Latest news with #SGLT2inhibitor
Medscape
4 days ago
- Health
- Medscape
Canagliflozin CV Benefits Appear to Be Dose-Dependent
Cardiovascular benefits associated with the SGLT2 inhibitor drug canagliflozin appear to be dose-dependent, with benefits in some key clinical endpoints — including mortality — observed only in the higher of the two key doses of 300 mg and 100 mg of the drug, new research shows. 'The benefit of canagliflozin on hard clinical endpoints may be dose-dependent, with the 300 mg dose showing a higher efficacy and a similar safety profile,' said first author Elias Elenjickal, MD, of the Research Institute of the McGill University Heath Centre, in Montreal, Quebec, in presenting the findings at the 62nd European Renal Association Congress 2025. Cardiovascular and renal benefits of SGLT2 inhibitor drugs are well established, and while dose-dependent effects have been reported in some pharmacokinetic studies, none — with the exception of the EMPA-REG OUTCOME trial (which was of empagliflozin) — have formally evaluated the impact of different doses on hard clinical endpoints, Elenjickal noted. To investigate whether dose indeed plays a role in those cardiovascular and renal endpoints with canagliflozin, Elenjickal and colleagues conducted a post-hoc analysis of the double-blind Canagliflozin Cardiovascular Assessment Study (CANVAS) study, which was part of the pivotal CANVAS Program. The CANVAS Program included the CANVAS and CANVAS-Renal studies. The results of the two trials were published together as part of the CANVAS program, not independently. The CANVAS study included 4330 patients with type 2 diabetes and a high cardiovascular risk, including known cardiovascular disease (CVD) or more than 2 risk factors for CVD. Those patients were randomized 1:1:1 to treatment with canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Patients in the study had a median age of 61 years, 66% were male, and baseline characteristics between the groups were similar. With a mean follow-up of 74 months, those in the canagliflozin 300 mg group showed significantly greater reductions in the composite cardiovascular endpoint, including non-fatal myocardial infarction, stroke, or cardiovascular death, compared with placebo (hazard ratio [HR], 0.82; P = .04) after adjustment for factors including age, sex, and history of CVD. However, these differences were not observed between canagliflozin 100 mg and placebo for the composite endpoint (HR, 0.95; P = .55). There were no significant differences between the two canagliflozin doses and the incidence of the composite renal endpoint that included doubling of serum creatinine, end-stage kidney disease, or renal death, compared with placebo (HR, 0.48 for canagliflozin 100 mg; P = .03; HR, 0.41 for canagliflozin 300 mg; P = .01). Those in the 300 mg dose group were less likely to have progression of albuminuria to a higher stage (A1 to A2, or A2 to A3), compared with placebo (HR, 0.83; P = .006), but the difference was not significant with the 100 mg dose (HR, 0.94; P = .33). Importantly, all-cause mortality was significantly lower with the 300 mg dose compared with placebo (HR, 0.78; P =.03), while the 100 mg group only showed a trend toward lower mortality (HR, 0.89; P = .29). There were no significant differences between the two dose groups and placebo in terms of the incidence of acute kidney injury, while the 300 mg group had a trend towards fewer severe hyperkalemia episodes (adjusted HR, 0.61; P = .27). There were no differences observed in safety outcomes between the two dose groups or placebo. A Gender Difference? Of note, a further subgroup analysis showed an effect of gender on hospitalization rates for heart failure events: with males in the 300 mg group having a significantly decreased risk of heart failure hospitalization vs placebo (HR,.62), while females in the 300 mg group had an increased risk (HR, 1.72; P for interaction .03). In the 100 mg group, males also had a lower risk for heart failure hospitalization vs females (HR, 0.65 vs HR, 1.05; P for interaction .37). As a caveat, Elenjickal noted that males did have a higher burden of CVD at baseline (65% vs 46%). 'Overall, we found that canagliflozin 300 mg significantly reduced major adverse cardiac events, and reduction in all-cause mortality was observed only with a 300 mg dose: not with a 100 mg dose,' Elenjickal said. 'There is evidence of a dose-dependent effect with canagliflozin, which is unique among other SGLT2 inhibitors for hard clinical endpoints,' Elenjickal said. The CANVAS study was funded by Janssen Research and Development; number NCT01032629 . Elenjickal reported an educational grant from Pfizer.
Medscape
5 days ago
- Health
- Medscape
Combination Therapy Offers CONFIDENCE to CKD+T2D Patients
VIENNA — Combining the SGLT2 inhibitor empagliflozin with finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), markedly and durably reduced albuminuria in patients with both chronic kidney disease (CKD) and type 2 diabetes (T2D), the CONFIDENCE trial showed in findings that offer hope of a long-term improvement in outcomes. In the trial, 70% of patients on both therapies achieved the American Diabetes Association recommended urinary albumin-to-creatinine ratio (UACR) reduction target of > 30%. 'Since UACR is a key mediator of kidney and cardiovascular outcomes, these results are highly relevant for clinical decision-making,' said lead researcher Rajiv Agarwal, MD, MS, professor emeritus of medicine, Indiana University School of Medicine, Indianapolis. The results were presented here at the 62nd European Renal Association (ERA) Congress 2025 on June 5 and sparked enthusiastic applause from the audience. The findings were simultaneously published in The New England Journal of Medicine. Agarwal, who shared the podium with three of his co-investigators to present the study, added that this was in keeping with 'other chronic conditions like heart failure or hypertension,' in that 'we're moving away from the traditional stepwise approach toward upfront combination therapy.' Session co-chair Mustafa Arici, MD, professor of medicine (nephrology), Hacettepe University, Ankara, Turkey, described the results as 'remarkable.' He told Medscape Medical News , 'For protecting the kidneys of type 2 diabetes patients, it looks like we now have the data to start an SGLT2 inhibitor plus an MRA in combination from the first day, because the data is very solid.' Arici noted, however, that the study did not include clinical endpoints and 'people usually would like to hear solid outcomes. We would like to see whether the number of dialyses decreased or the mortality decreased.' But — as the presenters themselves pointed out — the numbers required to show a clinical benefit are too large to feasibly conduct a trial, he said. 'Obviously there is a surrogate outcome here, which is the UACR,' said Arici. "And at the moment, we have data from 800 people with a good amount of follow up and with no safety signal, which is important." Implementing and Combining Additional Drugs Co-investigator of the CONFIDENCE study, Peter Rossing, MD, PhD, clinical professor, Steno Diabetes Center, Copenhagen, Denmark, noted that, in terms of treatment, the standard of care in patients with CKD and T2D is based on four pillars, with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) joined in recent years by SGLT2 inhibitors, MRAs, and GLP-1 receptor agonists. 'However, we do not know really how to implement these additional drugs and how to combine them,' Rossing said. Clues have come from combination trials in hypertension and heart failure with reduced ejection fraction, which led to the evolution of guideline recommendations and the mantra that, when it comes to using multiple drugs, it is better to give 'some of all, instead of all of some.' A recent analysis also suggested that steroidal MRAs and SGLT2 inhibitors may have additive effects in reducing UACR, far more than either drug alone, although only 32 patients in the study had both CKD and T2D. In the current trial, patients were enrolled if they had: a UACR of ≥ 100 – < 5000 mg/g; an estimated glomerular filtration rate (eGFR) of 30-90 mL/min/1.73 m2; T2D with an A1c < 11%; and were receiving clinically maximally tolerated doses of ACE inhibitors/ARBs for > 1 month. The participants were randomly assigned to one of three groups: simultaneous finerenone plus empagliflozin; finerenone plus placebo; or empagliflozin plus placebo. Patients were treated for 180 days, with clinical visits on days 14, 30, and 90, and then went through a washout period through to day 210. Choosing a composite kidney endpoint for the primary efficacy analysis would have required 41,000 patients to be enrolled into the trial, explained co-investigator Hiddo J.L. Heerspink, PhD, Department of Clinical Pharmacology, University Medical Center, Groningen, Netherlands. Instead, the researchers opted for the more feasible primary endpoint of relative change in UACR from baseline to day 180, as previous studies have shown that short-term UACR changes are associated with kidney protection in the long term. In all, 818 patients were randomly assigned from 143 sites in 14 countries, of whom 269 ended up receiving the combination therapy, 264 had finerenone monotherapy, and 267 were treated with empagliflozin alone. The mean age of the patients was 67 years, and 75% were male. Forty-six percent were Asian and 44% were White. Turning to the efficacy analysis, Agarwal asked the audience to vote on the percentage reduction in UACR that they expected the combination therapy would achieve. The most common answer, chosen by 37.7% of voters, was 30%-40%. Agarwal then showed that, in fact, combining finerenone with empagliflozin achieved a 52% reduction in UACR over baseline, 32% greater than that seen with empagliflozin alone, and 29% greater than that seen with finerenone monotherapy. 'It's great to see some positive trial results,' he added, in response to the audience's acclamation. In addition, only 52% of patients treated with either drug alone reached a > 30% reduction in UACR at day 180 compared to the 70% of patients treated with the combination. In addition, a total of 64% of patients treated with the combination achieved a > 40% reduction in UACR, and 55% reached a > 50% reduction. In both cases, the proportions of patients reaching the target with monotherapy were approximately 20% lower. The benefit in terms of serum potassium levels was also notable, as there was a 17.7% reduction in the incidence of treatment-emergent hyperkalemia, defined as serum levels > 5.5 mmol/L, with combination therapy vs finerenone monotherapy. Agarwal also noted that there was a low incidence of hypotension with combination therapy, with just three cases (1.1%), and a low incidence of acute kidney injury, at five cases (1.9%). There was an initial decline in eGFR, which was described as 'predictable' and largely reversible after drug withdrawal. Crucially, the researchers also showed that during the washout period, UACR levels returned to almost those seen at baseline. This pattern was also observed with the marked improvements in both serum potassium and blood pressure levels that were seen with finerenone plus empagliflozin, which were again greater than those achieved with either monotherapy. After the data were presented, study co-investigator Johannes F.E. Mann, MD, head, KfH Kidney Center, Munich, Germany, sought to explain the implications of the findings by pointing to a recent mediation analysis of pooled data from two phase 3, double-blind trials of finerenone. This revealed that reductions in UACR over the first 4 months of treatment explained 84% of the later reductions in kidney progression and 37% of the reductions in cardiovascular outcomes, suggesting that the findings from CONFIDENCE may well translate into later improvements in clinical endpoints. Muthiah Vaduganathan, MD, MPH, from the Department of Cardiovascular Medicine at Brigham and Women's Hospital, Boston, welcomed the findings. Commenting on X (formerly Twitter), he said that the simultaneous initiation of the combination therapy 'safely and rapidly delivers' in patients with both CKD and T2D. 'A new age of combination therapies has arrived.' The study was funded by Bayer. Agarwal declares relationships with Akebia Therapeutics, Alnylam, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Intercept, Novartis, UpToDate, Wolters Kluwer, Chinook, and Vertex. Rossing declares relationships with AstraZeneca, Bayer, Novo Nordisk, Abbott, Astellas, Boehringer Ingelheim, Eli Lilly, Gilead, Sanofi, Daiichi Sankyo, and Lexicon Pharma. Heerspink declares relationships with Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, BioCity, Dimerix, Eli Lilly, Janssen, Novartis, Novo Nordisk, Roche, and Travere Therapeutics. Mann declares relationships with Novo Nordisk, the European Union, Bayer, AstraZeneca, Bayer, Novartis, UpToDate, Cytel, IQVIA, Parexel, WCG, and Sanofi.
