Lung microbiome: new insights into the pathogenesis of respiratory diseases

SGLT2 Inhibitors Provide Cardiorenal Benefits For Patients With SLE And Type 2 Diabetes

Sodium-glucose cotransporter 2 (SGLT2) inhibitors provide significant renal benefits and similar safety outcomes compared with dipeptidyl peptidase 4 (DPP4) inhibitors among patients with systemic lupus erythematosus (SLE) and type 2 diabetes (T2D), though they are associated with increased risks for genital infections, according to study results published in Arthritis & Rheumatology.

Researchers evaluated the efficacy and safety of SGLT2 vs DPP4 inhibitors for the prevention of cardiovascular disease and renal events among patients with both SLE and T2D and assessed the associated risks for infections. Electronic health record data were sourced from a large insurance-based cohort involving 92 healthcare centers across the United States. Adult patients with both SLE and T2D who newly initiated SGLT2 or DPP4 inhibitors were eligible for inclusion.

Key outcomes included renal events (acute kidney injury [AKI], chronic kidney disease [CKD], end-stage renal disease [ESRD]), cardiovascular events (heart failure, myocardial infarction, stroke), infectious outcomes, safety outcomes, and all-cause mortality. 

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With known cardiorenal benefit and potential effects on reducing ESRD and heart failure, [SGLT2 inhibitors] could become a new widely accepted add-on therapy for SLE.

After 1:1 propensity score matching, a total of 2165 patients (mean age, 58.2 years; 89.5% women) who received SGLT2 inhibitors and 2165 patients (mean age, 58.3 years; 90.2% women) who received DPP4 inhibitors were included in the analysis.

The mean estimated glomerular filtration rate was slightly higher among the SGLT2 inhibitor vs DPP4 inhibitor group (78.2 vs 75.6 mL/min/1.73m2). Similar percentages of patients had CKD (11.8% vs 10.5%) and heart failure (10.5% vs 10.0%) at baseline.  

After an average of 753.1 days of follow-up, comparable risks for all-cause mortality (hazard ratio [HR], 0.89; 95% CI, 0.65-1.21) and incident lupus nephritis (LN) (HR, 0.67; 95% CI, 0.38-1.15) were found among the SGLT2 inhibitor vs DPP4 inhibitor groups. The use of SGLT2 inhibitors was associated with lower risks for AKI (HR, 0.49; 95% CI, 0.39-0.63), CKD (HR, 0.61; 95% CI, 0.50-0.76), and ESRD (HR, 0.40; 95% CI, 0.20-0.80).

Among cardiovascular outcomes, no significant between-group differences were found for myocardial infarction (HR, 0.81; 95% CI, 0.54-1.23) or stroke (HR, 1.03; 95% CI, 0.74-1.44) risks, but a reduced risk for heart failure (HR, 0.72; 95% CI, 0.56-0.92) was associated with SGLT2 inhibitor use.

The SGLT2 inhibitor group had a lower risk for emergency department visits (HR, 0.90; 95% CI, 0.82-0.99), while the risk for hospitalization was similar between groups (HR, 0.76; 95% CI, 0.51-1.12). Risks for urinary tract infections, severe sepsis, and herpes zoster were similar between groups, though SGLT2 inhibitor users were linked to a greater risk for genital infections (HR, 1.31; 95% CI, 1.07-1.61).

Results of sensitivity analyses confirmed these results, with reduced risks for AKI (HR, 0.51; 95% CI, 0.39-0.66), CKD (HR, 0.67; 95% CI, 0.52-0.86), and ESRD (HR, 0.35; 95% CI, 0.17-0.70) found among the SGLT2 inhibitor group. No significant differences were found in the risks for LN, myocardial infarction, or stroke between groups.

Results of subgroup analyses indicated persistent risk reductions for AKI and CKD among White patients receiving SGLT2 inhibitors, and for CKD and heart failure among Black/African American patients.

Study limitations include potential misclassification bias, as well as the lack of data on SLE and T2D durations before treatment initiation and renal biopsy results to establish LN.

The researchers concluded, "With known cardiorenal benefit and potential effects on reducing ESRD and heart failure, [SGLT2 inhibitors] could become a new widely accepted add-on therapy for SLE."

This article originally appeared on Rheumatology Advisor

Benefits Of Various SGLT2 Inhibitors Mostly Consistent In Observational Study

The SGLT2 inhibitors, as a class, lead to similar treatment benefits at comparable clinical doses, although there are some discrepancies between them, particularly when dapagliflozin (Farxiga; AstraZeneca) is used at low doses, a new observational study suggests.

Compared with empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), dapagliflozin produced a similar impact on MI/stroke risk but was associated with an increased risk of heart failure (HF) hospitalization, a risk that was elevated when the 5-mg dose was used.

"These findings reinforce the use of dapagliflozin 10 mg, or other SGLT2 inhibitors, when the therapeutic goal is to reduce the risk of heart failure," write HoJin Shin, PhD (Brigham and Women's Hospital, Boston, MA), and colleagues in the paper published this week in JAMA Internal Medicine.

Stephen Wiviott, MD (Brigham and Women's Hospital), who was not involved in the analysis but who led the DECLARE-TIMI 58 trial with dapagliflozin, urged caution in making too much of observational data. "This is true even when using advanced statistical techniques like propensity matching and trial emulation employed in this study," he told TCTMD. "[I] would not clinically choose one agent over another based on these types of data."

The "magic" of trial randomization is that it accounts for both measured and unmeasured confounders, he stressed, which observational studies do not. That's particularly true when physicians choose to select a lower dose because the treatment decision "may be based on unmeasured factors, such as perceived frailty or concern about tolerating a full dose medication," said Wiviott.  

No Head-to-Head Studies

SGLT2 inhibitors, which were initially approved for glycemic control, have been shown to protect the heart and kidneys in patients with type 2 diabetes, as well as reduce the risk of HF hospitalizations in patients at risk for cardiovascular disease.

However, as the researchers point out, the effect on atherosclerotic outcomes has varied between trials. Specifically, canagliflozin (Invokana; Janssen) and empagliflozin both reduced the risk of major adverse cardiovascular events compared with placebo in the CANVAS and EMPA-REG OUTCOME studies, respectively. In DECLARE-TIMI 58, dapagliflozin reduced the risk of study's primary endpoint—all-cause mortality and HF hospitalization—but didn't reduce the risk of MACE.

In the absence of head-to-head studies, researchers sought to compare the different SGLT2 inhibitors in adults with type 2 diabetes treated in clinical practice. Using data from three large US health insurance claims databases, they compared canagliflozin and dapagliflozin to empagliflozin using inclusion and exclusion criteria, treatment doses, and outcomes that emulated those of clinical trials. The dosages included two approved strengths of each of the SGLT2 inhibitors: canagliflozin 100 or 300 mg, dapagliflozin 5 or 10 mg, and empagliflozin 10 or 25 mg. Ertugliflozin (Steglatro; Merck Sharp & Dohme), the newest of the SGLT2 inhibitors, approved in late 2017, was excluded from the analysis.

Overall, 232,890 patients were treated with canagliflozin, 129,881 with dapagliflozin, and 295,043 with empagliflozin across the three datasets. Before propensity-score weighting, dapagliflozin-treated patients were younger than those treated with empagliflozin, both at the low and high doses, while empagliflozin-treated patients were more likely to have diabetes-related conditions, cardiovascular disease, or chronic kidney disease. Follow-up in the analysis was up to 8 years.

After propensity-score weighting, there was no difference in the risk of MI/stroke or HF hospitalization between canagliflozin- and empagliflozin-treated patients. When dapagliflozin and empagliflozin were compared, the risk of MI/stroke was similar, but dapagliflozin was associated with a higher risk of HF hospitalization (HR 1.19; 95% CI 1.02-1.39). Canagliflozin-treated patients had a borderline lower risk of all-cause mortality compared with empagliflozin (HR 0.87; 95% CI 0.76-1.00), but mortality was similar in the dapagliflozin and empagliflozin users.

The results were consistent across the three databases and when patients were stratified by cardiovascular disease history. In an analysis focused on dose, the pattern seen in the primary analysis was amplified, with low-dose dapagliflozin associated with a higher risk of HF hospitalization compared with empagliflozin (HR 1.30; 95% CI 1.12-1.50); no such difference was seen with the higher dose.

Consistent Results Seen in Other Studies

From a safety standpoint, use of canagliflozin or dapagliflozin was associated with a slightly lower risk of genital infections than empagliflozin. Risk of severe urinary tract infections was higher with canagliflozin, while dapagliflozin was associated with a lower risk of diabetic ketoacidosis.  

The researchers note that there is a risk of residual confounding by unmeasured factors, such as duration and severity of diabetes and cardiovascular disease. They even point that while they observed a higher risk of HF hospitalization with dapagliflozin, that finding was not seen in other observational studies, including one from Denmark and another from Japan. In 2024, they add, a network meta-analysis of 21 placebo-controlled, randomized trials testing multiple SGLT2 inhibitors found no differences in the risk of all-cause mortality, cardiovascular mortality, HF hospitalizations, and diabetic disease progression between the different drugs.

To TCTMD, Wiviott said there is a large body of evidence supporting the SGLT2 inhibitor drug class, noting the medications have been a "remarkable advance in diabetes management and the prevention and treatment of cardiovascular and renal outcomes in people with and without diabetes."

In his opinion, the results across the trials have been consistent, with the various agents reducing HF and kidney disease progression and demonstrating a modest effect on atherosclerotic outcomes, such as MI.

"There have been consistent safety observations such as a small increase in [diabetic ketoacidosis] and genital infections that do not seem to offset the overall benefit," said Wiviott. "The meta-analyses have largely supported consistency of effect among agents by showing a lack of statistical heterogeneity between trial results."

Kerendia Works In Heart Failure, But How Might It Be Used?

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Roman Kraft

Bayer's mineralocorticoid receptor antagonist (MRA) Kerendia hit the mark as a treatment for a common form of heart failure in the FINEARTS-HF study, setting up regulatory approvals, but there is some debate about how the drug may be used in clinical practice.

Kerendia (finerenone) is the first drug in its class to show a benefit in heart failure, achieving a statistically significant improvement in cardiovascular outcomes in heart failure patients with mildly reduced or preserved left ventricular ejection fraction (LVEF) of 40% or greater, according to data presented at the European Society of Cardiology (ESC) congress over the weekend.

Patients with LVEF of 40% or more account for around half of all heart failure patients, but have few available therapies, unlike heart failure with reduced ejection fraction (HFrEF). The life expectancy rate for patients hospitalised with heart failure is worse than many cancers.

Bayer's drug reduced the risk of the composite primary endpoint of cardiovascular death and hospitalisations or urgent visits for heart failure by 16% compared to placebo over a median follow-up of 32 months in the 6,000-patient study, which has also been published in the New England Journal of Medicine.

The result is a key component of Bayer's plan to build Kerendia – which is already approved to treat chronic kidney disease associated with type 2 diabetes – into a major near-term growth driver with a sales target of €3 billion ($3.3 billion). It has a long way to go, with sales of the drug coming in at €200 million in the first half of this year.

The challenge for Bayer will be carving out a role for Kerendia in mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) heart failure alongside SGLT2 inhibitors – AstraZeneca's Farxiga (dapagliflozin) and Eli Lilly/Boehringer Ingelheim's Jardiance (empagliflozin) – which are the only approved therapies for these patients recommended in treatment guidelines.

Novartis' Entresto (sacubitril/valsartan) is also an FDA-approved option for HFmrEF and HFpEF, although, it is recognised most of the drug's benefit comes from patients at the lower end of the LVEF spectrum.

No effect on cardiovascular death

There was discussion at ESC whether Kerendia should be used in place of the SGLT2 inhibitors, or in combination, given that all the benefits of the drug were tied to improvements in heart failure worsening – i.E., hospitalisations – rather than cardiovascular death. An effect on cardiovascular death can be tough to show in a single HFpEF trial, however, as the number of events will be low in an HFpEF population.

It is notable, though, that FINEARTS-HF included patients (around 14%) who were already on SGLT2 drugs, and the efficacy in that group was consistent with that in the overall study population, pointing to a benefit of dual use.

On safety, Kerendia was associated with a higher rate of elevated potassium levels in the blood (hyperkalaemia), but that reflects its mechanism of action and hospitalisation rates were low at 0.5% versus 0.2% for placebo.

"The FINEARTS-HF trial provides the first definite evidence that an MRA is beneficial in HFmrEF/HFpEF," according to Professor Scott Solomon, of Brigham and Women's Hospital in Boston, US, who is principal investigator for FINEARTS-HF and presented the results at ESC.

"We have four pillars of guideline-directed medical therapy in HFrEF, but only SGLT2 inhibitors as a treatment option for HFmrEF/HFpEF," he said. "Given that finerenone was beneficial in patients already receiving an SGLT2 inhibitor, our findings point to finerenone as a new second pillar in HFmrEF/HFpEF."

Bayer is running an open-label study – CONFIRMATION-HF – testing Kerendia with Jardiance in patients hospitalised or recently discharged with heart failure, regardless of their LVEF status. It is also testing the drug in the REDEFINE-HF trial as monotherapy in patients with an LVEF of 40% or more, and the FINALITY-HF study as a monotherapy in those with an LVEF below 40%.

The company is preparing to file for approval of the heart failure indication and has said it is hoping for a green light from regulators next year.

Photo by Roman Kraft on Unsplash

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