Exploring Interventions—Including Lifestyle—to Improve Cardiorenal Outcomes

Are today’s novel therapies enough to improve cardiorenal outcomes in patients with type 2 diabetes (T2D)? What about adding lipid-lowering medications? Does prescribing patients diet and exercise make a difference in cardiovascular (CV) outcomes? These were some of the questions addressed in a symposium Friday during the European Society of Cardiology 2023 Congress in Amsterdam that looked at the connections between T2D, heart failure, and renal disease and how to treat patients affected by these conditions.

Chaired by Bianca Roca, MD, associate professor, Catholic University School of Medicine in Rome, Italy, and Deepak Bhatt, MD, MPH, who is the director of Mount Sinai Heart, New York, New York, the session featured 4 speakers; discussant Katharina Schuett, MD, of RWTH University Hospital in Aachen, Germany, led a question and answer session. Speakers were:

• Ana Abreu, of Hospital de Santa Maria Faculty of Medicine, Lisbon, Portugal,
• Christoph Wanner, MD, of University Hospital Wuerzburg, Germany,
• Maddalena Lettino, MD, of IRCCS San Gerardo of Tintori Foundation in Monza, Italy, and
• Marco Roffi, MD, Geneva University Hospitals in Switzerland.

Lifestyle can’t be overlooked. Abreu reviewed results from the LOOK Ahead, the well-known trial that tracked the effects of an intensive lifestyle

Abreu

intervention on patients with T2D compared with a control group. Most of the weight lost came in the first year and some was regained, but some patients kept the weight off for close to 10 years. Although the intervention improved fitness and other biomarkers and lowered glucose, the National Institutes of Health suspended the trial after a decade when it didn’t bring the expected differences in cardiovascular (CV) outcomes—CV events were low overall. But as Abreu noted, there were other health benefits of the intervention, including behavioral health benefits. What, she asked, if different protocols had been used?

She then reviewed other well-known studies, including the Nurses’ Health Study, which found a relationship between changes in lifestyle—including weight gain—and cardiovascular outcomes, and the Swedish twins study, which found that the heavier twin was not more likely to have a heart attack. With the nurses’ study, she noted that one should consider that these are health care professionals—so they were possibly more health conscious. Abreu also noted that while therapy offers many benefits, pharmacological interventions can leave gaps.

“So, we know from just a few studies, that one of the benefits of exercise is an increase in functional capacity,” she said. This is hugely important for patients with diabetes who are at risk for heart failure, she said. As physicians focus on pharmacological interventions, “don’t forget about lifestyle changes and gains in functional capacity,” Abreu said. “Lifestyle changes should be recommended to every patient at risk of or with a heart failure diagnosis.”

The “pillars” of diabetic kidney care. Wanner, a nephrologist, has been at the center of the therapeutic revolution that showed how sodium glucose

Wanner

co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists could do more than lower glucose for patients with T2D. So far, only SGLT2 inhibitors as a class, he said, have “organ protective capacities,” and only 1 drug in the GLP-1 RA class fits this description. (The LEADER trial showed cardiovascular and renal benefits for liraglutide). Wanner noted that results are pending for the FLOW study of the GLP-1 RA semaglutide for patients with T2D and chronic kidney disease. Drugs such as DPP-4 inhibitors “have no impact on heart outcomes.”

Even so, he said, with SGLT2 inhibitors, “There are limitations in terms of glomerular filtration.” Drugs in this class are not initiated in patients with estimated glomerular filtration rate (eGFR) of less than 20 mL/min/1.73 m².

The “kidney community” he said, looks at the treatment armamentarium as a temple, with 3 pillars needed to optimize slowing progression of kidney disease and reducing heart failure risk. They are:

SGLT2 inhibitors, renin-angiotensin-system (RAS) blockers, and nonsteroidal mineralocorticoid receptor antagonists (MRAs), notably finerenone. Wanner was careful to note that finerenone was not approved as a diabetes medication, but it can be used in patients with T2D.

Combining this trio of drug classes gives clinicians the ability to “push dialysis away for many, many years,” Wanner said. “This is the revolution in the kidney field—coming from heart failure, and now in the kidney space. We are so excited to have tools at last.”

Wanner cited a recent meta-analysis in Lancet to show that 90,000 patients have been studied with SGLT2 inhibitors to date, and the results show a 37% risk reduction for progression of kidney disease—a huge leap forward from the prior standard of care. “I think the story is written, there will be no surprises anymore,” he said.

The role of novel lipid-lowering therapy. Lettino said dyslipidemia is a major health problem for many patients with diabetes. For many the need

Lettino

to reduce low-density lipoprotein (LDL) cholesterol is critical but out of reach with statins alone.

“Reducing LDL cholesterol has a huge impact on outcomes,” she said. Based on current risk classifications, most patients with T2D are considered high risk or very high risk, which means they need to bring their LDL cholesterol down 50%, to a range of 55 to 70 mg/dL.

Lettino said despite a pair of PCSK9 inhibitors being on the market for nearly 8 years, the evidence of how well they work for patients with T2D still isn’t that widely known.

“There are some add-on benefits compared with statins,” she said. First, there is no probably to develop diabetes or to have diabetes worsen, which can occur with statins. Second, the patient’s LDL cholesterol is significantly reduced. Finally, there is some action against plaque instability, “reducing the uptake of white blood cells in the plaque,” which means the drug has a role in reducing the mechanisms that lead to acute coronary syndrome.

Lettino then reviewed evidence for inclisiran, which has a different mechanism to “silence” PCSK9 and set in motion a process to ingest LDL particles.“ Inclisirian has a very stable action; it can be injected once every 6 months,” she said. Evidence for this drug’s LDL-cholesterol lowering qualities is strong; it’s now a matter of waiting on the outcomes trial.

Bempedoic acid acts on LDL cholesterol earlier in the process to reduce its production—its is better tolerated by patients who have shown statin intolerance, she said. The CLEAR Outcomes trial showed it cut the risk of major CV events by 13%, and more details by glycemic status are due to be presented at this year’s ESC Congress.

Finally, Lettino said the hunt is still on for therapies that fully treat triglycerides. Icosapent ethyl offers some benefit, as seen in the REDUCE-IT trial.

A look at newer-generation stents. Roffi, an interventional cardiologist, offered the final full talk of the symposium with a discussion on approaches

Roffi

for patients with T2D when the discussion is revascularization vs optimal medical therapy: is it now best to go with percutaneous coronary intervention (PCI), which would include the use of a stent to hold an artery open, or coronary artery bypass grafting (CABG), commonly called bypass surgery, to improve blood flow to the heart?

He started with a meta-analysis from 3 major revascularization trials in diabetes that found that CABG with optimal medical management brought better outcomes in death, MI, and stroke than medical management alone. An older trial from 2016 comparing PCI and medical management did not find the same results, nor did a trial comparing CABG plus medical management with PCI and medical management.

“The question is: can the newer generation stent change this?” Roffi asked.

A meta-analysis that enrolled 11,000 patients, of whom a third had newer generation stents, appeared to find that PCI and CABG produced similar results, but when patients with diabetes were examined separately, the results still favored CABG. Roffi showed data from the FREEDOM study and its follow-up, which studied first-generation stents, and data favored CABG over PCI.

But the question, Roffi said, is whether results in PCI for patients with diabetes are improving with newer generation stents?

First, he shared data from a meta-analysis showed an 18% relative risk (RR) reduction in major adverse cardiovascular events with second-generation drug-eluting stents compared with older stents in patients with diabetes. The benefit in MI was particularly impressive, with a 43% RR reduction.

This, Roffi said, raises 2 questions: “Is diabetes an independent predictor of worse outcomes in PCI if treated with second-generation drug-eluting stents? And have second-generation stents reduced the gap between PCI and CABG?”

Citing data Roffi’s team published involving 37,000 patients, he said diabetes remains an independent predictor of worse outcomes in PCI; however, the analysis was able to show that the insulin-dependent patients face the greatest risk, with a 36% increased risk of poor outcomes.

There are no specific trials of patients with diabetes and newer stents comparing CABG and PCI, so Roffi said one can only answer the second question by examining subgroups of larger trials and registries. A subset of the BEST trial, an early study with newer stents, showed CABG still had an advantage. The FAME III study, comparing PCI with newer stents and CABG, had 400 patients with diabetes, and data showed CABG had the advantage at 1 year in these patients for death, MI, stroke, and revascularization.

But registries tell another story: Data from SWEDEHEART and the NY State Registry, with thousands of patients, have given the newer drug-eluting stents a significant advantage for patients with diabetes, Roffi said. Nonetheless, in the absence of trial data, the 2023 ESC guidelines update in this area retain the recommendation for CABG in 3-vessel disease. “The gap between CABG and PCI is not closed.”

“We have to incorporate these trials into independent decision making,” Roffi said. “We have to decide if the patient was represented in randomized controlled trials.”