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.

How Old Is Too Old to Start Strength Training?

Aging is one of the greatest threats to your freedom and independence you'll ever know, only because of what it does to your muscles.

 

The body's hormones that are responsible for maintaining muscle mass decline with age. And, since older adults tend to be less active and eat less protein, which is important to keep muscles strong, we face more challenges as we get older, said Brandon Grubbs, PhD, an assistant professor of exercise science and co-leader of the Positive Aging Consortium at Middle Tennessee State University.

 

Not only that, but the "satellite cells" responsible for muscle repair become less responsive, Grubbs said, and the muscle fibres hold on to fewer of them. So growing muscle gets harder, too.

Luckily, there is a powerful remedy: lifting weights.

Strength training helps stop the loss of muscle function that comes with aging, Grubbs said. "It stimulates muscle growth and enhances muscle tissue quality, meaning you can generate more force with a given amount of muscle."

Research shows we begin losing muscle around age 35, and the process picks up after we hit 60. While many of us are dreaming up fun plans for retirement, we're also losing as much as 3% of our muscle per year.

 

But the loss of muscle due to aging, known as sarcopenia, affects more than your reflection in the mirror. It can greatly influence your health and well-being.

Sarcopenia has been linked to type 2 diabetes, high blood pressure, and obesity. It may increase the risk of heart disease and stroke, and take years off your life. It also jeopardizes your freedom to live on your own, not to mention traveling, spending time with grandkids, or doing so many of the things that make older adulthood joyful and fulfilling.

"Physical frailty" — that is, weakness, slowness, unintentional weight loss, and fatigue –"is intertwined with sarcopenia," Grubbs said. If your body starts wasting, so does your ability to go about your daily life and do things you enjoy.

 

Strength training boosts connective tissue strength and bone mineral density. "It can extend someone's ability to remain living independently and reduce the risk of falls and fractures. It's also good for one's psychological well-being," he said.

Yet, only 9% of people over 75 perform strength training regularly — that is, at least twice a week. It's not hard to see why.

 

Strength training can be intimidating for anyone, especially if you're north of 60 and you've never held a dumbbell in your life. Health problems, pain, fatigue, fear of injury — all can keep older adults out of the weight room. Other barriers include a lack of social support and exercise facilities.

But here's the thing: Being old by itself is not a limiting factor — so it's no excuse to avoid exercise.

Both the National Strength and Conditioning Association (NSCA) and the American College of Sports Medicine (ACSM) recommend strength training for older adults, noting that programs can be adapted for those with frailty or chronic conditions.

 

That's not news. The ACSM's original Position Stand on Exercise and Physical Activity for Older Adults put it plainly: "In general, frailty or extreme age is not a contraindication to exercise, although the specific modalities may be altered to accommodate individual disabilities."

The presence of disease commonly linked to aged populations — ranging from arthritis, cardiovascular disease, and diabetes to dementia, osteoporosis, and stroke — "is not by itself a contraindication to exercise" either, even if all are present within a single person.

"For many of these conditions," the guidelines say, "exercise will offer benefits not achievable through medication alone." And despite the common fear of pain or injury: "Sedentariness appears a far more dangerous condition than physical activity in the very old."

 

A 2022 study found that healthy older men who lifted weights strengthened the connections between their nerves and muscles, helping them maintain physical function. The subjects' average age was 72, but they were just kids compared to participants in a landmark 1990 trial that looked at frail, institutionalised people as old as 96.

 

The study was small — with just 10 people — but significant because of their age (86 to 96) and the remarkable results: After 8 weeks of resistance training, they improved their strength by 174% while adding 9% more muscle to their mid-thighs. These were residents of a long-term care facility; they were not acutely ill but not especially healthy, either.

"That study demonstrated that even the oldest of the old can improve strength and muscle mass," Grubbs said. "I'm not aware of an age where one can't improve those outcomes.

 

"There are bodybuilders who still compete in their 70s," Grubbs said. "Older adults don't gain muscle and strength as well as younger ones — the training response may be slower — but significant improvements in strength and muscle can be achieved with the right program."

What Is the 'Right' Strength Program for Older Adults?

 

The American College of Sports Medicine recommends that people ages 65 and up train two to four times per week in sessions lasting 30 to 60 minutes. Grubbs said just one workout per week is enough to start; a 2019 study in people over 75 suggests that as little as an hour of strength training per week can improve walking speed, leg strength, and one's ability to stand up out of a chair.

The recommendations are to perform one to three sets of eight to 15 repetitions per exercise, going as heavy as 80% of their "one-repetition maximum," or one-rep max (the greatest amount of weight you can lift one time). A one-rep max is difficult and potentially dangerous to test, so it's OK to estimate it conservatively. (Really, you just want a weight you can lift 8 to 15 times that's challenging enough but not so heavy that you sacrifice proper form.)

 

Do multi-joint exercises, Grubbs said — traditional strength moves like the squat, overhead press, chest press, seated row, and lat pulldown. These better prepare you for the activities of daily living than isolation exercises (those that target a specific muscle) or machine movements do — although machines may be better for people with balance issues or other difficulties that make multi-joint, free-weight exercises hard to do.

 

Keep in mind that any move can be made easier to suit your fitness level. You may not need to drop into a deep squat if a quarter-squat (squatting only a quarter of the way) feels challenging enough.

Rest between sets can be 2 to 3 minutes.

Focus on Power Training

 

Interestingly, while traditional resistance training will build muscle and strength, Grubbs suggested that older adults focus more on power — the skill of applying force quickly. "Power is better related to older adults' ability to perform activities of daily living," he said, including walking speed, and going from sitting to standing.

 

In fact, a 2022 review showed that power training may be better than traditional strength training at improving older adults' "functional performance." Meaning you'll have an easier time climbing stairs, getting out of a car, and standing up from a chair or the toilet.

The good news is power training is no more complicated than strength work, and it actually feels less challenging. With power, speed of movement is the focus, so you choose a light weight — around 40%-60% of your one-rep max, or really any load you can move quickly — and lift it as fast as you can (but safely, and with control). Take a second or two to lower the weight and reset. Repeat for three to six repetitions, or until you feel your form may be compromised, or you've lost significant speed. Do one to three sets.

 

What kind of moves are "power" moves? You can do the same ones you use for strength, just faster. If you want to get the most of your results, Grubbs said you can cycle your workouts, keeping the same movements but changing the speed at which you perform them and the level of weight you use to build muscle, strength, and power. For instance, you can train with heavier weights one day to focus more on strength, and then use lighter weights with faster rep speeds in your next workout to promote power. Keep going back and forth from there.

According to Laura Grissom, the health and wellness education program coordinator at St. Clair Senior Centre in Murfreesboro, TN, one exercise that all older adults should practice is the "sit to stand," which is just what it sounds like.

 

"Sit at the edge of a chair, with your feet on the floor, and cross your arms over your chest," she said. "Lean back until your back touches the back of the chair, brace your abs, and then come forward and stand up." That's one rep. Take it easy at first, with three sets of 10, and then work on doing it faster, as power training.

 

How to Get Started

 

Those brand-new to exercise may consider working with a physical therapist, who can help come up with a customised plan, educate patients on proper form, and advise how hard they should be working. In some cases, Medicare may cover physical therapy with a doctor's referral.

A personal trainer can be great for those who have the budget. (Some are specially certified to train older adults, such as those with the National Academy of Sports Medicine's Senior Fitness Specialisation.) Otherwise, advise patients to look for group fitness classes like the kind Grissom runs. Your patient's local senior centre may offer them, she said.

They can also search for a nearby SilverSneakersclass. Designed just for adults 65-plus, SilverSneakers fitness programs are available in thousands of gyms and community centres nationwide (and virtually via Zoom), and the cost is covered by many Medicare plans.

 

Working out in a group setting may be one of the best ways to see that you continue to work out at all. A study in Health Psychology found that adults 65 and up who exercised together in a program designed to foster a sense of social connection were better able to stick to their workouts.

"People don't come to our seniors' classes just to exercise," Grissom said. "It's a social event."

Retirees often find themselves with more time on their hands and aren't around other people as much. "But when they come to class, they make friends and have accountability. If someone doesn't show up to a class a couple of times, someone else in the class is going to call them and ask if everything's OK. Once they get into the camaraderie of the classes, most people come back again," Grissom said.

 

Seeing the benefits can help keep you motivated, as well.

"So many people have told me over the years that they've been able to stop taking medication because they came to my class," Grissom said. "They'll say, 'My blood sugar and cholesterol went down. … The pain in my shoulder went away. …' If you have a health problem, the best thing you can do is exercise."

No matter how old you are.

New COVID Variant on WHO's Radar Causing Itchy Eyes in Kids - Times of India

A new COVID-19 variant that recently landed on the World Health Organization's radar may cause previously unseen symptoms in children, according to a new report. 

While the variant, called "Arcturus," hasn't yet made the CDC's watchlist, a prominent pediatrician in India is seeing children with "itchy" or "sticky" eyes, as if they have conjunctivitis or pinkeye, according to  The Times of India. 

The new itchy eye symptom is in addition to kids having a high fever and cough, Vipin Vashishtha, MD, said on Twitter, noting that pediatric COVID cases have picked up there for the first time in 6 months.

The country has also seen a rise in another virus among children with similar symptoms, called adenovirus. COVID and adenovirus cannot be distinguished without testing, and many parents don't want to have their children tested because the swabs are uncomfortable, The Times of India reported. One doctor told the newspaper that among every 10 kids with COVID-like symptoms, two or three of them had tested positive on a COVID test taken at home.

Health officials in India are doing mock drills this week to check how prepared the country's hospitals are as India sees cases rise, the BBC reported. India struggled during a COVID-19 surge in 2021, at which time sickened people were seen lying on sidewalks outside overflowing hospitals, and reports surfaced of a black market for private citizens to buy oxygen. 

Arcturus (formally, Omicron subvariant XBB.1.16) made news 2 weeks ago as it landed on the WHO's radar after surfacing in India. A WHO official called it "one to watch." The Times of India reported that 234 new cases of XBB.1.16 were included in the country's latest 5,676 new infections, meaning the subvariant accounts for 4% of new COVID cases.