By HualinXMN – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=133759262
According to results from the SELECT trial run by Novo Nordisk, semaglutide dramatically reduces the risk of major adverse cardiovascular events (MACEs) in addition to its obesity benefits. This is bolstered by the results of another trial, STEP-1, which also suggested significant reduction in future cardiovascular events. These results have captured the attention of researchers, who commented in Nature that they could change the practice of cardiology.
Semaglutide, sold in the US for the treatment of both obesity (Wegovy) and diabetes (Ozempic), is an agonist for glucagon-like peptide 1 (GLP-1), a hormone associated with appetite.
”It’s hard to think of other [drugs], apart from statins, that have shown such a profound effect,” says Martha Gulati, director of preventive cardiology at Cedars-Sinai Medical Center in Los Angeles, USA.
It was expected that semaglutide would have cardiovascular benefits through promoting weight loss, but evidence shows that drugs mimicking GLP-1 can improve fatty-acid metabolism and reduce inflammation, for example, says Gulati. “This is what’s so fascinating about these drugs. They work on the brain, the pancreas, the cardiovascular system, the gastrointestinal tract … There’s more to them than simply weight loss.”
Recent studies have been encouraging in terms of semaglutide’s benefits for reducing cardiovascular disease risk. Earlier this month, Novo Nordisk announced the headline results from the SELECT cardiovascular outcomes trial. The double-blinded trial compared subcutaneous once-weekly semaglutide 2.4mg with placebo as an adjunct to standard of care for prevention of MACEs over a period of up to five years. The trial enrolled 17 604 adults aged 45 years or older with overweight or obesity and established cardiovascular disease (CVD) with no prior history of diabetes.
The trial showed 20% reduction in MACEs for people treated with semaglutide 2.4mg compared to placebo. The primary endpoint was a composite outcome of the first occurrence of MACE cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. All three of these components contributed to the MACE reduction. 1270 first MACEs were accrued.
Expanding GLP-1 analogues to cardiovascular disease prevention may not be without challenges, as the European Medicines Agency opened investigations into semaglutide and liraglutide over reports of suicidal thoughts and self-harm.
A separate study based on the STEP 1 trial data found that 93 million adults in the US could benefit from semaglutide, from a combination of weight loss and reduced cardiovascular benefits. They estimate a reduction in relative risk of 18% with the drug.
Dr Mark Blaylock, medical manager at Manguzi Hospital. PHOTO: Supplied.
By Sue Segar for Spotlight
There was a time, about 20 years ago, when, at the Manguzi district hospital in Northern KwaZulu-Natal, (and, of course, at hospitals throughout South Africa too) mothers and their babies were dying of AIDS at shockingly high rates.
“We used to get these patients who were slow progressors,” Mark Blaylock, medical manager at Manguzi, tells Spotlight. “Then there were the rapid progressors – babies who were HIV-positive who would get sick very quickly. There wasn’t much we could do for them. We’d give them vitamins and Bactrim, but ultimately they died. Then we had the ones who got sick a bit later, and those were even worse because now mum has had this baby for five years and they’ve bonded, and are a little family and now they are coming in with AIDS. Obviously, a huge number of mums died too. It was heartbreaking.
“It was the pregnancies that knocked their vulnerable immune systems. We’d watch it over and over again. The mums would come in looking ok and then they’d get pregnant and just go downhill. This was in the pre-ARV era. Pregnancy was a death sentence. I think people have forgotten what it was like in those days.”
Blaylock is talking to Spotlight from Northern KwaZulu-Natal, relaying how things have changed for the better since that terrible era. “It’s quite astounding,” he says. Blaylock returned to the hospital ten years ago after having been away for four.
“I was going through the stats recently, and in those days, 40 percent of all mothers who delivered were HIV positive, and about 40 percent of those babies born to HIV- positive mothers ended up with HIV either from birth or breastfeeding. About 20 percent would pick up HIV at birth and another 20 percent would pick it up subsequently through breastfeeding.
“These days, if we have one baby who is delivered HIV-positive or who picks up HIV, we get really upset. Our six-month HIV-positive rate now for babies is less than 0.6 percent and that is a dramatic change. It makes me so happy. Unfortunately, the young girls are still positive, but at least their babies are not becoming positive.”
Blaylock puts the changes down, “purely”, to prevention of mother-to-child transmission (PMCT) using antiretroviral therapy (ART). “Remember how, at one stage, we only gave HIV treatment if a patient was below a certain CD4 count? That was changed to test-and-treat, so regardless of their CD4 count, patients will get HIV treatment which brings the viral load down dramatically,” he says. “And now we have dolutegravir (an ARV), which is the backbone of our current HIV treatment. The success is due to prevention of mother-to-child transmission (PMTC) as well as the test-and-treat policy.”
‘A mixed bag’
It’s Sunday, a day off for Blaylock, and he’s speaking from a place with the best reception near his house on the edge of the Shengeza Lake. He lives here with his wife, Liz and their 13-year-old home-schooled daughter, Una. The sound of birds in the background makes it hard to hear him on the call. “It’s peaceful. There are hippos all around and lots of birds. It’s Eskom-free, which is even better. I love it. We live with three dogs, three cats, a genet, and I can’t tell you how many snakes. It’s paradise.”
It’s taken a long time to clinch this interview, but Blaylock has finally relented and forwarded us the provincial health department’s media protocol he has to adhere to. On problems in KwaZulu-Natal’s health system, he is reticent, saying only that it’s a “mixed bag”. “There’s a lot of dead wood, but there are real areas of excellence,” he says.
His reticence is understandable.
There was a time, also about 15 years ago, amidst the noise and turmoil of the last few years of state-backed AIDS denialism, when Blaylock was going through his own personal trauma. In April 2008, whilst working as chief medical officer at Manguzi, he was suspended for throwing an official photograph of then-Health MEC Peggy Nkonyeni into a dustbin in the hospital’s foyer. He did this out of anger and frustration, after his colleague at the hospital, Colin Pfaff was charged with misconduct for sourcing funding for antiretroviral drugs for pregnant women, and for implementing dual antiretroviral therapy to save babies from HIV – because politicians were not doing so.
He was also furious about comments made by Nkonyeni, questioning the integrity of rural doctors and suggesting they were racist. The South African National AIDS Council soon after asked the Human Rights Commission to probe the ‘racial tone’ of Nkonyeni’s remarks and to curb her ‘harassment’ of Manguzi doctors.
At the time, Blaylock (and Pfaff) were hailed by many working in the health sector as heroes with a deep commitment to their patients. In a letter to the provincial health department at the time, Blaylock said he had given his “heart and soul” to the under-resourced hospital, going beyond the call of duty.
Needing a change
Blaylock was reinstated but, in December 2008, he decided to leave, saying he needed a change and because the KwaZulu-Natal Department of Health was in “absolute disarray”. He says his old colleague Pfaff went to work as a missionary doctor in Malawi.
There was more to Blaylock’s decision to leave Manguzi than just the public disagreement with Nkonyeni. In our interview, he describes those days as “a really tough decade”. “Working in paediatrics, as I did for my first couple of years at Manguzi, I couldn’t take it anymore, emotionally. I just couldn’t do it, so I taught myself surgery. That was easier, as you could fix people. We were also so broken from losing so many friends, colleagues, and patients from HIV at the time. It was definitely traumatising and emotionally exhausting, not just for me but for Liz.
“There’s no doubt most of us were burnt out,” he says. “We kind of knew it, but we pushed on anyway. We were also quite a bit wilder and younger. We’d blow off steam by recklessly taking tiny boats across the lake, in the big waves, with lots of hippos – or we’d go for runs along the beach or naked midnight swims.”
The years outside SA
After leaving Manguzi, Blaylock moved to Ghana, where he took up a position as a general doctor at ABA Hospital in Tarkwa, north-east of Accra. “The hospital was part of the national health system but contracted to a mine, so we would treat people and then try and charge the government, fairly unsuccessfully, for the treatment,” he says. “I’d always fancied the idea of Ghana. I had this fantasy about Kwame Nkrumah and it being the first country to throw off Britain in Africa – but I didn’t enjoy it as much as I’d hoped. Everywhere you went, the police were pulling you over and asking for bribes.”
A defining moment was when Blaylock says he noticed the anti-malaria medication the hospital was giving patients was “just not working”. “Our malaria patients kept coming back full of parasites. I knew there were similar drugs in South Africa which were fantastic, so there was definitely something wrong.” He says he sent a sample to South Africa for testing and realised that “they weren’t as full of the good stuff as they were meant to be”. “I handed in the report and said ‘deal with it.”
From Ghana, where he married Liz and where his daughter Una was born, the family moved to the Kansanshi Mine Hospital in Zambia where they lived on a “beautiful golf estate, surrounded by poverty”.
“It didn’t feel right at all and was quite unfulfilling work,” he recalls. “I did GP work and there was lots of babbalaria – that’s when mostly the expat wives have a hangover on a Monday morning and they think they have malaria.”
Being “medically bored” in Zambia, Blaylock returned to Newcastle in KZN with the aim of specialising in anaesthetics. He worked in Madadeni Hospital’s anaesthetics department, before getting into a registrar’s programme on the anaesthetics circuit at various hospitals in Durban.
‘Like walking back home’
Then, in 2012, his friend and colleague Etienne Immelman, then working as medical manager of Manguzi, suggested that Blaylock should “come home”. “Etienne had been at Manguzi for more than 20 years when he retired six years ago. We’d always had a friendship and a mutual loyalty. He wanted someone to take over.”
Blaylock decided that indeed, it was time. It meant losing the opportunity to specialise, but he says it “felt right”. He went back as medical officer, before becoming manager.
“When I first arrived back, we were a small team, working hard. We all had the same commitment. It gave me a sense of purpose and belonging which hasn’t left.”
Blaylock said the hospital went through a “wonderful period” with a core team of great doctors. “But I burnt them all out during COVID – we had 164 deaths, but we pulled a lot of people through and many of the doctors have moved on. We have a young team now and they are getting there, but we don’t have the broad skill range we used to have. That is common across most district hospitals nowadays.”
So, is he happy to have come full circle, back to the place that was once a source of deep distress to him? “Yes,” he says. “For me, it’s about the community. This place gives me that, as well as a sense of stability and purpose. If you go into a little shop in Manguzi, everyone knows who you are. You say hallo to each other. You shout at a taxi driver and he says, ‘Hey Mark, don’t be so naughty’. When I came back ten years ago, it was like walking back home. It’s just a nice feeling.”
He says a lot has changed in the area. “People say there’s been no development, but when I first arrived at Manguzi in 2002, we knew every car on the road. Today, the town is overwhelmed with vehicles. There’s more money around. We almost never see malnutrition anymore. A lot of government programmes are working, as much as we like to diss them.”
Taking a stand
Given the toll that taking a stand has taken on doctors like Blaylock and Pfaff, one might be forgiven for wondering whether it was all worth it.
Did it make a difference to how things turned out? “Absolutely,” says Blaylock. “There were people scattered people around South Africa at the time who were doing great things. In our part of the world, it was Victor Friedland at Mseleni Hospital and Colin Pfaff (at Manguzi) who were the big drivers, pushing for the right actions to provide the services that the HIV Clinicians Society at the time thought was the correct one and was affordable. The Western Cape had already started, so we weren’t doing anything that groundbreaking except that it hadn’t been official policy yet,” he says.
“Can you believe that when HIV treatment first came to South Africa, it was going to be done at tertiary hospitals only? Imagine the repercussions for us sending a patient to Durban – in those days the Hluhluwe road was 160 kilometres of dirt road – to go and get their HIV treatment once a month. It was not sustainable.
“The HIV (Clinicians) Society pushed hard to get it decentralised to all hospitals. Then it was just going to be done by doctors and they said we absolutely cannot do it just with doctors. It has to be a nurse-run programme. Their vision became our current system. They weren’t the only people, but they were at the forefront of it at the time.”
‘Keeping it going’
Apart from the many advances in HIV treatment, much else has changed at Manguzi over the last 15 years. Blaylock says these days the hospital’s gastro wards are empty “thanks to the rotavirus vaccine”. “We’ve also seen a turnaround in acute respiratory tract infection,” he says. “The pneumococcal conjugate vaccine has changed that dramatically. We have also seen the pushing out of Continuous Positive Pressure Airway Ventilation (CPAP) for neonatal respiratory distressed newborns to district hospitals. This is a non-invasive way of ventilating babies with immature lungs,” he says.
“Our next great hope is the HPV vaccine, which will be a groundbreaker. It’s been rolled out in the past couple of years, but we’ll only see the effects in ten years or so because cervical cancer takes a few decades to come about. The other thing I really want to get in,” he insists, “is that our therapy department (offers occupational therapy, speech and hearing, and physiotherapy) at Manguzi is astonishingly fantastic. There are a lot of good things happening,” he says. “It is so easy to sit on the things that irritate you, but it is worth trying to remember the wins.”
As with several other rural doctors Spotlight has interviewed over the years, Blaylock seems deeply committed to building on what works at Manguzi and simply getting things done. As he says, “When you’ve invested so much into a hospital, you want to keep going as much as you can.”
A new study suggests that depression after traumatic brain injury (TBI) could be a clinically distinct disorder rather than traditional major depressive disorder. The findings, which are published in Science Translational Medicine, hold important implications for patient treatment.
“Our findings help explain how the physical trauma to specific brain circuits can lead to development of depression. If we’re right, it means that we should be treating depression after TBI like a distinct disease,” said corresponding author Shan Siddiqi, MD, from Brigham and Women’s Hospital,. “Many clinicians have suspected that this is a clinically distinct disorder with a unique pattern of symptoms and unique treatment response, including poor response to conventional antidepressants – but until now, we didn’t have clear physiological evidence to prove this.”
Siddiqi, who led the study, was motivated by a patient he shared with David Brody, MD, PhD, a co-author on the study and a neurologist at Uniformed Services University. The two started a small clinical trial that used personalised brain mapping to target brain stimulation as a treatment for TBI patients with depression. In the process, they noticed a specific pattern of abnormalities in these patients’ brain maps.
The current study included 273 adults with TBI, usually from sports injuries, military injuries, or car accidents. People in this group were compared to other groups who did not have a TBI or depression, people with depression without TBI, and people with posttraumatic stress disorder. Study participants went through a resting-state functional connectivity MRI, a brain scan that looks at how oxygen is moving in the brain. These scans gave information about oxygenation in up to 200 000 points in the brain at about 1000 different points in time, leading to about 200 million data points in each person. Based on this information, a machine learning algorithm was used to generate an individualised map of each person’s brain.
The location of the brain circuit involved in depression was the same among people with TBI as people without TBI, but the nature of the abnormalities was different. Connectivity in this circuit was decreased in depression without TBI and was increased in TBI-associated depression. This implies that TBI-associated depression may be a different disease process, leading the study authors to propose a new name: “TBI affective syndrome.”
“I’ve always suspected it isn’t the same as regular major depressive disorder or other mental health conditions that are not related to traumatic brain injury,” said Brody. “There’s still a lot we don’t understand, but we’re starting to make progress.”
With so much data, the researchers were not able to do detailed assessments of each patient beyond brain mapping. To overcome this limitation, investigators would like to assess participants’ behaviour in a more sophisticated way and potentially define different kinds of TBI-associated neuropsychiatric syndromes.
Siddiqi and Brody are also using this approach to develop personalized treatments. Originally, they set out to design a new treatment in which they used this brain mapping technology to target a specific brain region for people with TBI and depression, using transcranial magnetic stimulation (TMS). They enrolled 15 people in the pilot and saw success with the treatment. Since then, they have received funding to replicate the study in a multicentre military trial.
“We hope our discovery guides a precision medicine approach to managing depression and mild TBI, and perhaps even intervene in neuro-vulnerable trauma survivors before the onset of chronic symptoms,” said Rajendra Morey, MD, a professor of psychiatry at Duke University School of Medicine, and co-author on the study.
A study of nearly 9000 older people in Japan found that those who have little social contact with others may be more likely to have reduction of overall brain volume, and in areas of the brain affected by dementia, compared with those who have more frequent social contact. The study results were published in Neurology.
“Social isolation is a growing problem for older adults,” said study author Toshiharu Ninomiya, MD, PhD, of Kyushu University in Fukuoka, Japan. “These results suggest that providing support for people to help them start and maintain their connections to others may be beneficial for preventing brain atrophy and the development of dementia.”
The study involved 8896 people without dementia, average age 73. They had MRI brain scans and health exams, and were asked how often they were in contact with friends or relatives that did not live with them.
The people with the lowest amount of social contact had overall brain volume that was significantly lower than those with the most social contact. The total brain volume, or the sum of white and grey matter, as a percentage of the total intracranial volume, or the volume within the cranium, including the brain, meninges, and cerebrospinal fluid, was 67.3% in the lowest contact group compared to 67.8% in the highest contact group. They also had lower volumes in areas of the brain such as the hippocampus and amygdala that play a role in memory and are affected by dementia.
The researchers took into account other factors that could affect brain volume, such as age, diabetes, smoking and exercise.
The socially isolated people also had more small areas of damage in the brain, called white matter lesions, than the people with frequent social contact. The percentage of intracranial volume made up of white matter lesions was 0.30 for the socially isolated group, compared to 0.26 for the most socially connected group.
The researchers found that symptoms of depression partly explained the relationship between social isolation and brain volumes. However, symptoms of depression accounted for only 15% to 29% of the association.
“While this study is a snapshot in time and does not determine that social isolation causes brain atrophy, some studies have shown that exposing older people to socially stimulating groups stopped or even reversed declines in brain volume and improved thinking and memory skills, so it’s possible that interventions to improve people’s social isolation could prevent brain volume loss and the dementia that often follows,” Ninomiya said.
Since the study involved only older Japanese people, a limitation is that the findings may not be generalisable to people of other ethnicities and younger people.
People who have low bone density may have an increased risk of developing dementia compared to people who have higher bone density, according to a study of over 3500 people published in Neurology. As an observational study, it only shows an association and cannot prove that low bone density causes dementia.
“Low bone density and dementia are two conditions that commonly affect older people simultaneously, especially as bone loss often increases due to physical inactivity and poor nutrition during dementia,” said study author Mohammad Arfan Ikram, MD, PhD, of the Erasmus University Medical Center in Rotterdam, Netherlands. “However, little is known about bone loss that occurs in the period leading up to dementia. Our study found that bone loss indeed already occurs before dementia and thus is linked to a higher risk of dementia.”
The study involved 3651 people in the Netherlands with an average age of 72 who did not have dementia at the start of the study. Over an average of 11 years of follow-up, 688 people or 19% developed dementia.
X-rays were used to identify bone density, and participants were interviewed every four to five years and completed physical tests such as bone scans and tests for dementia.
Of the 1211 people with the lowest total body bone density, 90 people developed dementia within 10 years, compared to 57 of the 1211 people with the highest bone density.
After adjusting for factors such as age, sex, education, other illnesses and medication use, and a family history of dementia, researchers found that within 10 years, people with the lowest total body bone density were 42% more likely to develop dementia than people in the highest group.
“Previous research has found factors like diet and exercise may impact bones differently as well as the risk of dementia,” Ikram added. “Our research has found a link between bone loss and dementia, but further studies are needed to better understand this connection between bone density and memory loss. It’s possible that bone loss may occur already in the earliest phases of dementia, years before any clinical symptoms manifest themselves. If that were the case, bone loss could be an indicator of risk for dementia and people with bone loss could be targeted for screening and improved care.”
A limitation of the study is that participants were primarily of European origin and age 70 or older at the start of the study, so these findings may vary in different races, ethnicities, and younger age groups.
