LBS 01: Celebrating a century of cardiovascular science
Intensive blood pressure control, tirzepatide and novel gene editing therapy.
Trial results were presented for new approaches to managing blood pressure in diabetes, HFpEF and obesity, and transthyretin amyloid cardiomyopathy at the Opening Session on Saturday. They found:
- Intensive blood pressure control strategy may improve cardiovascular outcomes in patients with type 2 diabetes.
- Tirzepatide shows clinical benefit in patients with heart failure with preserved ejection fraction and obesity.
- Novel gene editing therapy shows promise for patients with transthyretin amyloid cardiomyopathy.
An intensive blood pressure control strategy for patients with type 2 diabetes may be considered
There is a lack of consensus on blood pressure reduction targets in patients with type 2 diabetes and current clinical guidelines offer inconsistent recommendations due to limited evidence from well-conducted clinical trials. Still, results of the Intensive Blood-Pressure Control in Patients with Type 2 Diabetes (BPROAD) trial contribute to the body of evidence supporting more intensive systolic blood pressure control in patients with type 2 diabetes for the prevention of major cardiovascular events.
The multicenter, open-label, parallel-group clinical trial randomized 12,821 patients with type 2 diabetes and elevated systolic blood pressure and increased cardiovascular risk from 145 clinical sites in mainland China between February 2019 and December 2021 to intensive treatment (6,414 patients) or standard treatment (6,407 patients) for up to five years.
Systolic blood pressure was targeted to <120 mmHg in the intensive treatment group and <140 mmHg in the standard treatment group. Mean age of patients was 63.8 years; 45.3% were women and 22.5% had a self-reported history of cardiovascular disease at baseline. Median follow-up was 4.2 years. The primary outcome was major cardiovascular events defined as the composite endpoint of the first occurrence of non-fatal stroke, non-fatal myocardial infarction, treated or hospitalized heart failure and cardiovascular death.
Following randomization, the intensive treatment was associated with a significant 21% reduction in risk of cardiovascular disease compared with patients receiving the standard treatment during up to five years of follow-up. At one year, the mean (median) systolic blood pressure was 121.6 mm Hg (118.3mm Hg) in the intensive-treatment group and 132.2 mm Hg (135.0 mm Hg) in the standard-treatment group.
Primary outcome events occurred in 393 patients (1.65 events per 100 person-years) in the intensive group and 492 patients (2.09 events per 100 person-years) in the standard treatment group (HR = 0.79; 95% CI; 0.69 to 0.90; p < 0.001). Serious adverse events were generally similar between the two groups. However, symptomatic hypotension and hyperkalemia occurred more frequently in the intensive-treatment group.
“For most people with type 2 diabetes with an elevated cardiovascular disease risk, intensive treatment to lower systolic blood pressure to a level less than 120 mmHg might have additional benefits in the prevention of major cardiovascular diseases compared with standard treatment to lower systolic blood pressure to a level less than 140 mmHg,” said Guang Ning, MD, PhD, the study’s principal investigator and the Guang Qi Professor at Shanghai Jiao Tong University School of Medicine in China. “Meanwhile, although it is generally safe, hypotension and hyperkalemia should be monitored and prevented during intensive blood pressure reduction.”
Ning noted that BPROAD’s results are consistent with findings from the SPRINT study, which found a significant 27% reduction in the incidence of cardiovascular diseases in patients with hypertension but without diabetes. “Future clinical practice guidelines should consider these lines of evidence when making recommendations of blood pressure treatment in patients with type 2 diabetes,” he said. The study was published in the New England Journal of Medicine following the presentation.
Weight-loss drug reduced worsening heart failure in people with obesity
Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, significantly reduced the risk of a composite of cardiovascular death or worsening heart failure and improved health status in patients with heart failure with preserved ejection fraction (HFpEF) and obesity, according to Tirzepatide for Patients With Heart Failure With Preserved Ejection Fraction and Obesity: The SUMMIT Trial.
Tirzepatide and other incretin-based drugs are approved for use in adults with type 2 diabetes and for patients with obesity or overweight in the presence of at least one weight-related comorbid condition, such as cardiovascular disease. “Data were lacking on the effects of incretin-based drugs on cardiovascular outcomes in patients with heart failure, but we now have compelling information about the influence of these drugs on the clinical course of patients with heart failure and preserved ejection fraction with obesity,” said Milton Packer, MD, distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas and the study’s principal investigator.
The international, multicenter, double-blind randomized placebo-controlled trial randomly assigned 731 patients with heart failure, ejection fraction ≥50% and body mass index ≥30 kg/m2 1:1 to tirzepatide up to 15 mg subcutaneously weekly or placebo for a median of 104 weeks.
The two primary outcomes were the time to first cardiovascular death or worsening heart failure events and the change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks. Scores ranged from 0 to 100, with higher scores indicating better health status.
Overall, tirzepatide benefited patients with HFpEF and obesity compared with placebo. Cardiovascular death or worsening heart failure events occurred in 9.9% of patients in the tirzepatide group and 15.3% in the placebo group (HR 0.62; P=0.026).
Worsening heart failure events occurred in 8% of patients in the tirzepatide group and 14.2% in the placebo group (HR 0.54, P=0.008), with no apparent differences between groups in cardiovascular death. At 52 weeks, the mean change in KCCQ-CSS was 19.5 in the tirzepatide group compared with 12.7 in the placebo group (P<0.001).
Tirzepatide was also well tolerated; 6.3% of patients in the tirzepatide group stopped the drug due to adverse events (mainly gastrointestinal), compared with 1.4% in the placebo group.
“The SUMMIT Trial’s impressive outcomes data shows that tirzepatide doesn’t just make people with obesity feel better, it changes the clinical trajectory of heart failure with preserved ejection fraction in these patients,” Packer said.
Packer noted that the SUMMIT Trial’s results can’t be extrapolated to patients with heart failure with reduced ejection fraction (HFrEF); these patients were not enrolled in the trial. “For the heart failure benefits of incretin-based drugs, the type of heart failure matters,” he said. The study was published simultaneously in the New England Journal of Medicine.
Novel gene editing therapy shows promise for patients with transthyretin amyloidosis with cardiomyopathy
Despite earlier diagnosis and currently available therapies, transthyretin amyloidosis with cardiomyopathy (ATTR-CM) remains a progressive and ultimately fatal disease with significant unmet need. But a single dose of Nexiguran ziclumeran (nex-z), previously known as NTLA-2001, an investigational CRISPR/Cas9-based in vivo gene editing therapy, demonstrated favorable safety, tolerability, durable reductions in serum TTR levels with very low variability among patients, and evidence of disease stabilization, according to CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy therapy for patients with ATTR-CM: interim report of the Phase 1 study.
In the open label trial, 36 patients with ATTR-CM, 50% New York Heart Association (NYHA) class 1-III; 31% variant ATTR-CM, received a weight-based (0.7 or 1.0mg/kg) or fixed dose (55mg) of nex-z as a one-time IV infusion and completed at least 12 months of follow-up. The primary outcome assessed nex-z safety and serum TTR levels. Secondary endpoints included nex-z effect on N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-Troponin-T), 6-minute walk test (6MWT) distance in addition to changes in NYHA class, measurements of cardiac remodeling on echocardiography and cardiovascular magnetic resonance imaging (CMR), cardiopulmonary exercise testing (CPET) and KCCQ score.
Reductions in TTR were accompanied by stability or improvement of several disease markers. Mean 95% CI percent change from baseline in serum TTR levels at day 28 and month 12 was -89% and 90%, respectively. Geometric mean (95% CI) fold change from baseline to month 12 in NT-proBNP and hs-Troponin-T was 1.02 (0.88 to 1.17) and 0.95 (0.89 to 1.01), respectively. Median interquartile range change from baseline to month 12 in 6MWT distance was 5 meters and 92% of patients experienced an improvement or no change in NYHA class. Mild to moderate, transient infusion-related reactions were the most common treatment-related adverse events.
Nex-z is a single-guide RNA molecule that targets the human TTR gene and the human-codon–optimized mRNA sequence encoding the Streptococcus pyogenes Cas9 protein, encapsulated in a lipid nanoparticle (LNP). Following IV administration of the LNP, nex-z is transported directly to the liver and taken up via the LDL receptor on hepatocytes. The Cas9 mRNA is translated, producing the Cas9 enzyme, which interacts with the single guide RNA to form a complex that binds to the TTR gene and leads to precise cleavage in the targeted TTR gene sequence to reduce TTR production.
“For the results we’ve seen thus far, patients would only need a one-time nex-z treatment to obtain, rapid, deep and durable knockdown of TTR, which translates into a clinically meaningful benefit without the need for long-term therapy,” said Marianna Fontana, MD, PhD, professor of cardiology and honorary consultant cardiologist at the National Amyloidosis Center at University College London, the study’s principal investigator. Although results will need to be confirmed in a randomized controlled trial, “this therapy is a potential game changer for patients with ATTR-CM,” Fontana said.
The study was simultaneously published in the New England Journal of Medicine.