Experimental Pill May Be New Way to Control Cholesterol

Denise Mann wrote . . . . . . . . .

Millions of people take daily medication to lower their cholesterol levels and prevent heart attacks, but there hasn’t been a drug that targets a dangerous type of cholesterol in the blood known as lipoprotein(a), or Lp(a).

That’s why a new study of an investigational drug called olpasiran, which blocks the production of apolipoprotein(a) — a key component of Lp(a) — is generating a lot of excitement in scientific circles.

“Unlike other types of cholesterol, there is, unfortunately, no approved treatment that is currently available to lower Lp(a),” explained study author Dr. Michelle O’Donoghue, a cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston.

Olpasiran binds to the body’s own mRNA, to prevent it from making apolipoprotein(a).

The study looked at different doses of the new drug in about 230 people with high levels of Lp(a). Folks who received the highest doses of olpasiran in the study reduced their Lp(a) concentration by more than 95% compared with placebo. The drug is given via injection every 12 weeks.

Study patients’ Lp(a) levels were about 260.3 nanomoles per liter of blood (nmol/L), on average, when the study started. The U.S. Centers for Disease Control and Prevention defines high Lp(a) levels as greater than 125 nmol/L. Most people in the study were also taking drugs to lower their cholesterol levels, mainly statins.

What’s more, the treatment was safe. Injection site reactions were more common with olpasiran than a placebo shot, but they tended to be mild and resolve on their own, O’Donoghue said.

A phase 3 trial will be launching in December to evaluate the efficacy and safety of olpasiran, she added.

Millions of people take statins or other drugs to lower their cholesterol levels, but these drugs mainly target low-density lipoprotein (LDL) cholesterol, she explained.

“Statins don’t lower Lp(a) [and] statins may even raise Lp(a),” O’Donoghue said. “That’s one of the reasons that it’s exciting to have a novel therapy in development that leads to such a marked and sustained reduction in Lp(a).”

The findings were presented Sunday at the American Heart Association (AHA) annual meeting, in Chicago, and were published simultaneously in the New England Journal of Medicine.

Lp(a) is potentially the most dangerous molecule in the blood, and high levels increase the risk of heart attack, stroke and death, said Dr. Manesh Patel, chief of the division of cardiology and the division of clinical pharmacology at Duke University School of Medicine in Durham, N.C. He is also the chair of the AHA’s 2022 council on scientific sessions programming.

Source: HealthDay






Want That Pill to Work Fast? Your Body Position Matters

If you need to take a pill, you might want to take it lying down — on your right side, that is.

Researchers studying how body positioning affects the absorption of pills found that one taken when a person was lying on the right side speeded pills to the deepest part of the stomach. That pill could then dissolve 2.3 times faster than if the person was upright.

“We were very surprised that posture had such an immense effect on the dissolution rate of a pill,” said senior author Rajat Mittal, a professor at Johns Hopkins Whiting School of Engineering and an expert in fluid dynamics. “I never thought about whether I was doing it right or wrong but now I’ll definitely think about it every time I take a pill.”

For the study, researchers used a model called StomachSim, which relies on physics, biomechanics and fluid mechanics to mimic what happens inside one’s gut as it digests food or medicine.

Researchers knew that most pills don’t start working until the stomach ejects its contents into the intestine. That would mean that a pill landing in the last part of the stomach, an area called the antrum, would begin dissolving faster. It would also begin emptying its contents more quickly through the pylorus into the duodenum, the first part of the small intestine.

To land a pill there would require a posture that uses both gravity and the natural asymmetry of the stomach to its benefit.

In addition to the right side, the team tested taking pills on the left side, standing upright and lying straight back.

Surprisingly, a pill that dissolves in 10 minutes with a patient lying on his or her right side could take 23 minutes to dissolve in an upright posture and more than 100 minutes with the person on his or her left side. Lying straight back tied with standing upright in terms of pill dissolution.

“For elderly, sedentary or bedridden people, whether they’re turning to left or to the right can have a huge impact,” Mittal said in a Hopkins news release.

Lead author Jae Ho “Mike” Lee, a former postdoctoral researcher at Johns Hopkins, noted that even small changes in stomach conditions could significantly affect dissolution — when someone’s gut isn’t functioning at its best because of conditions such as diabetes and Parkinson’s syndrome, for example.

The impacts of posture and stomach disease were similar on drug dissolution.

“Posture itself has such a huge impact … it’s equivalent to somebody’s stomach having a very significant dysfunction as far as pill dissolution is concerned,” Mittal said.

Plans for future work include attempting to predict how changes in the biomechanics of the stomach affect how the body absorbs drugs.

The findings were recently published in the journal Physics of Fluids.

Source: HealthDay





Injected ‘Hydrogel’ May Be New Option Against Back Pain

Dennis Thompson wrote . . . . . . . . .

Like fixing a flat on the roadside, a new injectable hydrogel is showing promise as a remedy for worn-down spinal discs — pumping them back up and relieving chronic back pain.

The gel, with the brand name Hydrafil, is injected directly into worn discs using X-rays to guide the needle, said lead researcher Dr. Douglas Beall, chief of radiology services at Clinical Radiology of Oklahoma in Edmond. As outlined in a pilot study,. the gel fills in cracks and tears in the spinal disc, adhering to the disc’s center and outer layer.

“It goes in as a heated liquid that cools off and becomes kind of the consistency of a medium hard eraser,” Beall said. “It creates kind of a Fix-a-Flat, filling the disc back up and returning the biomechanical integrity of the disc.”

Twenty patients treated with the gel experienced a 67% reduction in their back pain during a one-year follow-up, Beall said.

The patients also experienced an 85% improvement in disability caused by their back pain. Beall said the gel caused no harmful reactions in any of the patients.

The bones in your spinal column — the vertebrae — are separated by rubbery cushions called spinal discs. These discs act as shock absorbers, preventing the vertebrae from rubbing together and allowing you to move, bend and twist comfortably.

Degenerative disc disease occurs as people age. Spinal discs tend to dry out and wear away over time. They also can be torn or injured as a result of daily activities or sports.

By Beall’s estimates, as many two-thirds of people with back pain caused by degenerative disc disease could be considered candidates for this hydrogel therapy.

He is scheduled to present these findings Sunday in Boston at a meeting of the Society of Interventional Radiology. Findings presented at meetings are considered preliminary until published in a peer-reviewed journal.

Hydrafil was designated as a breakthrough device in 2020 by the U.S. Food and Drug Administration, which allows expedited review when evidence suggests an experimental product could provide more effective treatment for a serious condition compared to current options, researchers said.

Other hydrogels already are being used to treat injured or worn discs, but those products are inserted surgically as a soft solid, “which can pop out of place if you’re not highly skilled in placing it,” Beall said.

“Because this gel is injectable, it requires no incision, and it augments the whole disc, restoring its structural integrity, which nothing we have currently can do,” he said.

Dr. J. David Prologo, an interventional radiologist at Emory University School of Medicine in Atlanta, reacted to the findings.

“The impact of this study I don’t think can be overstated — degenerated disc disease is a condition that affects hundreds of millions of people worldwide, for which there is really no definitive treatment other than a big surgery, with all of the associated costs and risks,” he said.

“Dr. Beall is spearheading the ability to literally inject a liquid replacement to the disc using only a needle and image guidance, removing the needle after the injection and sending the patient home with a replaced disc and Band-Aid over the puncture site,” said Prologo, who chairs the Society for Interventional Radiology’s Pain Management/MSK Clinical Specialty Council.

Dr. Alan Hilibrand, co-director of spinal surgery at the Rothman Orthopaedic Institute in Philadelphia, agreed.

Disc repairs conducted via injection are “almost like the holy grail of treatment for back problems,” he said.

Hilibrand noted that other research groups are trying to repair discs by injecting growth factors or biologic agents intended to promote regrowth of healthy disc material.

These new results come from what Beall characterized as an early feasibility trial, which was conducted among 20 patients ages 22 to 69 in Colombia. All had chronic low back pain due to degenerative disc disease.

A pilot trial involving more patients is underway in Canada, and based on those results a full-scale clinical trial will be conducted in the United States.

The hydrogel therapy is new, but relies on existing techniques and skills regularly used by interventional radiologists, surgeons and other specialists, Beall and Prologo said.

“Interventional radiologists already embody the skillset to perform this procedure,” Prologo said. “Widespread dissemination should follow FDA approval and U.S. studies reproducing its effectiveness. The cost will be many multiples less than an open surgical alternative.”

One major question remains, and should be answered by the full clinical trial: How long will the hydrogel last in a repaired disc?

Beall said Hydrafil has been subjected to a “repetitive stress simulation that simulates 90 years of stress and strain, so hopefully this will be a forever fix.”

But that will need to be demonstrated in actual humans over time, Hilibrand said.

Trials will need to show that the gel “can be maintained in the disc and doesn’t wear out or leak out over time,” he said.

“If something lasts for six months or even 12 months, I don’t think that we as a society can afford to pay for that,” Hilibrand said. “It may not be very cost-effective if it only lasts for a short period of time.”

ReGelTec Inc. is the company that developed Hydrafil, and paid for this early feasibility study, Beall said. Beall is a medical adviser to the company.

Source: HealthDay

Common Prostate Cancer Medications May be Less Safe Than Previously Thought

Men taking either of the two most common oral medications for advanced prostate cancer who had also undergone hormone therapy to treat their disease were at higher risk of serious metabolic or cardiovascular issues than patients who were only receiving hormone therapy, Michigan Medicine researchers found.

Patients taking abiraterone had 1.77 times the risk of being admitted to the emergency room or the hospital due to diabetes, hypertension or heart disease compared to those who were only on hormone therapy. Those receiving enzalutamide were at 1.22 times the risk of these issues.

Compared to patients not receiving abiraterone, those taking abiraterone were also more likely to need an outpatient visit with their physician related to at least one of these health conditions. That was not the case if the man was taking enzalutamide.

Abiraterone and enzalutamide were both found to be relatively safe in clinical trials, but concerns that the population of patients who participated in the trials was different than those in real-life settings prompted the researchers to take another look at the effects of the drugs.

For instance, this research exclusively analyzed patients with Medicare health insurance, and the majority of men studied were significantly older than those in the drugs’ clinical trials.

“Patients enrolled in clinical trials tend to be highly selected and often times do not reflect the patient population in day-to-day practice,” said Lillian Y. Lai, M.D., M.S., a National Institutes of Health T32 Urologic Oncology Research Fellow at Michigan Medicine and the first author of the study. “Trial participants also undergo stringent safety evaluations that some of our patients do not have access to. By studying adverse events in real-life settings, we can better understand the risks of these life-prolonging cancer treatments and help clinicians and patients make informed decisions regarding treatment.”

Since metabolic and cardiovascular conditions tend to be under the purview of primary care providers, Lai and her fellow authors recommend team-based care that involves PCPs for patients with advanced prostate cancer as a way to manage these higher risks.

“With continued expansion of the indications for abiraterone and enzalutamide to earlier stages of the disease, increasing numbers of men will be receiving these therapies for longer periods of time,” Lai said. “This will potentially amplify the scope of men affected and increase the magnitude of the risks of adverse events, making careful attention to management of these issues crucial.”

Source: University of Michigan

Lifestyle Changes, Meds Effective to Prevent or Delay Type 2 Diabetes; No Change in CVD

A lifestyle intervention program of increased physical activity, healthy eating and aiming for weight loss of 7% or more, or taking the medication metformin were effective long-term to delay or prevent Type 2 diabetes in adults with prediabetes. Neither approach, however, reduced the risk of cardiovascular disease for study participants over 21 years of the study, according to the findings of the multicenter Diabetes Prevention Program Outcomes Study (DPPOS), published today in the American Heart Association’s flagship, peer-reviewed journal Circulation.

Type 2 diabetes (T2D) is the most common form of diabetes, affecting more than 34 million people in the U.S., representing nearly 11% of the U.S. population, according to the U.S. Centers for Disease Control and Prevention’s 2020 National Diabetes Statistics Report, and cardiovascular disease (CVD) is the leading cause of death and disability among people with T2D. Type 2 diabetes occurs when the body is unable to efficiently use the insulin it makes and the pancreas is unable to produce sufficient amounts of insulin. Adults with T2D are twice as likely to die from CVD — including heart attack, stroke or heart failure — compared to adults who do not have T2D. People with T2D often have other cardiovascular disease risk factors, including being overweight or having obesity, high blood pressure or high cholesterol.

The DPPOS evaluated 21-years of follow-up (through 2019) for the 3,234 adults who participated in the original, 3-year Diabetes Prevention Program (DPP) trial. This analysis of the DPPOS was focused on determining whether the medication metformin or lifestyle intervention might reduce the risk of cardiovascular disease or the rate of major cardiac events such as heart attack, stroke or death due to cardiovascular disease.

“The risk of cardiovascular disease in people with prediabetes is increased, and CVD risk further increases over time after Type 2 diabetes develops and progresses,” said Ronald B. Goldberg, M.D., chair of the writing group for the DPPOS and a professor of medicine, biochemistry and molecular biology in the division of diabetes, endocrinology and metabolism, and senior faculty member and co-director of the Diabetes Research Institute Clinical Laboratory at the University of Miami’s Miller School of Medicine in Miami, Florida. “We were focused on assessing the impact of lifestyle or metformin interventions for prevention of Type 2 diabetes in people with prediabetes to reduce cardiovascular disease.”

The DPP was a landmark, 27-center randomized trial across the U.S. from 1996-2001 to assess how to prevent or delay the onset of T2D in people with prediabetes. Study participants were screened and accepted in the DPP based upon these criteria: initially, a 2-hour glucose reading of 140-199 mg/dL on an oral glucose tolerance test; fasting glucose levels of 95-125 mg/dL; and body mass index of 24 kg/m2 or higher.

A racially diverse group of 3,234 adults were studied in the original DPP for almost three years. The participants were an average age of 51 years, and nearly 70% of the participants were women. People in the intensive lifestyle intervention group (nutritional improvement and physical activity aimed at achieving a weight loss of 7%) reduced the incidence of developing T2D by 58%, and participants who took twice daily doses of metformin had a reduced incidence of 31% for T2D, when compared to people in the placebo group who received standard care, which included information about effective treatment and management of T2D at the time of diagnosis.

The DPPOS began in 2002 and was open to all participants in the original DPP trial. The DPPOS enrolled almost 90% of the original study participants for up to 25 years of follow-up to assess the long-term impact of the interventions on the development of T2D and its complications. Due to the success of the lifestyle intervention, everyone in the study was offered enrollment in the lifestyle intervention through a group format during a one-year bridge period. The group who took metformin in the original DPP trial were able to continue take the medication during the DPPOS, and they were aware that they were taking metformin not the placebo. (The metformin and placebo groups were blinded in the original DPP, so participants did not know whether they were taking metformin or placebo during that time period.)

“From the beginning of the Diabetes Prevention Program, we were primarily interested in whether prevention of diabetes would lead to a reduction in the development of the complications that are caused by Type 2 diabetes — cardiovascular disease, kidney disease, retinopathy and neuropathy,” said Goldberg. “Managing blood glucose levels is important, and we encourage interventions to prevent the long-term complications of Type 2 diabetes.”

The DPPOS assessed cardiovascular disease outcomes in order to determine the effects of lifestyle and metformin interventions on participants’ risk of having a non-fatal heart attack, stroke or death due to a cardiovascular occurrence, by comparing outcomes of each intervention group to the placebo group. Researchers reported results based on a median follow-up of 21 years, which included the average three-year follow-up period of the original DPP trial. The authors conducted a futility analysis of the cardiovascular outcomes, which resulted in ending the study prior to completing the planned 25-year follow-up.

Throughout the entire study, participants were screened annually with electrocardiogram testing; measures of their cardiovascular disease risk factors, including smoking, cholesterol levels and blood pressure levels; and body mass index measurements. The percentage of all participants taking blood pressure and cholesterol lowering medications increased over the duration of the study and was slightly lower among the participants in the lifestyle group versus the other two groups.

After an average 21 years of follow-up, researchers found no significant differences in the incidence of heart attacks, stroke or cardiovascular death among the three intervention groups. Specifically, the analysis found:

  • There was a continued reduction or delay in the development of T2D for up to 15 years.
  • The number of non-fatal heart attacks across each group was similar: 35 heart attacks occurred in the lifestyle intervention group; 46 in the metformin group; and 43 in the placebo group.
  • Similarities were also found in the number of non-fatal strokes: 39 incidences of stroke in the lifestyle intervention group; 16 in the metformin-only group; and 28 in the placebo group.
  • The number of deaths due to cardiovascular occurrences were low: 37 deaths among the lifestyle intervention participants; 39 in the metformin group; and 27 in the participants who took the placebo during the original DPP trial.

“The fact that neither a lifestyle intervention program nor metformin led to a decrease in cardiovascular disease among people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, even though they are highly effective in preventing or delaying the development of Type 2 diabetes,” said Goldberg. “It’s important to note that most study participants also received treatment with cholesterol and blood pressure medications, which are known to reduce CVD risk. Therefore, the low rate of development of cardiovascular disease found overall may have been due to these medications, which would make it difficult to identify a beneficial effect of lifestyle or metformin intervention. Future research to identify higher risk subgroups is needed to develop a more targeted approach to cardiovascular disease prevention in people with prediabetes and Type 2 diabetes.”

There were several limitations to the study. The researchers selected a subgroup of people who met the criteria for prediabetes, however, these results are not generalizable to everyone with prediabetes. Additionally, the intensity of the lifestyle intervention was reduced after the initial DPP phase, and, over the 21-year study period, there was a gradual reduction in medication adherence by participants in the metformin group. There was also out-of-study metformin use in patients who were diagnosed with Type 2 diabetes, which may have diluted differences among the study groups. The high level of blood pressure and cholesterol medications prescribed by the participants’ primary care team, as well as lower use of blood pressure medications in the lifestyle group, may have influenced results. There may have also been some under-estimation of cardiovascular events since some participants did not complete 21 years of follow-up.

”These long-term findings confirm the link between Type 2 diabetes and cardiovascular disease is complex and requires more research to understand it better,” said the American Heart Association’s Chief Medical Officer for Prevention Eduardo Sanchez, M.D., M.P.H., FAHA, FAAFP, and clinical lead for Know Diabetes by Heart, a collaborative initiative between the American Heart Association and the American Diabetes Association addressing the link between diabetes and cardiovascular disease. “However, these important results also tell us that lifestyle intervention is incredibly effective to delay or prevent Type 2 diabetes, which, itself, reduces the risk for cardiovascular disease. The CDC estimates nearly 1 of every 3 adults in the U.S. has prediabetes, therefore, preventing or delaying Type 2 diabetes is a public health imperative to help extend and improve the lives of millions of people.”

Source: American Heart Association