnostic USA. Research Support; Self; Janssen Pharmaceuticals, Inc. Funding Janssen Research &amp; Development, LLC

P1839GLOMERULAR HYPERFILTRATION: THEORY AND APPLICATIONS

Abstract Background and Aims The role of glomerular hyperfiltration in the development and progression of diabetic and non-diabetic chronic kidney disease (CKD) was established during the 80’s of the last century and represented a paradigm shift in current nephrology practice. Method A web-based review of relevant bibliography: articles and textbooks, reporting the development of hyperfiltration theory and its clinical applications was conducted. Results In 1982, after a series of animal studies, Brenner and colleagues proposed that glomerular hyperfiltration, in diabetic and other glomerulopathies, contributes to intrarenal hypertension and predispose to progressive glomerular sclerosis and deterioration of renal function. Clinical trials during late 80’s and early 90’s then focused on inhibition of Renin Angiotensin Aldosteron system (RAAS) to reverse glomerular hyperfiltration, and suggested that ACE inhibitors can be anti-proteinuric independent of their blood pressure-lowering effect in non-diabetic and diabetic nephropathies. In 1993, a randomized controlled trial (RCT) by Lewis and colleagues proved a beneficial effect of captopril in patients with nephropathy caused by type 1 diabetes. Few years later, the results of Ramipril Efficacy in Nephropathy (REIN) study proved the renoprotective role of ACE inhibition in patients with non-diabetic nephropathies with nephrotic and non-nephrotic proteinuria in 2 Lancet articles in 1997 and 1999 respectively. The renoprotective role of RAAS inhibition with ARBs in patients with type 2 diabetes was proven in 3 RCTs published in the New England Journal of Medicine in 2001: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) Study, Irbesartan Diabetic Nephropathy Trial (IDNT), and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Dual blockade with an ACE inhibitor and an ARB was then attempted to further ameliorate glomerular hyperfiltration. Yet this approach was faced by an increased risk of hyperkalemia and acute kidney injury in 2 RCTs: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) in 2008 and The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study in 2013. It was until 2014 when evidence appeared for a potential role of SGLT2 inhibition in attenuating glomerular hyperfiltration. The 1st clinical evidence of renoprotective effect of SGLT2i appeared in 2016 when the results of the EMPA-REG OUTCOME study found that empagliflozin was associated with lower rates of renal events. Subsequently, the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program trials and the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial found similar reductions in composite renal endpoints. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial published in 2019 was the first study designed to assess the effects of a SGLT2i, canagliflozin, on renal outcomes in patients with type 2 diabetes and albuminuric CKD, and proved significant reduction in the composite renal outcome with canagliflozin. The potentiality for renoprotective role of SGLT2i in patients with non-diabetic CKD has stimulated a number of ongoing clinical trials: DIAMOND and Dapa-CKD using Dapagliflozin and EMPATHY and EMPA-KIDNEY using Empagliflozin. Conclusion The hyperfiltration theory represents the basis for current therapeutic interventions in diabetic and non-diabetic CKD. Current guidelines recommend using RAAS blockers in diabetic and non-diabetic proteinuric CKD and SGLT2i in patients with type 2 diabetes and CKD. Whether SGLT2i could be considered in patients with CKD independent of the diabetic state awaits the results of ongoing studies which might change the management practice of CKD.

Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

The effect of luseogliflozin on bone microarchitecture in older patients with type 2 diabetes: study protocol for a randomized controlled pilot trial using second-generation, high-resolution, peripheral quantitative computed tomography (HR-pQCT)

BackgroundOlder patients with type 2 diabetes mellitus (T2DM) have an increased risk of bone fracture independent of their bone mineral density (BMD), which is explained mainly by the deteriorated bone quality in T2DM compared to that in non-diabetic adults. Sodium-glucose co-transporter (SGLT) 2 inhibitors have been studied in several trials in T2DM, and the Canagliflozin Cardiovascular Assessment Study showed an increased fracture risk related to treatment with the SGLT2 inhibitor canagliflozin, although no evidence of increased fracture risk with treatment with other SGLT2 inhibitors has been reported. The mechanism of the difference in the fracture risk between the SGLT2 inhibitors is unknown, but the differences among the SGLT2 inhibitors in the selectivity of SGLT2 against SGLT1 may affect bone metabolism, since among the SGLT2 inhibitors the selectivity of canagliflozin is lowest. We will investigate whether the SGLT2 inhibitor luseogliflozin, which has the higher SGLT2 selectivity, affects bone metabolism by using high-resolution, peripheral quantitative computed tomography (HR-pQCT) which provides direct in vivo morphometric information about the bone microarchitecture.Methods/designThis is a single-center, randomized, open-label, active-controlled, parallel pilot trial. Eligible participants are older (age ≥ 60 years) individuals with T2DM with HbA1c levels at 7.0–8.9%. A total of 24 participants will be allocated to either the luseogliflozin group (taking luseogliflozin) or the control group (taking metformin) in a 1:1 ratio to compare the groups’ changes in bone microarchitecture of the radius and tibia which are analyzed by HR-pQCT before and at 48 weeks after the administration of each medication. The laboratory data associated with glycemic control and bone metabolism will be collected every 12 weeks during the study. Recruitment began in June 2019.DiscussionThe reason that we use metformin as an active control is to avoid yielding differences in glycemic control between the luseogliflozin and control groups. Besides, metformin is considered to have a neutral effect on bone. This trial should reveal the effect of luseogliflozin on bone metabolism in older patients with T2DM.Trial registrationThe study was registered with the University Hospital Medical Information Network (UMIN000036202) on 1 April 2019 and with the Japan Registry of Clinicla Trials (jRCTs071180061) on 14 March 2019.

Using the BRAVO Risk Engine to Predict Cardiovascular Outcomes in Clinical Trials With Sodium-Glucose Transporter 2 Inhibitors.

This study evaluated the ability of the Building, Relating, Assessing, and Validating Outcomes (BRAVO) risk engine to accurately project cardiovascular outcomes in three major clinical trials-BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), Canagliflozin Cardiovascular Assessment Study (CANVAS), and Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction (DECLARE-TIMI 58) trial-on sodium-glucose cotransporter 2 inhibitors (SGLT2is) to treat patients with type 2 diabetes. Baseline data from the publications of the three trials were obtained and entered into the BRAVO model to predict cardiovascular outcomes. Projected benefits of reducing risk factors of interest (A1C, systolic blood pressure [SBP], LDL, or BMI) on cardiovascular events were evaluated, and simulated outcomes were compared with those observed in each trial. BRAVO achieved the best prediction accuracy when simulating outcomes of the CANVAS and DECLARE-TIMI 58 trials. For EMPA-REG OUTCOME, a mild bias was observed (∼20%) in the prediction of mortality and angina. The effect of risk reduction on outcomes in treatment versus placebo groups predicted by the BRAVO model strongly correlated with the observed effect of risk reduction on the trial outcomes as published. Finally, the BRAVO engine revealed that most of the clinical benefits associated with SGLT2i treatment are through A1C control, although reductions in SBP and BMI explain a proportion of the observed decline in cardiovascular events. The BRAVO risk engine was effective in predicting the benefits of SGLT2is on cardiovascular health through improvements in commonly measured risk factors, including A1C, SBP, and BMI. Since these benefits are individually small, the use of the complex, dynamic BRAVO model is ideal to explain the cardiovascular outcome trial results.

Clinical Influence of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors for Cardiovascular and Renal Points of View

Diabetes has been a major medical and health problem worldwide. Adequate glycemic control has shown a clinically beneficial effect for long-term prognosis, with recent anti-diabetic agents. There are some mega studies concerning Sodium-glucose cotransporter 2 (SGLT2) inhibitors. They are i) Canagliflozin cardioVascular Assessment Study (CANVAS), ii) Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), iii) Dapagliflozin Effect on CardiovascuLAR Events (DECLARE) -TIMI 58, iv) Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) study. Current topics of SGLT2 inhibitors for cardiovascular and renal points of view were described.

Sodium glucose co-transporter 2 inhibitors and cardiovascular event protections: how applicable are clinical trials and observational studies to real-world patients?

ObjectiveThis study evaluated the characteristics of new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) in clinical practice to assess the applicability of the findings from clinical trials (Empagliflozin, Cardiovascular...

The effects of canagliflozin on gout in type 2 diabetes: a post-hoc analysis of the CANVAS Program.

Sodium glucose co-transporter 2 inhibitors have been shown to reduce serum urate concentration. The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program integrated data from two similarly designed, randomised, double-blind, placebo-controlled trials (CANVAS and CANVAS-Renal) assessing the cardiovascular and renal safety of canagliflozin compared with placebo in patients with type 2 diabetes. In this post-hoc analysis, we aimed to investigate the effect of canagliflozin compared with placebo on gout in the CANVAS Program. In the CANVAS Program, individuals with type 2 diabetes and an elevated risk of cardiovascular disease were randomly assigned to receive either canagliflozin (100 or 300 mg) or placebo. In this post-hoc analysis, we assessed the effects of canagliflozin versus placebo on serum urate concentration using mixed linear models and the occurrence of either an adverse event attributed to gout flare or the commencement of a drug for gout using Kaplan-Meier analysis with Cox proportional hazards models to determine a hazard ratio (HR) and 95% CIs. All analyses were done according to the principle of intention to treat, and there was no imputation for missing data. 10 142 participants were included in analyses. At baseline, mean age was 63 years (SD 8), 3633 (36%) participants were female, mean serum urate concentration was 348·9 μmol/L (95·5), and 471 (5%) of participants had a history of gout. Mean follow-up was 3·6 years (SD 2·0) and mean serum urate concentration was -23·3 μmol/L (95% CI -25·4 to -21·3) lower in participants treated with canagliflozin than in those who received placebo, equating to a 6·7% reduction in serum urate (percentage difference -6·7%, 95% CI -7·3 to -6·1). During follow-up, 80 individuals reported an episode of gout flare and 147 commenced a drug for gout. The occurrence of gout flare or the need for treatment for gout was lower in participants treated with canagliflozin than in those who received placebo (HR 0·53, 95% CI 0·40-0·71; p<0·0001). The proportional reduction for gout flare adverse events (2·0 patients with an event per 1000 patient-years in the canagliflozin group vs 2·6 patients with an event per 1000 patient-years in the placebo group; 0·64, 95% CI 0·41-0·99; p=0·046) was similar in size to that for commencement of a drug for gout (3·3 vs 5·4 patients with an event per 1000 patient-years; 0·52, 0·38-0·72; p<0·0001) and hyperuricaemia (1·8 vs 2·5 patients with an event per 1000 patient-years; 0·59, 0·37-0·93; p=0·023). In this post-hoc analysis, compared with placebo, canagliflozin reduced serum urate concentration and also reduced events related to gout flare among patients with type 2 diabetes. A trial explicitly designed to test the effects of sodium glucose co-transporter 2 inhibition on gout is required to confirm these observations. Janssen Research & Development.

Sodium Glucose Cotransporter 2 Inhibition Heralds a Call-to-Action for Diabetic Kidney Disease.

Diabetes is a global health emergency with 425 million people affected in the year 2017 and a projection for 629 million by 2045. Half develop diabetic kidney disease, and its prevalence is rising progressively in concert with the overall diabetes epidemic, largely driven by type 2 diabetes ([1][1

Sodium-Glucose Co-Transporter2 Inhibitors and Fracture Risk.

Patients with type 2 diabetes mellitus (T2DM) appear to have increased risk for fractures. In this context, the finding that canagliflozin, a sodium-glucose co-transporter-2 (SGLT) inhibitor, increased the risk for fracture compared with placebo in the Canagliflozin Cardiovascular Assessment Study (CANVAS), a large randomized controlled trial (RCT) in patients with established cardiovascular disease or multiple cardiovascular risk factors, created concern. In the present review, we summarize the data regarding the association between SGLT2 inhibitors and fracture risk in patients with T2DM. In contrast to the findings reported in CANVAS, canagliflozin did not affect the risk of fracture in a more recent, large RCT in patients with diabetic nephropathy. In addition, empagliflozin and dapagliflozin, other members of this class, also do not appear to affect the incidence of fracture. Moreover, there is no clear pathogenetic mechanism through which SGLT2 inhibitors increase the risk for fractures. Therefore, available data are inconclusive to attribute to these drugs a direct responsibility for bone fractures.

Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes

ObjectivesThe purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study–Renal; NCT01989754). BackgroundCanagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain. MethodsThe percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses. ResultsEarly changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%). ConclusionsA diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.

How Does CREDENCE Inform Best Use of SGLT2 Inhibitors in CKD?

CKD is a common complication in people with diabetes ([1][1]) and contributes to approximately half of all incident cases of ESKD in the developed world ([2][2]). CKD occurs in approximately 40% of people with type 2 diabetes ([3][3]); given the health-related effects of CKD, there is great need for

Effect of Canagliflozin on Renal and Cardiovascular Outcomes across Different Levels of Albuminuria: Data from the CANVAS Program.

If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more. We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR >300 mg/g) at baseline. Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across albuminuria subgroups, with greater absolute reductions in participants with severely increased albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m2 per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased albuminuria (P heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for amputation across albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria (P heterogeneity=0.004). The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of albuminuria, but absolute benefits are greatest among those with severely increased albuminuria.

Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program

Aims/hypothesisAn increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R.MethodsThis study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time.ResultsA total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls.Conclusions/interpretationThere was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.Trial registration: ClinicalTrials.gov NCT01032629, NCT01989754.