Monday 5 August 2024
Coffee and Your Brain Health: Striking the Right Balance ☕ðŸ§
Friday 3 May 2024
Boosting Brain Power: Can Brain Training Really Enhance Cognitive Function?
Sunday 24 December 2023
Eat Carrots and Prevent Cancer: Unveiling the Superfood's Hidden Powers
Wednesday 15 November 2023
The Link Between Sleep and Dementia Risk: A Wake-Up Call
Monday 31 July 2023
Snoring Could Be Harming Your Brain
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.
Thursday 20 April 2023
Intermittent Fasting Plus Early Eating May Prevent Type 2 Diabetes
The study involved more than 200 individuals randomized to one of three groups: eat only in the morning (from 8:00 AM to noon) followed by 20 hours of fasting 3 days per week and eat as desired on the other days; daily calorie restriction to 70% of requirements; or standard weight loss advice.
The IF plus early time-restricted eating intervention was associated with a significant improvement in a key measure of glucose control versus calorie restriction at 6 months, while both interventions were linked to benefits in terms of cardiovascular risk markers and body composition, compared with the standard weight loss advice.
However, the research, published in Nature Medicine, showed that the additional benefit of IF plus early time-restricted eating did not persist, and less than half of participants were still following the plan at 18 months, compared with almost 80% of those in the calorie-restriction group.
"Following a time-restricted, IF diet could help lower the chances of developing type 2 diabetes," said senior author Leonie K. Heilbronn, PhD, University of Adelaide, South Australia, in a press release.
This is "the largest study in the world to date, and the first powered to assess how the body processes and uses glucose after eating a meal," with the latter being a better indicator of diabetes risk than a fasting glucose test, added first author Xiao Tong Teong, a PhD student, also at the University of Adelaide.
"The results of this study add to the growing body of evidence to indicate that meal timing and fasting advice extends the health benefits of a restricted-calorie diet, independently from weight loss, and this may be influential in clinical practice," Teong added.
Adherence Difficult to IF Plus Early Time-Restricted Eating
Asked to comment, Krista Varady, PhD, said that the study design "would have been stronger if the time-restricted eating and IF interventions were separated" and compared.
"Time-restricted eating has been shown to naturally reduce calorie intake by 300-500 kcal/day," she told Medscape Medical News, "so I'm not sure why the investigators chose to combine [it] with IF. It...defeats the point of time-restricted eating."
Varady, who recently coauthored a review of the clinical application of intermittent fasting for weight loss, also doubted whether individuals would adhere to combined early time-restricted eating and IF. "In all honesty, I don't think anyone would follow this diet for very long," she said.
She added that the feasibility of this particular approach is "very questionable. In general, people don't like diets that require them to skip dinner with family/friends on multiple days of the week," explained Varady, professor of nutrition at the University of Illinois, Chicago. "These regimens make social eating very difficult, which results in high attrition."
"Indeed, evidence from a recent large-scale observational study of nearly 800,000 adults shows that Americans who engage in time-restricted eating placed their eating window in the afternoon or evening," she noted.
Varady therefore suggested that future trials should test "more feasible time-restricted eating approaches," such as those with later eating windows and without "vigilant calorie monitoring."
"These types of diets are much easier to follow and are more likely to produce lasting weight and glycemic control in people with obesity and prediabetes," she observed.
A Novel Way to Cut Calories?
The Australian authors say there is growing interest in extending the established health benefits of calorie restriction through new approaches such as timing of meals and prolonged fasting, with IF — defined as fasting interspersed with days of ad libitum eating — gaining in popularity as an alternative to simple calorie restriction.
Time-restricted eating, which emphasizes shorter daily eating windows in alignment with circadian rhythms, has also become popular in recent years, although the authors acknowledge that current evidence suggests any benefits over calorie restriction alone in terms of body composition, blood lipids, or glucose parameters are small.
To examine the combination of IF plus early time-restricted eating, in the direct trial, the team recruited individuals aged 35-75 years who had a score of at least 12 on the Australian Type 2 Diabetes Risk Assessment Tool but did not have a diagnosis of diabetes and had stable weight for more than 6 months prior to study entry.
The participants were randomized to one of three groups:IF plus early time-restricted eating, which allowed consumption of 30% of calculated baseline energy requirements between 8:00 AM and midday, followed by a 20-hour fast from midday on 3 nonconsecutive days per week. They consumed their regular diet on nonfasting days.Calorie restriction, where they consumed 70% of daily calculated baseline energy requirements each day and were given rotating menu plans, but no specific mealtimes.Standard care, where they were given a booklet on current guidelines, with no counseling or meal replacement.
There were clinic visits every 2 weeks for the first 6 months of follow-up, and then monthly visits for 12 months. The two intervention groups had one-on-one diet counseling for the first 6 months. All groups were instructed to maintain their usual physical activity levels.
Two hundred and nine individuals were enrolled between September 26, 2018 and May 4, 2020. Their mean age was 58 years, and 57% were women. Mean body mass index (BMI) was 34.8 kg/m2.
In all, 40.7% of participants were allocated to IF plus early time-restricted eating, 39.7% to calorie restriction, and the remaining 19.6% to standard care.
The results showed that IF plus early time-restricted eating was associated with a significantly greater improvement in the primary outcome of postprandial glucose area under the curve (AUC) at month 6 compared with calorie restriction, at –10.1 mg/dL/min versus –3.6 mg/dL/min (P = .03).
"To our knowledge, no [prior] studies have been powered for postprandial assessments of glycemia, which are better indicators of diabetes risk than fasting assessment," the authors underline.
IF plus early time-restricted eating was also associated with greater reductions in postprandial insulin AUC versus calorie restriction at 6 months (P = .04). However, the differences between the IF plus early time-restricted eating and calorie restriction groups for postmeal insulin did not remain significant at 18 months of follow-up.
Both IF plus early time-restricted eating and calorie restriction were associated with greater reductions in A1c levels at 6 months versus standard care, but there was no significant difference between the two active interventions (P = .46).
Both interventions were also associated with improvements in markers of cardiovascular risk versus standard care, such as systolic blood pressure at 2 months, diastolic blood pressure at 6 months, and fasting triglycerides at both time points, with no significant differences between the two intervention groups.
IF plus early time-restricted eating and calorie restriction were also both associated with greater reductions in BMI and fat mass in the first 6 months, as well as in waist circumference.
Calorie Restriction Easier to Stick to, Less Likely to Cause Fatigue
When offered the chance to modify their diet plan at 6 months, 46% of participants in the IF plus early time-restricted eating group said they would maintain 3 days of restrictions per week, while 51% chose to reduce the restrictions to 2 days per week.
In contrast, 97% of those who completed the calorie-restriction plan indicated they would continue with their current diet plan.
At 18 months, 42% of participants in the IF plus early time-restricted eating group said they still undertook 2 to 3 days of restrictions per week, while 78% of those assigned to calorie restriction reported that they followed a calorie-restricted diet.
Fatigue was more common with IF plus early time-restricted eating, reported by 56% of participants versus 37% of those following calorie restriction, and 35% of those in the standard care group at 6 months. Headaches and constipation were more common in the intervention groups than with standard care.
The study was supported by a National Health and Medical Research Council Project Grant, an Australian Government Research Training Program Scholarship from the University of Adelaide, and a Diabetes Australia Research Program Grant.
No relevant financial relationships were declared.
Nat Med. Published online April 6, 2023. Full text