Monday 11 December 2023
The Excessive TV-Watching will cause Dementia, Depression and Parkinson’s Disease
Saturday 22 April 2023
The New Obesity Breakthrough Drugs
There are many holy grails in medicine, with failure after
failure, like finding a way to prevent Alzheimer's disease or a non-invasive
means for accurately measuring ambulatory blood pressure. But one of the
biggest and most daunting has been finding drugs that can tackle obesity —
achieving a substantial amount of weight loss without serious side effects.
Many attempts to get there now fill a graveyard of failed drugs, such as
fen-phen in the 1990s when a single small study of this drug combination in 121
people unleashed millions of prescriptions, some leading to serious heart valve
lesions that resulted in withdrawal of the drug in 1995. The drug rimonabant,
an endocannabinoid receptor blocker (think of blocking the munchies after
marijuana) looked encouraging in randomized trials. However, subsequently, in a
trial that I led of nearly 19,000 participants in 42 countries around the
world, there was a significant excess of depression, neuropsychiatric
side-effects and suicidal ideation which spelled the end of that drug's life.
In the United States, where there had not been an
anti-obesity drug approved by the FDA since 2014, Wegovy (semaglutide), a
once-weekly injection was approved in June 2021. The same drug, at a lower
dose, is known as Ozempic (as in O-O-O, Ozempic, the ubiquitous commercial that
you undoubtedly hear and see on TV) and had already been approved in January
2020 for improving glucose regulation in diabetes. The next drug on fast track
at FDA to be imminently approved is tirzepatide (Mounjaro) following its
approval for diabetes in May 2022. It is noteworthy that the discovery of these
drugs for weight loss was serendipitous: they were being developed for
improving glucose regulation and unexpectedly were found to achieve significant
weight reduction.
Both semaglutide and tirzepatide underwent randomized,
placebo-controlled trials for obesity, with marked reduction of weight as shown
below. Tirzepatide at dose of 10 to 15 mg per week achieved >20% body weight
reduction. Semaglutide at a dose of 2.4 mg achieved ~17% reduction. These per
cent changes in body weight are 7-9 fold more than seen with placebo (2-3%
reduction). Note: these levels of per cent body weight reduction resemble what
is typically achieved with the different types of bariatric surgery, such as
gastric bypass.
Another way to present the data for the 2 trials is shown
here, with an edge for tirzepatide at high (10-15 mg) doses, extending to
>25% body weight reduction.
The results with semaglutide were extended to teens in a
randomized trial (as shown below), and a similar trial with tirzepatide is in
progress.
How Do These Drugs Work?
These are peptides in the class of incretins, mimicking gut
hormones that are secreted after food intake which stimulate insulin secretion.
These 2 drugs have in common long half-lives (~ 5 days),
which affords once-weekly dosing, but have different mechanisms of action.
Semaglutide activates (an agonist) the GLP-1 receptor, while tirzepatide is in
a new class of dual agonists: it activates (mimics) both the GLP-1 receptor and
GIP receptors (Gastric inhibit polypeptide is also known as glucose-dependent
insulinotropic polypeptide.) The potency of activation for tirzepatide is
5-fold more for GIPR than GLP1. As seen below, there are body wide effects that
include the brain, liver, pancreas, stomach, intestine, skeletal muscle and fat
tissue. While their mode of action is somewhat different, their clinical
effects are overlapping, which include enhancing satiety, delaying gastric
emptying, increasing insulin and its sensitivity, decreasing glucagon, and, of
course, reducing high glucose levels. The overlap extends to side effects of
nausea, vomiting, abdominal pain, constipation and diarrhea. Yet only 4 to 6%
of participants discontinued the drug in these trials, mostly owing to these GI
side effects (and 1-2% in the placebo group discontinued the study drug for the
same reasons).
In randomized trials among people with Type 2 diabetes, the
drugs achieved HbA1c reduction of at least an absolute 2 percentage points
which led to their FDA approvals (For semaglutide in January 2020, and for
tirzepatide in May 2022). The edge that tirzepatide has exhibited for weight
loss reduction may be related to its dual agonist role, but the enhancement via
GIP receptor activation is not fully resolved (as seen below with GIP?
designation). The Amgen drug in development (AMG-133) has a marked weight loss
effect but inhibits GIP rather than mimics it, clouding our precise
understanding of the mechanism.
The gut-brain regulation of food intake with the many gut hormones (including leptin, gherlin, PYY, amylin) and targets in the body and brain regions. From Muller et al, Nature Reviews Drug Discovery March 2022.
Nevertheless, when the two drugs were directly compared in a
randomized trial for improving glucose regulation, tirzepatide was superior to
semaglutide, as shown below. Of note, both drugs achieved very favorable
effects on lipids, reducing triglycerides, LDL and raising HDL cholesterol,
along with reduction of blood pressure, an outgrowth of the indirect effect of
weight reduction and direct metabolic effects of the drugs.
While there has been a concern about other side effects
besides the GI ones noted above, review of all the trials to date in these
classes of medication do not reinforce a risk of acute pancreatitis. Other rare
side effects that have been noted with these drugs include allergic reactions,
gallstones (which can occur with a large amount of weight loss), and potential
of medullary thyroid cancer (so far only documented in rats, not people), which
is why they are contraindicated in people with Type 2 multiple endocrine
neoplasia syndrome.
How They Are Given and Practical Considerations
For semaglutide, which has FDA approval, the indication is a
BMI of 30 kg/m2 or greater than 27 kg/m2 and a weight related medical condition
(such as hypertension. hypercholesterolemia or diabetes). To reduce the GI side
effects, which mainly occur in the early dose escalation period, semaglutide is
given in increasing doses by a prefilled pen by self-injection under the skin
(abdomen, thigh or arm) starting at 0.25 mg for a month and gradual increases
each month reaching the maximum dose of 2.4 mg at month 5. The FDA label for
dosing of tirzepatide has not been provided yet but in the weight loss trial
there was a similar dose escalation from 2.5 mg up to 15 mg by month 5. The
escalation is essential to reduce the frequent GI side effects, such as seen below
in the tirzepatide trial.
Semaglutide is very expensive, ~$1500 per month, and not
covered by Medicare. There are manufacturer starter coupons from Novo Nordisk,
but that is just for the first month. These drugs have to be taken for a year to
18 months to have their full effect and without changes in lifestyle that are
durable, it is likely that weight will be regained after stopping them.
What Does This Mean?
More than 650 million adults are obese and 13% of the 8
billion world's population (including over 340 million ages 5-18) is obese —
that sums us to over 1 billion people. The global obesity epidemic has been
relentless, worsening each year, and a driver of "diabesity," the
combined dual epidemic. We now have a breakthrough class of drugs that can
achieve profound weight loss equivalent to bariatric surgery, along with the
side benefits of reducing cardiovascular risk factors (hypertension and
hyperlipidemia), improving glucose regulation, reversing fatty liver, and the
many detrimental long-term effects of obesity such as osteoarthritis and
various cancers. That, in itself, is remarkable. Revolutionary.
But the downsides are also obvious. Self-injections, even
though they are once a week, are not palatable for many. We have seen far more
of these injectables in recent years such as the PCSK-9 inhibitors for
hypercholesterolemia or the TNF blockers for autoimmune conditions. That still
will not make them a popular item for such an enormous population of potential
users.
That brings me to Rybelsus, the oral form of semaglutide,
which is approved for glucose regulation improvement but not obesity. It
effects for weight loss have been modest compared to Wegovy (5 to 8 pounds for
the 7 and 14 mg dose, respectively). But the potential for the very high
efficacy of an injectable to be achievable via a pill represents an important
path going forward—it could help markedly reduce the cost and uptake.
The problem of discontinuation of the drugs is big, since
there are limited data and the likelihood is that the weight will be regained
unless there are substantial changes in lifestyle. We know how hard it is to
durably achieve such changes, along with the undesirability (and uncertainty
with respect to unknown side-effects) of having to take injectable drugs for
many years, no less the cost of doing that.
The cost of these drugs will clearly and profoundly
exacerbate inequities, since they are eminently affordable by the rich, but the
need is extreme among the indigent. We've already seen celebrities take Wegovy
for weight loss who are not obese, a window into how these drugs can and will
be used without supportive data. As one physician recently observed,
"Other than Viagra and Botox, I've seen no other medication so quickly
become part of modern culture's social vernacular." Already there are
concerns that such use is preventing access to the drugs for those who qualify
and need them.
There are multiple agents in the class under development
which should help increase competition and reduce cost, but they will remain
expensive. There is private insurance reimbursement, often with a significant
copay, for people who tightly fit the inclusion criteria. Eventual coverage by
Medicare will markedly expand their use, and we can expect cost-effectiveness
studies to be published showing how much saving there is for the drugs compared
with bariatric surgery or not achieving the weight loss. But that doesn't
change the cost at the societal level. Even as we've seen with generics, which
will ultimately be available, the alleviation of the cost problem isn't what
we'd hoped.
This is not unlike the recent triumphs of gene therapy, as
in $3.5 million for a cure of hemophilia that just got FDA approval, but
instead of a rare disease we are talking about the most common medical
condition in the world. We finally get across the long sought after (what many
would qualify as miraculous) goal line, but the economics collide with the
uptake and real benefit.
These concerns can't be put aside in the health
inequity-laden world we live in, that will unquestionably be exacerbated.
However, we cannot miss that this represents one of the most important, biggest
medical breakthroughs in history. This may signify the end or marked reduction
in the need for bariatric surgery. These drugs will likely become some of the
most prescribed of all medications in the upcoming years. While there are many
drawbacks, we shouldn't miss such an extraordinary advance in medicine—the
first real, potent and safe treatment of obesity.
Sunday 16 April 2023
High Salt Intake Linked to Atherosclerosis Even With Normal Blood Pressure
The study, including more than 10,000 individuals between the ages of 50 and 64 years from the Swedish Cardiopulmonary bioImage Study, showed a significant link between dietary salt intake and the risk for atherosclerotic lesions in the coronary and carotid arteries, even in participants with normal blood pressure and without known cardiovascular disease.
The finding suggests that salt could be a damaging factor in its own right before the development of hypertension, the authors write. The results were published online March 30 in European Heart Journal Open.
It has been known for a long time that salt is linked to hypertension, but the role that salt plays in atherosclerosis has not been examined, first author, Jonas Wuopio, MD, Karolinska Institutet, Huddinge, and Clinical Research Center, Falun, Uppsala University, both in Sweden, told theheart.org | Medscape Cardiology.
"Hardly anyone looks at changes in the arteries' calcification, the atherosclerotic plaques and the association with salt intake," Wuopio said. "We had this exclusive data from our cohort, so we wanted to use it to close this knowledge gap."
The analysis included 10,788 adults ages 50 to 64 years, (average age, 58 years; 52% women) who underwent a coronary computed tomography angiography (CCTA) scan. The estimated 24-hour sodium excretion was used to measure sodium intake.
CCTA was used to obtain 3D images of the coronary arteries to measure the degree of coronary artery calcium as well as detect stenosis in the coronary arteries. Participants also had an ultrasound of the carotid arteries.
After adjusting for age, sex, and study site (the study was done at Uppsala and Malmö), the researchers found that rising salt consumption was linked with increasing atherosclerosis in a linear fashion in both the coronary and carotid arteries.
Each 1000 mg rise in sodium excretion was associated with a 9% increased occurrence of carotid plaque (odds ratio [OR], 1.09; P < .001; confidence interval [CI], 1.06 - 1.12), a higher coronary artery calcium score (OR, 1.16; P < .001; CI, 1.12 - 1.19), and a 17% increased occurrence of coronary artery stenosis (OR, 1.17; P < .001; CI, 1.13 - 1.20).
The association was abolished, though, after adjusting for blood pressure, they note. Their "interpretation is that the increase in blood pressure from sodium intake, even below the level that currently defines arterial hypertension, is an important factor that mediates the interplay between salt intake and the atherosclerotic process," they write. "As we observed an association in individuals with normal blood pressure, one possible explanation for these findings is that the detrimental pathological processes begin already prior to the development of hypertension," they note, although they caution that no causal relationships can be gleaned from this cross-sectional study.
They also reported no sign of a "J-curve"; participants with the lowest levels of sodium excretion had the lowest occurrence of both coronary and carotid atherosclerosis, which contradicts findings in some studies that found very low sodium linked to increased cardiovascular disease–related events.
"There have been some controversies among researchers regarding very low intake, where some say very low salt intake can increase the risk of cardiovascular disease, but we could not find this in this study," Wuopio said.
"Our study is confirming that excess salt is not a good thing, but the fact that it is linked to atherosclerosis, even in the absence of hypertension, was a bit of a surprise," he said.
"I will be telling my patients to follow the advice given by the World Health Organization and other medical societies, to limit your intake of salt to approximately 1 teaspoon, even if your blood pressure is normal."
Maciej Banach, MD, Medical University of Lodz, and Stanislaw Surma, MD, Faculty of Medical Sciences in Katowice, both in Poland, write that excessive dietary salt intake is a well-documented cardiovascular risk factor, and that the association is explained in most studies by increased blood pressure.
"We should look more extensively on the role of dietary salt, as it affects many pathological mechanisms, by which, especially with the coexistence of other risk factors, atherosclerosis may progress very fast," they write."The results of the study shed new light on the direct relationship between excessive dietary salt intake and the risk of ASCVD [atherosclerotic cardiovascular disease], indicating that salt intake might be a risk factor for atherosclerosis even prior to the development of hypertension," they conclude.
Wednesday 22 March 2023
Parkinson Disease
Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years and causing progressive disability that can be slowed, but not halted, by treatment. The 2 major neuropathologic findings in Parkinson disease are loss of pigmented dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neurites.
Signs and symptoms
Initial clinical symptoms of Parkinson disease include the following:
- Tremor
- Subtle decrease in dexterity
- Decreased arm swing on the first-involved side
- Soft voice
- Decreased facial expression
- Sleep disturbances
- Rapid eye movement (REM) behavior disorder (RBD; a loss of normal atonia during REM sleep)
- Decreased sense of smell
- Symptoms of autonomic dysfunction (eg, constipation, sweating abnormalities, sexual dysfunction, seborrheic dermatitis)
- A general feeling of weakness, malaise, or lassitude
- Depression or anhedonia
- Slowness in thinkin
Onset of motor signs include the following:
- Typically asymmetric
- The most common initial finding is a resting tremor in an upper extremity
- Over time, patients experience progressive bradykinesia, rigidity, and gait difficulty
- Axial posture becomes progressively flexed and strides become shorter
- Postural instability (balance impairment) is a late phenomenon
Nonmotor symptoms
Nonmotor symptoms are common in early Parkinson disease. Recognition of the combination of nonmotor and motor symptoms can promote early diagnosis and thus early intervention, which often results in a better quality of life.
Diagnosis
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on routine magnetic resonance imaging and computed tomography scans are unremarkable.
Clinical diagnosis requires the presence of 2 of 3 cardinal signs:
- Resting tremor
- Rigidity
- Bradykinesia
Management
The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects.
Symptomatic drug therapy
- Usually provides good control of motor signs of Parkinson disease for 4-6 years
- Levodopa/carbidopa: The gold standard of symptomatic treatment
- Monoamine oxidase (MAO)–B inhibitors: Can be considered for initial treatment of early disease
- Other dopamine agonists (eg, ropinirole, pramipexole): Monotherapy in early disease and adjunctive therapy in moderate to advanced disease
- Anticholinergic agents (eg, trihexyphenidyl, benztropine): Second-line drugs for tremor only
Treatment for nonmotor symptoms
- Sildenafil citrate (Viagra): For erectile dysfunction
- Polyethylene glycol: For constipation
- Modafinil: For excessive daytime somnolence
- Methylphenidate: For fatigue (potential for abuse and addiction)
Deep brain stimulation
- Surgical procedure of choice for Parkinson disease
- Does not involve destruction of brain tissue
- Reversible
- Can be adjusted as the disease progresses or adverse events occur
- Bilateral procedures can be performed without a significant increase in adverse events
Prognosis
Before the introduction of levodopa, Parkinson disease caused severe disability or death in 25% of patients within 5 years of onset, 65% within 10 years, and 89% within 15 years. The mortality rate from Parkinson disease was 3 times that of the general population matched for age, sex, and racial origin. With the introduction of levodopa, the mortality rate dropped approximately 50%, and longevity was extended by many years. This is thought to be due to the symptomatic effects of levodopa, as no clear evidence suggests that levodopa stems the progressive nature of the disease.
The American Academy of Neurology notes that the following clinical features may help predict the rate of progression of Parkinson disease :
Older age at onset and initial rigidity/hypokinesia can be used to predict (1) a more rapid rate of motor progression in those with newly diagnosed Parkinson disease and (2) earlier development of cognitive decline and dementia; however, initially presenting with tremor may predict a more benign disease course and longer therapeutic benefit from levodopa
A faster rate of motor progression may also be predicted if the patient is male, has associated comorbidities, and has postural instability/gait difficulty (PIGD)
Older age at onset, dementia, and decreased responsiveness to dopaminergic therapy may predict earlier nursing home placement and decreased survival
Patient Education
Patients with Parkinson disease should be encouraged to participate in decision making regarding their condition. In addition, individuals and their caregivers should be provided with information that is appropriate for their disease state and expected or ongoing challenges. Psychosocial support and concerns should be addressed and/or referred to a social worker or psychologist as needed.
Prevention of falls should be discussed. The UK National Institute for Health and Clinical Excellence has several guidance documents including those for patients and caregivers.
Other issues that commonly need to be addressed at appropriate times in the disease course include cognitive decline, personality changes, depression, dysphagia, sleepiness and fatigue, and impulse control disorders. Additional information is also often needed for financial planning, insurance issues, disability application, and placement (assisted living facility, nursing home).
Tuesday 21 March 2023
55 countries facing serious health worker shortages – World Health Organisation
The World Health Organisation has said that no less than 55 countries are struggling with serious health worker shortages as they continue to seek better-paid opportunities in wealthier nations.
They continue to seek better-paid opportunities in wealthier nations that have stepped up efforts to recruit them amid the COVID-19 pandemic.
According to WHO, African nations have been worst hit by the phenomenon, with 37 countries on the continent facing health worker shortages.
“Health workers shortage have threatened their chances of achieving universal health care by 2030 – a key Sustainable Development Goals pledge.’’
The actions of wealthy countries that belong to the Organisation for Economic Cooperation and Development come under scrutiny in the WHO alert, among other regions.
“Within Africa, it’s a very vibrant economy that is creating new opportunities,” Dr Jim Campbell, the Director responsible for health worker policy at WHO, said in a statement on Tuesday.
“The Gulf States have traditionally been reliant on international personnel and then some of the OECD high-income countries have really accelerated their recruitment and employment to respond to the pandemic and respond to the loss of lives, the infections, the absences of workers during the pandemic”.
To help countries protect their vulnerable healthcare systems, WHO has issued an updated health workforce support and safeguards list, which highlights nations with low numbers of qualified healthcare staff.
“These countries require priority support for health workforce development and health system strengthening, along with additional safeguards that limit active international recruitment,” the WHO insisted.
Supporting the call for universal healthcare for all countries in line with the SDGs, WHO Director-General, Dr Tedros Ghebreyesus, called on all countries to respect the provisions in the WHO health workforce support and safeguards list.
“Health workers are the backbone of every health system, and yet 55 countries with some of the world’s most fragile health systems, do not have enough and many are losing their health workers to international migration,” he added.
Although many countries do respect existing WHO guidelines on the recruitment of health care workers, the principle is not accepted wholesale, WHO warned.
“What we are seeing is that the majority of countries are respecting those provisions by not actively recruiting from these (vulnerable) countries,” Campbell said.
“But there is also a private recruitment market that does exist and we’re looking to them to also reach some of the global standards that are anticipated in terms of their practice and behaviour.”
Mechanisms also exist for governments or other individuals to notify WHO if they are “worried” about the behaviour of recruiters, the WHO official said.
The WHO health workforce support and safeguard list does not prohibit international recruitment but recommends that governments involved in such programmes are informed about the impact on the health system in countries where they source qualified health professionals.