Ozempic and Wegovy have received a lot of publicity as revolutionizing treatment options for obesity. Both medications form a class of GLP-1 receptor agonists, which mimic a hormone in the body called glucagon-like peptide-1 and are involved in the regulation of appetite and blood sugar. Indeed, in initial clinical studies, the majority of those on the drugs lost 15% to 22% of body weight, hence much optimism. For most patients, these medications are underwhelming for about 20% of patients due to minimal weight loss or other challenges.

Take a closer look at why the weight loss drugs may not work for everyone, together with what options exist when they don't deliver the expected outcomes.

Why Weight Loss Drugs May Not Work

While GLP-1 receptor agonists have produced phenomenal responses in a majority of patients, it remains a reality that these drugs work differently for different people. Here's why:

1. Genetic and Hormonal Variability

Weight loss medications interact with complex systems in the body that differ from person to person. Genetics, hormones, and individual brain responses to energy regulation play significant roles in determining how a person responds to drugs like Ozempic and Wegovy.

2. Underlying Medical Conditions

Other conditions, such as sleep apnea, may be prevalent and prevent or delay the achievement of weight loss goals. Prescription drugs like antidepressants, steroids, or contraceptives are other medications that can nullify weight loss medication benefits.

3. Unrealistic Expectations

Often, they come to these medications with enormous hopes; expecting the promised rapid and dramatic weight loss. Progress creates disappointment if it has not stalled. In patients who rigidly follow recommended lifestyle modifications, frustration and disappointment are most common.

Why it is Important to Identify Non-responders

For most patients, the effectiveness of GLP-1 receptor agonists is evident within a few weeks of treatment. Weight loss typically begins within a few weeks of initiating therapy and tends to increase with dosage. However, some patients respond very little, if at all, despite strict adherence to their regimen.

For nonresponders, this can feel like a dead end. However, understanding the unique complexities of obesity is essential. This condition stems from brain dysfunction, and the pathways that contribute to weight regulation differ among individuals.

Alternative Treatment Options

When Ozempic or Wegovy doesn’t yield desired results, there are still many paths to explore:

1. Switching to Another GLP-1 Drug

For example, some patients who don't respond well to one GLP-1 receptor agonist might find success with another drug in the same class. Newer medications, such as Zepbound, target other hormone pathways and seem promising even for those not responsive to earlier drugs.

2. Use of Older Medications

While there is much to say about newer drugs, older treatments can still be useful and work for some patients. One can also seek the help of a medical provider specializing in obesity treatments in order to identify the best alternatives.

3. Lifestyle Changes

Diet, exercise, sleep, and stress management continue to be integral components of any weight loss program. New changes may be small but can make an enormous difference in one's health and success.

4. Medical Management of Obesity

It is a complex disorder, and most patients should receive a multidisciplinary treatment. Collaboration with an obesity-aware doctor may mean access to tailored treatment plans, ranging from psychological support all the way to metabolic testing, and many others.

Why Side Effects of Weight Loss Drug Ozempic May Be a Barrier

For others, side effects like nausea, vomiting, or diarrhea hinder them from continuing with these drugs. These symptoms often reduce as the body becomes accustomed, but for some, they might be severe enough to stop treatment altogether. In those instances, alternative drugs or procedures become vital to find.

Long-term effects of Ozempic or Wegovy on the Brain

Another largely unexplored area relates to GLP-1 drugs' long-term effects on the brain's regulation of hunger and satiety. Although GLP-1 drugs suppress appetite and can lead to effective weight loss, emerging research suggests that they may also affect brain reward mechanisms, changing the way patients experience foods.

This aspect could prove of paramount significance in the future treatment of obesity. Perhaps GLP-1 receptor agonists do indeed affect and rewire the brain's reward pathways and will thus provide sustained benefits beyond discontinuation. However, more research is required to understand this phenomenon fully.

While for many, Ozempic and Wegovy have revolutionized obesity treatment, these are certainly not a one size fits all. Nonresponders need not lose hope- alternative strategies and medications abound. A consultation with an obesity expert healthcare provider is essential to put together a comprehensive, tailored treatment plan.

The route toward effective weight loss may be challenging, but with the evolution of obesity medicine and a better understanding of individual needs, there is a path forward for everyone.

The liver and heart are two of the most vital organs of the body, and although they perform very different functions, they are closely connected. When the liver is not functioning properly, it can place significant stress on the heart and circulatory system of the body.

Liver disease not only affects the digestion process, metabolism, and detoxification but can also trigger serious cardiovascular changes that may go unnoticed in the early stages. Understanding this particular connection is significant for timely diagnosis and better overall care.

The Liver-Heart Connection

The liver helps to regulate the flow of blood, fluid balance, cholesterol metabolism, and inflammation as well. When liver disease develops—whether due to fatty liver, hepatitis, cirrhosis, or alcohol-related damage—all these processes become disturbed.

As a result of the same, the heart may have to work harder to maintain circulation, while blood vessels may also undergo certain changes that impact blood pressure and delivery of oxygen as well.

Changes In Blood Circulation

In well-advanced liver disease, especially cirrhosis, the flow of blood through the liver becomes restricted. This can also increase pressure in the portal vein, a condition known as portal hypertension. At the same point in time, blood vessels in the rest of the body may also widen, causing a drop in effective blood pressure.

To compensate, the heart pumps faster and harder. With the passage of time, this constant strain can weaken cardiac function and even lead to a condition sometimes referred to as cirrhotic cardiomyopathy, where the heart does not respond normally under stress.

Fluid Retention And Heart Stress

Liver disease often causes the body to retain both salt and water. This can also lead to swelling in the legs, abdomen, and surrounding tissues as well. Extra fluid in the body increases the workload on the heart, making it more difficult for it to pump blood in an efficient way. In severe cases, this may also contribute to shortness of breath, fatigue, and worsening cardiovascular strain.

Inflammation And Metabolic Impact

Some of the conditions, such as non-alcoholic fatty liver disease, are also linked with diabetes, obesity, high levels of cholesterol, and high blood pressure – all of which are the major risk factors for heart disease. Chronic inflammation, well-associated with liver damage, may further increase the risk of atherosclerosis and other cardiac complications.

GLP-1 receptor agonist drugs such as Ozempic and Wegovy have shown significant benefits for people with diabetes and obesity. However, not everyone experiences the same results.

Now, a study suggests that this variation may be due to genetic resistance, which means that some people are biologically less responsive to these medications, making these drugs less effective.

The new study by scientists at Stanford University in the US showed that about 10 per cent of the general population carry genetic variants that lead to what the researchers called “GLP-1 resistance”.

The GLP-1- receptor agonist drugs typically work by mimicking the hormone GLP-1 (glucagon-like peptide-1), which naturally helps regulate blood sugar by stimulating insulin release. The process slows the emptying of the stomach and reduces appetite.

However, in individuals with certain genetic variants, the team found that higher levels of GLP-1 did not regulate blood sugar better.

The researchers noted that the findings, published in the journal Genome Medicine, may be key to developing new therapies for people with GLP-1 resistance.

“There are a whole class of medications that are insulin sensitizers, so perhaps we can develop medications that will allow people to be sensitized to GLP-1s or find formulations of GLP-1, like the longer-acting versions, that avoid the GLP-1 resistance,” said Anna Gloyn, professor of pediatrics and of genetics at Stanford Medicine.

The Gene Linked to GLP-1 Resistance

Also read: Foundayo: US FDA Approves Eli Lilly’s GLP-1 Weight Loss Pill

To zero in on the gene resistant to GLP-1 drugs, the team conducted experiments in humans. They traced this resistance to a PAM variant known as p.S539W.

PAM (peptidyl-glycine alpha-amidating monooxygenase) is an enzyme that is uniquely capable of activating many hormones in the body, including GLP-1.

While the researchers suspected that people with the PAM variant would have lower levels of GLP-1 in their blood, it actually increased levels of GLP-1. Although the exact mechanism is still unclear, experiments in both humans and mice confirmed signs of reduced response to GLP-1.

Analyzing diabetes drug trial data, they found that individuals with these variants were less able to lower their blood sugar levels even after six months of treatment. This suggests that despite having more circulating GLP-1, their bodies are less responsive to it.

“When I treat patients in the diabetes clinic, I see a huge variation in response to these GLP-1-based medications and it is difficult to predict this response clinically,” said Mahesh Umapathysivam, an endocrinologist and clinical researcher at Adelaide University in Australia.

“This is the first step in being able to use someone’s genetic make-up to help us improve that decision-making process,” he added.

Also read: Can Weight Loss Jabs Surge Divorce Rates? What Experts Are Saying

Importantly, participants with the PAM variants did not respond differently to other common diabetes treatments, including sulfonylureas, metformin, and DPP-4i.

The finding may help develop precision medicine, the researchers said. Knowing ahead of time who is likely to respond would help patients get on the right drugs faster, Gloyn said.

Reasons Why Ozempic May Not Help All People Lose Weight

Ozempic is primarily indicated for type 2 diabetes management. But some doctors may prescribe it for weight loss in appropriate patients without diabetes.

Previous research has shown that medical conditions such as sleep apnea, along with certain common medications, such as antidepressants, steroids, and contraceptives, can hamper the process of shedding extra pounds.

Another major reason that can hamper weight loss is the side-effects of these drugs that can prompt a person to halt their prescription mid-way.

Once widely known as non-alcoholic fatty liver disease (NAFLD), the common and dangerous fatty liver condition was rephrased as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) due to its strong link to metabolic health issues like obesity and diabetes.

MASLD now includes patients with fatty liver disease linked to metabolic risk factors such as obesity, diabetes, and hypertension.

MASLD: So What Prompted The Change?

Globally, it was observed that all patients who have non-alcoholic fatty liver disease also have some associated form of metabolic dysfunction. The patients reported having either obesity, diabetes, metabolic syndrome, hypertension, or cholesterol problems.

And all these problems eventually lead to significant comorbidities later, like some people developed heart disease, while others developed complications of diabetes.

In view of these, a global consensus process in 2023 involving hundreds of experts from different countries adopted MASLD as it better reflected these underlying causes of the condition.

What Does MASLD Mean?

Also read: Lancet Study Shows Metabolic Liver Disease To Rise Over 38% By 2050: What’s Behind The Surge

MASLD is an umbrella term for liver conditions that develop in the presence of 1 or more cardiometabolic risk factors—including high blood sugar, elevated body mass index (BMI), and hypertension—but in the absence of other causes of liver fat accumulation.

The condition can be defined by excess liver fat accumulation (more than 5 per cent of liver weight) in the presence of metabolic dysfunction, independent of alcohol intake.

It encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.

“Initially, it was thought that having fatty liver disease without alcohol was a benign condition, but now it is recognized that, since it is associated with lots of metabolic comorbidities, it's no longer benign,” Dr. Ashish Kumar, Professor of gastroenterology and hepatology at Sir Ganga Ram Hospital in New Delhi, told HealthandMe.

He stated that whenever a diagnosis of fatty liver is present, "we should actually include other comorbidities, like obesity, dyslipidemia, which means cholesterol problem, diabetes, sugar problem, pre-diabetes, and hypertension. At least 50–70–80 percent of these patients will have one or more of these comorbidities".

Why Alcohol Is Not The Only Culprit For Fatty Liver

Although alcohol has remained the number one risk for liver disease, MASLD seems to be rising globally, including among people who do not drink. Why?

The reasons include:

a sedentary lifestyle,

increased consumption of fast and processed food,

lack of exercise,

lack of sleep,

stressful life.

Also read: Why Regular Scans Are Crucial for Liver Cancer Patients: Doctors Explain

The experts noted that food, especially the increasingly accessible junk food or processed food, is a major culprit.

“So even if the person is not drinking alcohol, people are developing addiction to processed food, and this is causing an epidemic level of obesity and diabetes. Consequently, MASLD is also increasing, and now it is becoming the number one cause of liver disease,” Dr Kumar said.

How To Prevent MASLD?

According to Dr. Sanjay Goja, Director, Liver Transplant & HPB Surgery, Narayana Hospital, Gurugram, prevention must focus on following a healthy lifestyle like maintaining a healthy BMI, engaging in regular physical activity, and eating a balanced diet.

Controlling diabetes, cholesterol, and blood pressure is also important to prevent the risk of MASLD.

Dr Siddharth Badola, Manipal Hospital, Ghaziabad, suggested sustainable lifestyle changes such as:

Maintaining an adequate body weight: Even slight weight loss (5–10 percent) has been shown to significantly reduce liver fat and inflammation.

Follow a balanced and nutrient-rich diet: People should focus on consuming whole grains, fresh fruits and vegetables, lean proteins, and healthy fats, while limiting refined carbohydrates and processed foods.

Avoid foods with added sugar: Excess consumption of fructose, commonly found in packaged foods and sugary beverages, is a key contributor to fat accumulation in the liver.

Engage in regular physical activity: At least 150 minutes of moderate-intensity exercise per week is recommended to improve insulin sensitivity and liver health.

Manage associated metabolic conditions: Effective control of diabetes, hypertension, and dyslipidemia is essential in reducing the risk of MASLD progression.

Ensure adequate sleep and stress management: Poor sleep quality and chronic stress can negatively impact metabolic balance and liver function.

Keep your body hydrated with ample water intake and follow structured meal timings.