As Health Disparities “Weave Their Way Through Hypertension,” New Agents Are on the Way

Shifting guidelines, lack of access to insurance, and a failure to focus on lifestyle as the primary tool to manage hypertension have allowed the United States to lose ground in the battle for blood pressure control, according to 3 of the country’s leading experts on cardiovascular and kidney disease who spoke during the recent 2022 Congress of the American Society for Preventive Cardiology (ASPC), held July 29-31 in Louisville, Kentucky.

Keith C. Ferdinand, MD, professor of medicine at Tulane University School of Medicine; Kim Allan Williams, MD, who last month became the chair of the Department of Medicine at the University of Louisville; and George C. Bakris, MD, professor of Medicine and director, Comprehensive Hypertension Center, University of Chicago Medicine, spoke about different aspects of hypertension treatment and access to care—and how management of hypertension is essential to avoid chronic kidney disease (CKD).

Bakris said that in 2014, improvements in treatment had allowed blood pressure (BP) control rates among US adults to reach 53.8%, up from 31.8% in the early 2000s. Williams explained how the Joint National Committee 8 guidelines (JNC 8) in 2014 included a hotly debated recommendation to not initiate treatment for hypertension for patients over age 60 until BP reached 150/90; this contributed to a nosedive in control rates, until they hit 43.7% in 2018.

Then in 2015, the SPRINT trial, funded by the National Institutes of Health, showed beyond a doubt that controlling BP to below 140/90, even down to 121/80 dramatically reduced heart attacks, strokes, and cardiac deaths with limited effect on acute kidney injury, from which patients recovered. Williams retraced how the findings propelled the American College of Cardiology (ACC) and the American Heart Association (AHA) to execute new BP guidelines in 2017 that list BP just above that level as “elevated” and BP that reaches 130/90 as “Stage 1” hypertension.

Confusion over guidelines played a role in the United States’ regression in BP control, but Bakris said that doesn’t tell the whole story. He noted in sharing a global report card on hypertension that the countries with the best rankings—Canada, Costa Rica, South Korea, and Taiwan—all had universal health coverage. “That’s not a political statement. That’s just a fact,” he said.

Ferdinand, who spoke a day prior to Williams and Bakris during a symposium on women’s heart health, also raised the issue of access to insurance coverage for at-home BP monitors. Williams and Ferdinand agreed that hypertension cannot be properly diagnosed and managed without out-of-office BP readings. Besides the well-known “white coat” effect, which can lead to higher-than-normal readings in the physician’s office, the phenomenon of masked hypertension can cause some patients to have lower readings when away from stressful home environment.

Ferdinand discussed findings from a small, unpublished sample that showed when patients had access to a BP device and at-home results were transmitted to the clinic via Bluetooth technology, “We’re able to show increased adherence and improvement in blood pressure.”

Hypertension and Disparities

Ferdinand reviewed why hypertension is so important in addressing health disparities: although longevity has increased overall prior to the pandemic, “the shortest life expectancy among the major racial/ethnic groups are the non-Hispanic Black populations.

“The White-Black gap has been present for decades,” he continued, and COVID-19 has only made the gap worse. “And the protective effect of being Latino has been lost.”

Meanwhile, “Hypertension in the Black population is perhaps the most powerful risk factor,” he said, tracing data that show how it appears first among males but then rises over time among females, until the disease burden is significantly higher among women as they get past age 60. Loss of estrogen between age 50 and 60 is a factor for increased hypertension in older women, Ferdinand said.

Williams continued this theme. “If we can just control hypertension, we’re going to do so much better,” he said. “We know what it does, and if we focus on the fact that our ethnic disparities really weave their way through hypertension,” starting with renal disease and congestive heart failure, the need to keep BP levels below 140/90 to reduce the risk of cardiovascular mortality makes sense.

“Hypertension is the most powerful and potent predictor for morbidity and mortality both in men and women, but even more so in women—especially in older women,” Ferdinand said. “Combination drug therapy is now the best practice in order to control blood pressure, and we need more attention to hypertension and appropriate diversity in research.”

Starting With Lifestyle

Williams, who has long advocated plant-based diets, addressed criticism that the 2017 ACC/AHA update to the blood pressure guidelines was a way to get patients to take more medication. “We weren’t recommending more drugs for a lot of people,” he said. “We were talking about lifestyle.”

Williams spent most of his talk on the need to give more attention lifestyle change, including weight loss, smoking cessation, and limiting alcohol consumption. “But I always like to focus on dietary evidence,” he said.

There’s abundant evidence in support of the DASH diet (Dietary Approaches to Stop Hypertension), “but not everyone looks at the DASH diet the way I do.” he said.

The key takeaways from the many studies are that diets with less fat and less cholesterol, which are “more towards a vegetarian, non-exclusive vegetarian diet—that gives you the largest impact on blood pressure.”

More studies have accumulated about the mechanisms of why these diets work as an intervention. “Some of them are very strong, some of them are less strong, but the data is really bending toward the more intervention you do with plants, the better off you're going to be. And I'm irritated that we've had to say it for quite a while, we just didn't know exactly why.”

However, in the last 3 to 5 years, that’s changed. “It’s all about the microbiome,” Williams said, offering a primer on microbiology—and how the bacteria, fungi, and viruses, which help digest food and make up a person’s immune system, are affected by the environment—in other words, by the people around them. This was seen during COVID-19, he said, as people who ate a lot of red meat got very sick.

When it comes to hypertension, he said, a major factor is, “What species do you have in your microbiome?”

Bakris, who followed Williams, agreed. One factor that makes kidney disease such a major cardiovascular risk factor, he said, is that when the estimated glomerular filtration rate (eGFR) gets down to the 40s (90 is normal; below 15 is kidney failure), “the microbiome totally changes and becomes very cardiotoxic.”

Flurry of Activity in Drug Pipeline

Medication adherence is a known problem in managing hypertension, but so is measuring BP correctly, which gets less notice. “We are not paying attention to very simple things,” Bakris said.

“Hypertension has been perceived as dead for the last decade, because nothing really new is happening,” he said. “But there’s a huge flurry of activity coming in the next 5 to 7 years specifically in resistant hypertension.”

He highlighted the current recommendation for resistant hypertension, published in 2018 for the AHA, which calls for:

• maximization of lifestyle interventions, use of a long-acting thiazide-like diuretics,
• addition of a mineralocorticoid receptor antagonist (MRA), and,
• if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP.

However, he noted that these recommendations were based on a trial where patients had close to normal eGFR; most patients with advanced hypertension also have advanced CKD, with eGFR in the 40s. “It’s not so easy to go to spironolactone (an MRA) with potassium issues,” he said.

“It’s important to keep in mind what could be coming soon.” He discussed:

Nonsteroidal MRAs. Bakris said these agents have “a very different chemistry” from MRAs with far less adverse effects. He mentioned finerenone, already approved as Kerendia to reduce renal and cardiovascular risks in patients with type 2 diabetes. “The gossip is it doesn’t lower blood pressure,” he said, “Well, it actually does, and the papers are in press.”

He focused discussed several possible therapies being studied for resistant BP, including ocedurenone, which he said, “lowers blood pressure significantly… and has a very good pharmacological profile.”

Bakris then discussed the BLOCK-CKD trial involving KBP-5074, an investigational agent being developed by KBP Biosciences. Results of the phase 2b study in patients with stage 3b/4 CKD showed a reduction of 10.2 mm Hg compared with placebo of systolic BP at the larger dose (0.5 mg), with some elevation of hyperkalemia.

Like other speakers at ASPC, Bakris warned that albumin, not just eGFR, must be monitored to catch CKD at early stages.

Endothelin receptor agonists. Therapies in this class are already approved to treat pulmonary arterial hypertension (PAH), but Bakris said what’s coming is a joint endothelin A/endothelin B receptor agonist. He urged the audience to look forward to results from the PRECISON trial, studying aprocitentan.

Brain aminopeptidase inhibitor. Bakris said the first drug in this class, firibastat, appears to offer more benefit in treating hypertension to Black patients, although the reasons for this are unclear.

Angiotensinogen “knockouts.”Yet another approach is to target angiotensinogen, which would address hypertension by addressing overactivity at the top of the reninangiotensin-aldosterone system pathway. According to an article in JACC: Basic to Translational Science that Bakris cited, the idea is to go after the RAAS pathway at its source, rather than “downstream” which is how angiotensin-converting enzyme inhibitors or type I angiotensin receptor blockers work.

“So, we’ve left the kidney; we’ve left the vessels, and we’ve moved into the liver,” Bikras said.

He cited an article that presented phase 2 results for IONIS-AGT-LRx, which is being developed for hypertension and heart failure indications. Early data for a therapy that would treat BP by injection for up to 6 months are promising very promising, but Bakris noted the need for reversal agent, which he said is being addressed.

In the near term, Bakris expects the FDA to consider renal denervation, a process that removes nerves from the renal artery. This is already approved in some parts of Europe.

With at least 4 different classes of BP lowering agents in the pipeline, he said, “I'm confident that over the next 3 to 4 years, there's going to be a lot more in the armamentarium to use, to get the blood pressure lower with fewer side effects than what we have right now.”