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When to prescribe semaglutide?
A 36-year-old woman presents to your office for assistance with weight loss. She usually weighs around 150 lb, but she had two pregnancies in the past 4 years and has gained 70 lb. Her current weight is 220 lb with a body mass index (BMI) of 36.6 kg/m2, and she has been unable to lose any weight despite diet and exercise. She reports back pain and generalized fatigue but is primarily worried about developing type 2 diabetes, which runs in her family. Her insurance covers weight loss medications, but
More and more people are turning to “medical weight management” to drop pounds and improve their health. This is a strategy that adds pharmacotherapy to lifestyle modifications to treat the chronic disease of obesity, and it is analogous to the treatment of high blood pressure or high cholesterol with medications.
This patient meets the criteria set forth by the American Heart Association, American College of Cardiology, and The Obesity Society for the management of obesity with antiobesity medications:
- BMI ≥ 30 or BMI ≥ 27 with weight-related comorbidities and
- Has been unable to achieve ≥ 5% weight loss with lifestyle changes alone.
Several U.S. Food and Drug Administration–approved antiobesity medications have been proven to cause clinically significant weight loss:
- orlistat (Alli or Xenical).
- phentermine/topiramate (Qsymia).
- naltrexone/bupropion (Contrave).
- liraglutide 3.0 mg subcutaneously daily (Saxenda).
- semaglutide 2.4 mg subcutaneously weekly (Wegovy).
When considering an antiobesity medication for a patient, it’s important to discuss efficacy, side-effect profile, contraindications, cost and coverage, and long-term use.
In this commentary, we’ll specifically focus on semaglutide (Wegovy) as it is currently the most effective FDA-approved medication for weight loss.
Efficacy
In a phase 3 clinical trial, patients on semaglutide 2.4 mg weekly lost an average of 15% of their body weight at 68 weeks, or approximately 33 lb. It is important to note that there is variability in treatment response to semaglutide 2.4 mg, just like with any other medication. About 1 in 3 individuals lost ≥ 20% of their weight, but about 1 in every 10 patients did not lose any weight.
In this patient, who has a family history of type 2 diabetes, weight loss with semaglutide 2.4 mg will probably reduce her risk of developing diabetes. With just 5%-10% weight loss, she will see improvements in her blood glucose, blood pressure, and cholesterol. Even greater weight loss (≥ 10%) has been associated with resolution of fatty liver and sleep apnea.
Side effects
Before starting semaglutide, patients should be counseled about potential gastrointestinal side effects, including nausea, upset stomach, diarrhea, constipation, and reflux.
Side effects can be managed with dietary modifications, over-the-counter treatments, and slow dose escalation. Some common tips include:
- Eat slowly.
- Eat a bland diet.
- Avoid fatty or fried foods.
- Avoid lying down immediately after eating.
- Prioritize water and fiber intake to mitigate constipation.
- Use over-the-counter treatments as needed (for example, laxative for constipation).
Most of these side effects are present only during dose escalation and resolve once the patient is on a stable dose.
Patients should be counseled about the less than 1% risk for gallbladder issues or pancreatitis. They should be instructed to go to an urgent care or emergency room if they develop severe abdominal pain, recurrent vomiting, or the inability to eat or drink.
Contraindications
We don’t prescribe GLP-1 receptor agonists, including semaglutide 2.4 mg, in patients with a personal or family history of medullary thyroid cancer. GLP-1 agonists are contraindicated in patients with a history of pancreatitis or gastroparesis. All FDA-approved antiobesity medications are contraindicated in women who are breastfeeding or trying for pregnancy. If this patient would like to pursue pregnancy again, semaglutide 2.4 mg should be stopped 2 months prior to conception.
Access
In this case, the patient’s insurance covered semaglutide 2.4 mg with a copay of $25 per month. Without insurance, semaglutide 2.4 mg (Wegovy) costs about $1,400 per month, and semaglutide 2.0 mg (Ozempic), the formulation approved for type 2 diabetes, costs up to $1,000 per month. These price ranges are often cost-prohibitive and unsustainable, especially because these medications are intended for long-term use.
Currently, Medicare does not cover antiobesity medications nor do most state Medicaid plans. Therefore, these medications are usually not considered by patients who have Medicare or Medicaid insurance.
Because insurance coverage varies and out-of-pocket costs can be prohibitive, many individuals seek other ways of acquiring semaglutide. The off-label use of semaglutide 2.0 mg (Ozempic) for obesity is scientifically supported and safe, whereas the use of compounded semaglutide is risky due to lack of regulation.
Compounded semaglutide should be avoided, given that these products are not controlled by the FDA, and adverse events have been reported in connection with compounded semaglutide.
In our clinical practice, patients have reported advertisements for “generic semaglutide” compounded with vitamins like vitamin B12 or B6. This is a significant area of concern because some vitamins (for instance, vitamin B6) are toxic at high doses.
We discussed the dangers of compounded semaglutide with our patient and told her that this isn’t something we recommend prescribing. If the patient didn’t want to wait for semaglutide 2.4 mg to be available at her pharmacy, we discussed alternative medications used for the management of obesity, such as other FDA-approved GLP-1 agonists (that is, liraglutide 3.0 mg) and off-label medications. In this case, the patient opted to wait for semaglutide 2.4 mg because she preferred a weekly injectable medication, given her busy lifestyle as a new mom.
Dr. Schmitz, of Weill Cornell Medicine, New York, disclosed no relevant financial relationships. Dr. Tchang, of Weill Cornell Medicine and the Iris Cantor Women's Health Center, both in New York, serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for Gelesis and Novo Nordisk, and has received income from Gelesis.
A version of this article first appeared on Medscape.com.
A 36-year-old woman presents to your office for assistance with weight loss. She usually weighs around 150 lb, but she had two pregnancies in the past 4 years and has gained 70 lb. Her current weight is 220 lb with a body mass index (BMI) of 36.6 kg/m2, and she has been unable to lose any weight despite diet and exercise. She reports back pain and generalized fatigue but is primarily worried about developing type 2 diabetes, which runs in her family. Her insurance covers weight loss medications, but
More and more people are turning to “medical weight management” to drop pounds and improve their health. This is a strategy that adds pharmacotherapy to lifestyle modifications to treat the chronic disease of obesity, and it is analogous to the treatment of high blood pressure or high cholesterol with medications.
This patient meets the criteria set forth by the American Heart Association, American College of Cardiology, and The Obesity Society for the management of obesity with antiobesity medications:
- BMI ≥ 30 or BMI ≥ 27 with weight-related comorbidities and
- Has been unable to achieve ≥ 5% weight loss with lifestyle changes alone.
Several U.S. Food and Drug Administration–approved antiobesity medications have been proven to cause clinically significant weight loss:
- orlistat (Alli or Xenical).
- phentermine/topiramate (Qsymia).
- naltrexone/bupropion (Contrave).
- liraglutide 3.0 mg subcutaneously daily (Saxenda).
- semaglutide 2.4 mg subcutaneously weekly (Wegovy).
When considering an antiobesity medication for a patient, it’s important to discuss efficacy, side-effect profile, contraindications, cost and coverage, and long-term use.
In this commentary, we’ll specifically focus on semaglutide (Wegovy) as it is currently the most effective FDA-approved medication for weight loss.
Efficacy
In a phase 3 clinical trial, patients on semaglutide 2.4 mg weekly lost an average of 15% of their body weight at 68 weeks, or approximately 33 lb. It is important to note that there is variability in treatment response to semaglutide 2.4 mg, just like with any other medication. About 1 in 3 individuals lost ≥ 20% of their weight, but about 1 in every 10 patients did not lose any weight.
In this patient, who has a family history of type 2 diabetes, weight loss with semaglutide 2.4 mg will probably reduce her risk of developing diabetes. With just 5%-10% weight loss, she will see improvements in her blood glucose, blood pressure, and cholesterol. Even greater weight loss (≥ 10%) has been associated with resolution of fatty liver and sleep apnea.
Side effects
Before starting semaglutide, patients should be counseled about potential gastrointestinal side effects, including nausea, upset stomach, diarrhea, constipation, and reflux.
Side effects can be managed with dietary modifications, over-the-counter treatments, and slow dose escalation. Some common tips include:
- Eat slowly.
- Eat a bland diet.
- Avoid fatty or fried foods.
- Avoid lying down immediately after eating.
- Prioritize water and fiber intake to mitigate constipation.
- Use over-the-counter treatments as needed (for example, laxative for constipation).
Most of these side effects are present only during dose escalation and resolve once the patient is on a stable dose.
Patients should be counseled about the less than 1% risk for gallbladder issues or pancreatitis. They should be instructed to go to an urgent care or emergency room if they develop severe abdominal pain, recurrent vomiting, or the inability to eat or drink.
Contraindications
We don’t prescribe GLP-1 receptor agonists, including semaglutide 2.4 mg, in patients with a personal or family history of medullary thyroid cancer. GLP-1 agonists are contraindicated in patients with a history of pancreatitis or gastroparesis. All FDA-approved antiobesity medications are contraindicated in women who are breastfeeding or trying for pregnancy. If this patient would like to pursue pregnancy again, semaglutide 2.4 mg should be stopped 2 months prior to conception.
Access
In this case, the patient’s insurance covered semaglutide 2.4 mg with a copay of $25 per month. Without insurance, semaglutide 2.4 mg (Wegovy) costs about $1,400 per month, and semaglutide 2.0 mg (Ozempic), the formulation approved for type 2 diabetes, costs up to $1,000 per month. These price ranges are often cost-prohibitive and unsustainable, especially because these medications are intended for long-term use.
Currently, Medicare does not cover antiobesity medications nor do most state Medicaid plans. Therefore, these medications are usually not considered by patients who have Medicare or Medicaid insurance.
Because insurance coverage varies and out-of-pocket costs can be prohibitive, many individuals seek other ways of acquiring semaglutide. The off-label use of semaglutide 2.0 mg (Ozempic) for obesity is scientifically supported and safe, whereas the use of compounded semaglutide is risky due to lack of regulation.
Compounded semaglutide should be avoided, given that these products are not controlled by the FDA, and adverse events have been reported in connection with compounded semaglutide.
In our clinical practice, patients have reported advertisements for “generic semaglutide” compounded with vitamins like vitamin B12 or B6. This is a significant area of concern because some vitamins (for instance, vitamin B6) are toxic at high doses.
We discussed the dangers of compounded semaglutide with our patient and told her that this isn’t something we recommend prescribing. If the patient didn’t want to wait for semaglutide 2.4 mg to be available at her pharmacy, we discussed alternative medications used for the management of obesity, such as other FDA-approved GLP-1 agonists (that is, liraglutide 3.0 mg) and off-label medications. In this case, the patient opted to wait for semaglutide 2.4 mg because she preferred a weekly injectable medication, given her busy lifestyle as a new mom.
Dr. Schmitz, of Weill Cornell Medicine, New York, disclosed no relevant financial relationships. Dr. Tchang, of Weill Cornell Medicine and the Iris Cantor Women's Health Center, both in New York, serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for Gelesis and Novo Nordisk, and has received income from Gelesis.
A version of this article first appeared on Medscape.com.
A 36-year-old woman presents to your office for assistance with weight loss. She usually weighs around 150 lb, but she had two pregnancies in the past 4 years and has gained 70 lb. Her current weight is 220 lb with a body mass index (BMI) of 36.6 kg/m2, and she has been unable to lose any weight despite diet and exercise. She reports back pain and generalized fatigue but is primarily worried about developing type 2 diabetes, which runs in her family. Her insurance covers weight loss medications, but
More and more people are turning to “medical weight management” to drop pounds and improve their health. This is a strategy that adds pharmacotherapy to lifestyle modifications to treat the chronic disease of obesity, and it is analogous to the treatment of high blood pressure or high cholesterol with medications.
This patient meets the criteria set forth by the American Heart Association, American College of Cardiology, and The Obesity Society for the management of obesity with antiobesity medications:
- BMI ≥ 30 or BMI ≥ 27 with weight-related comorbidities and
- Has been unable to achieve ≥ 5% weight loss with lifestyle changes alone.
Several U.S. Food and Drug Administration–approved antiobesity medications have been proven to cause clinically significant weight loss:
- orlistat (Alli or Xenical).
- phentermine/topiramate (Qsymia).
- naltrexone/bupropion (Contrave).
- liraglutide 3.0 mg subcutaneously daily (Saxenda).
- semaglutide 2.4 mg subcutaneously weekly (Wegovy).
When considering an antiobesity medication for a patient, it’s important to discuss efficacy, side-effect profile, contraindications, cost and coverage, and long-term use.
In this commentary, we’ll specifically focus on semaglutide (Wegovy) as it is currently the most effective FDA-approved medication for weight loss.
Efficacy
In a phase 3 clinical trial, patients on semaglutide 2.4 mg weekly lost an average of 15% of their body weight at 68 weeks, or approximately 33 lb. It is important to note that there is variability in treatment response to semaglutide 2.4 mg, just like with any other medication. About 1 in 3 individuals lost ≥ 20% of their weight, but about 1 in every 10 patients did not lose any weight.
In this patient, who has a family history of type 2 diabetes, weight loss with semaglutide 2.4 mg will probably reduce her risk of developing diabetes. With just 5%-10% weight loss, she will see improvements in her blood glucose, blood pressure, and cholesterol. Even greater weight loss (≥ 10%) has been associated with resolution of fatty liver and sleep apnea.
Side effects
Before starting semaglutide, patients should be counseled about potential gastrointestinal side effects, including nausea, upset stomach, diarrhea, constipation, and reflux.
Side effects can be managed with dietary modifications, over-the-counter treatments, and slow dose escalation. Some common tips include:
- Eat slowly.
- Eat a bland diet.
- Avoid fatty or fried foods.
- Avoid lying down immediately after eating.
- Prioritize water and fiber intake to mitigate constipation.
- Use over-the-counter treatments as needed (for example, laxative for constipation).
Most of these side effects are present only during dose escalation and resolve once the patient is on a stable dose.
Patients should be counseled about the less than 1% risk for gallbladder issues or pancreatitis. They should be instructed to go to an urgent care or emergency room if they develop severe abdominal pain, recurrent vomiting, or the inability to eat or drink.
Contraindications
We don’t prescribe GLP-1 receptor agonists, including semaglutide 2.4 mg, in patients with a personal or family history of medullary thyroid cancer. GLP-1 agonists are contraindicated in patients with a history of pancreatitis or gastroparesis. All FDA-approved antiobesity medications are contraindicated in women who are breastfeeding or trying for pregnancy. If this patient would like to pursue pregnancy again, semaglutide 2.4 mg should be stopped 2 months prior to conception.
Access
In this case, the patient’s insurance covered semaglutide 2.4 mg with a copay of $25 per month. Without insurance, semaglutide 2.4 mg (Wegovy) costs about $1,400 per month, and semaglutide 2.0 mg (Ozempic), the formulation approved for type 2 diabetes, costs up to $1,000 per month. These price ranges are often cost-prohibitive and unsustainable, especially because these medications are intended for long-term use.
Currently, Medicare does not cover antiobesity medications nor do most state Medicaid plans. Therefore, these medications are usually not considered by patients who have Medicare or Medicaid insurance.
Because insurance coverage varies and out-of-pocket costs can be prohibitive, many individuals seek other ways of acquiring semaglutide. The off-label use of semaglutide 2.0 mg (Ozempic) for obesity is scientifically supported and safe, whereas the use of compounded semaglutide is risky due to lack of regulation.
Compounded semaglutide should be avoided, given that these products are not controlled by the FDA, and adverse events have been reported in connection with compounded semaglutide.
In our clinical practice, patients have reported advertisements for “generic semaglutide” compounded with vitamins like vitamin B12 or B6. This is a significant area of concern because some vitamins (for instance, vitamin B6) are toxic at high doses.
We discussed the dangers of compounded semaglutide with our patient and told her that this isn’t something we recommend prescribing. If the patient didn’t want to wait for semaglutide 2.4 mg to be available at her pharmacy, we discussed alternative medications used for the management of obesity, such as other FDA-approved GLP-1 agonists (that is, liraglutide 3.0 mg) and off-label medications. In this case, the patient opted to wait for semaglutide 2.4 mg because she preferred a weekly injectable medication, given her busy lifestyle as a new mom.
Dr. Schmitz, of Weill Cornell Medicine, New York, disclosed no relevant financial relationships. Dr. Tchang, of Weill Cornell Medicine and the Iris Cantor Women's Health Center, both in New York, serves or has served as a director, officer, partner, employee, advisor, consultant, or trustee for Gelesis and Novo Nordisk, and has received income from Gelesis.
A version of this article first appeared on Medscape.com.
Obesity in GI care
While AGA’s advocacy efforts related to access to colorectal cancer screening are frequently highlighted, this is one aspect of a larger advocacy agenda.
This month, I wish to highlight AGA’s extensive advocacy efforts focused on expanding access to obesity treatment. More than 2 in 5 adults in the U.S. have obesity, and weight management has been shown to be beneficial in patients with comorbid gastrointestinal diseases, such as metabolic dysfunction–associated steatotic liver disease, gastroesophageal reflux disease, gallbladder disease, pancreatitis, and GI malignancy.
In 2022, Inside Scope, a podcast by AGA, featured a 6-part seriescalled “Obesity in GI.” In July, Drs. Octavia Pickett-Blakely and Naresh Gunaratnam moderated a Gastro Bites lunch-and-learn session on “Obesity in GI Care – Embracing and Putting It into Practice” in which they discussed models of care delivery supporting obesity management in GI practice.
In November 2022, AGA released “AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity,” (https://shorturl.at/bDNOV) to aid clinicians in appropriately prescribing obesity pharmacotherapy on the front lines of care.
On the policy front, in June, AGA held a Capitol Hill briefing in support of H.R.1577 - Treat and Reduce Obesity Act of 2021 (TROA), a bipartisan bill that would improve access to obesity treatment and care by expanding coverage under Medicare Part D for FDA-approved obesity pharmacotherapy, as well as related services such as behavioral, nutrition, and other counseling. Please check out our new obesity advocacy toolkit for more information.
This month we update you on important multi-society guidance regarding peri-endoscopic management of GLP-1 receptor agonists. We highlight new AGA Clinical Practice Updates on ostomy management and use of gastric POEM for treatment of gastroparesis, as well as a randomized controlled trial from Gastroenterology showing the effectiveness of hemostatic powder in the management of malignant GI bleeding as compared with standard care.
In our Member Spotlight, we feature gastroenterologist Sameer Berry, MD, MBA, who discusses his role as a physician-entrepreneur seeking to transform GI care delivery through his AGA GI Opportunity Fund–supported company, Oshi Health.
This issue includes our annual supplement, “Gastroenterology Data Trends.” It features a collection of contributions on GI and climate change, long COVID and the GI tract, and the evolution of targeted therapies for C. difficile, among others.
We hope you enjoy this, and all the exciting content included in our October issue.
Megan A. Adams, MD, JD, MSc
While AGA’s advocacy efforts related to access to colorectal cancer screening are frequently highlighted, this is one aspect of a larger advocacy agenda.
This month, I wish to highlight AGA’s extensive advocacy efforts focused on expanding access to obesity treatment. More than 2 in 5 adults in the U.S. have obesity, and weight management has been shown to be beneficial in patients with comorbid gastrointestinal diseases, such as metabolic dysfunction–associated steatotic liver disease, gastroesophageal reflux disease, gallbladder disease, pancreatitis, and GI malignancy.
In 2022, Inside Scope, a podcast by AGA, featured a 6-part seriescalled “Obesity in GI.” In July, Drs. Octavia Pickett-Blakely and Naresh Gunaratnam moderated a Gastro Bites lunch-and-learn session on “Obesity in GI Care – Embracing and Putting It into Practice” in which they discussed models of care delivery supporting obesity management in GI practice.
In November 2022, AGA released “AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity,” (https://shorturl.at/bDNOV) to aid clinicians in appropriately prescribing obesity pharmacotherapy on the front lines of care.
On the policy front, in June, AGA held a Capitol Hill briefing in support of H.R.1577 - Treat and Reduce Obesity Act of 2021 (TROA), a bipartisan bill that would improve access to obesity treatment and care by expanding coverage under Medicare Part D for FDA-approved obesity pharmacotherapy, as well as related services such as behavioral, nutrition, and other counseling. Please check out our new obesity advocacy toolkit for more information.
This month we update you on important multi-society guidance regarding peri-endoscopic management of GLP-1 receptor agonists. We highlight new AGA Clinical Practice Updates on ostomy management and use of gastric POEM for treatment of gastroparesis, as well as a randomized controlled trial from Gastroenterology showing the effectiveness of hemostatic powder in the management of malignant GI bleeding as compared with standard care.
In our Member Spotlight, we feature gastroenterologist Sameer Berry, MD, MBA, who discusses his role as a physician-entrepreneur seeking to transform GI care delivery through his AGA GI Opportunity Fund–supported company, Oshi Health.
This issue includes our annual supplement, “Gastroenterology Data Trends.” It features a collection of contributions on GI and climate change, long COVID and the GI tract, and the evolution of targeted therapies for C. difficile, among others.
We hope you enjoy this, and all the exciting content included in our October issue.
Megan A. Adams, MD, JD, MSc
While AGA’s advocacy efforts related to access to colorectal cancer screening are frequently highlighted, this is one aspect of a larger advocacy agenda.
This month, I wish to highlight AGA’s extensive advocacy efforts focused on expanding access to obesity treatment. More than 2 in 5 adults in the U.S. have obesity, and weight management has been shown to be beneficial in patients with comorbid gastrointestinal diseases, such as metabolic dysfunction–associated steatotic liver disease, gastroesophageal reflux disease, gallbladder disease, pancreatitis, and GI malignancy.
In 2022, Inside Scope, a podcast by AGA, featured a 6-part seriescalled “Obesity in GI.” In July, Drs. Octavia Pickett-Blakely and Naresh Gunaratnam moderated a Gastro Bites lunch-and-learn session on “Obesity in GI Care – Embracing and Putting It into Practice” in which they discussed models of care delivery supporting obesity management in GI practice.
In November 2022, AGA released “AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity,” (https://shorturl.at/bDNOV) to aid clinicians in appropriately prescribing obesity pharmacotherapy on the front lines of care.
On the policy front, in June, AGA held a Capitol Hill briefing in support of H.R.1577 - Treat and Reduce Obesity Act of 2021 (TROA), a bipartisan bill that would improve access to obesity treatment and care by expanding coverage under Medicare Part D for FDA-approved obesity pharmacotherapy, as well as related services such as behavioral, nutrition, and other counseling. Please check out our new obesity advocacy toolkit for more information.
This month we update you on important multi-society guidance regarding peri-endoscopic management of GLP-1 receptor agonists. We highlight new AGA Clinical Practice Updates on ostomy management and use of gastric POEM for treatment of gastroparesis, as well as a randomized controlled trial from Gastroenterology showing the effectiveness of hemostatic powder in the management of malignant GI bleeding as compared with standard care.
In our Member Spotlight, we feature gastroenterologist Sameer Berry, MD, MBA, who discusses his role as a physician-entrepreneur seeking to transform GI care delivery through his AGA GI Opportunity Fund–supported company, Oshi Health.
This issue includes our annual supplement, “Gastroenterology Data Trends.” It features a collection of contributions on GI and climate change, long COVID and the GI tract, and the evolution of targeted therapies for C. difficile, among others.
We hope you enjoy this, and all the exciting content included in our October issue.
Megan A. Adams, MD, JD, MSc
FDA gives semaglutide two drug safety–related label changes
The FDA added a warning to the drug-interaction section of the Ozempiclabel that reiterates a warning that is already in place in other label sections, reinforcing the message that the glucagon-like peptide-1 (GLP-1) receptor agonist Ozempiccan potentially interact with the action of certain other agents to increase a person’s risk for hypoglycemia.
The added text says: “Ozempic stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving Ozempic in combination with an insulin secretagogue (for instance, sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.”
This text was already included in both the “Warning and Precautions” and the “Adverse Reactions” sections of the label. The warning also advises, “The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.”
Reports of ileus episodes after approval
The second addition concerns a new adverse reaction that was identified during the postmarketing experience.
The FDA has received more than 8,500 reports of gastrointestinal issues among patients prescribed glucagon-like peptide-1 (GLP-1) receptor agonists. Ileus is mentioned in 33 cases, including two deaths, associated with semaglutide. The FDA stopped short of saying there is a direct link between the drug and intestinal blockages.
“Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the FDA stated in its approval of the label update.
The same warning for the risk of intestinal blockages is already listed on the labels for tirzepatide (Mounjaro, Lilly) and semaglutide injection 2.4 mg (Wegovy, Novo Nordisk).
The label change comes after a Louisiana woman filed a lawsuit in August that claims she was “severely injured” after using Mounjaro and Ozempic. She claimed the drug makers failed to disclose risks of vomiting and diarrhea due to inflammation of the stomach lining, as well as the risk of gastroparesis.
*Correction, 10/3/23: An earlier version of this article misstated the semaglutide formulation that received the updates.
A version of this article first appeared on Medscape.com.
The FDA added a warning to the drug-interaction section of the Ozempiclabel that reiterates a warning that is already in place in other label sections, reinforcing the message that the glucagon-like peptide-1 (GLP-1) receptor agonist Ozempiccan potentially interact with the action of certain other agents to increase a person’s risk for hypoglycemia.
The added text says: “Ozempic stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving Ozempic in combination with an insulin secretagogue (for instance, sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.”
This text was already included in both the “Warning and Precautions” and the “Adverse Reactions” sections of the label. The warning also advises, “The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.”
Reports of ileus episodes after approval
The second addition concerns a new adverse reaction that was identified during the postmarketing experience.
The FDA has received more than 8,500 reports of gastrointestinal issues among patients prescribed glucagon-like peptide-1 (GLP-1) receptor agonists. Ileus is mentioned in 33 cases, including two deaths, associated with semaglutide. The FDA stopped short of saying there is a direct link between the drug and intestinal blockages.
“Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the FDA stated in its approval of the label update.
The same warning for the risk of intestinal blockages is already listed on the labels for tirzepatide (Mounjaro, Lilly) and semaglutide injection 2.4 mg (Wegovy, Novo Nordisk).
The label change comes after a Louisiana woman filed a lawsuit in August that claims she was “severely injured” after using Mounjaro and Ozempic. She claimed the drug makers failed to disclose risks of vomiting and diarrhea due to inflammation of the stomach lining, as well as the risk of gastroparesis.
*Correction, 10/3/23: An earlier version of this article misstated the semaglutide formulation that received the updates.
A version of this article first appeared on Medscape.com.
The FDA added a warning to the drug-interaction section of the Ozempiclabel that reiterates a warning that is already in place in other label sections, reinforcing the message that the glucagon-like peptide-1 (GLP-1) receptor agonist Ozempiccan potentially interact with the action of certain other agents to increase a person’s risk for hypoglycemia.
The added text says: “Ozempic stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving Ozempic in combination with an insulin secretagogue (for instance, sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.”
This text was already included in both the “Warning and Precautions” and the “Adverse Reactions” sections of the label. The warning also advises, “The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.”
Reports of ileus episodes after approval
The second addition concerns a new adverse reaction that was identified during the postmarketing experience.
The FDA has received more than 8,500 reports of gastrointestinal issues among patients prescribed glucagon-like peptide-1 (GLP-1) receptor agonists. Ileus is mentioned in 33 cases, including two deaths, associated with semaglutide. The FDA stopped short of saying there is a direct link between the drug and intestinal blockages.
“Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the FDA stated in its approval of the label update.
The same warning for the risk of intestinal blockages is already listed on the labels for tirzepatide (Mounjaro, Lilly) and semaglutide injection 2.4 mg (Wegovy, Novo Nordisk).
The label change comes after a Louisiana woman filed a lawsuit in August that claims she was “severely injured” after using Mounjaro and Ozempic. She claimed the drug makers failed to disclose risks of vomiting and diarrhea due to inflammation of the stomach lining, as well as the risk of gastroparesis.
*Correction, 10/3/23: An earlier version of this article misstated the semaglutide formulation that received the updates.
A version of this article first appeared on Medscape.com.
Gastroenterology Data Trends 2023
GI&Hepatology News and the American Gastroenterological Association present the 2023 issue of Gastroenterology Data Trends, a special report on hot topics in gastroenterology told through original infographics and visual storytelling.
In this issue:
- Gastroenterology and Climate Change: Assessing and Mitigating Impacts
Swapna Gayam, MD, FACG - MASLD/MASH and Weight Loss
Arpan Mohanty, MD, MSc - Digital Tools in the Management of IBS/Functional GI Disorders
Eric D. Shah, MD, MBA, FACG - Long COVID and the Gastrointestinal System: Emerging Evidence
Daniel E. Freedberg, MD, MS, and Lin Chang, MD, AGAF - Germline Genetic Testing in CRC: Implications for Familial and Population-Based Testing
Fay Kastrinos, MD, MPH - Evolution of Targeted Therapies for C difficile
Sahil Khanna, MBBS, MS, FACG, AGAF - Harnessing the Power of AI to Enhance Endoscopy: Promises and Pitfalls
Eugenia Uche-Anya, MD, MPH - The Evolving Role of Surgery for IBD
Julie K.M. Thacker, MD, FACS, FASCRS
GI&Hepatology News and the American Gastroenterological Association present the 2023 issue of Gastroenterology Data Trends, a special report on hot topics in gastroenterology told through original infographics and visual storytelling.
In this issue:
- Gastroenterology and Climate Change: Assessing and Mitigating Impacts
Swapna Gayam, MD, FACG - MASLD/MASH and Weight Loss
Arpan Mohanty, MD, MSc - Digital Tools in the Management of IBS/Functional GI Disorders
Eric D. Shah, MD, MBA, FACG - Long COVID and the Gastrointestinal System: Emerging Evidence
Daniel E. Freedberg, MD, MS, and Lin Chang, MD, AGAF - Germline Genetic Testing in CRC: Implications for Familial and Population-Based Testing
Fay Kastrinos, MD, MPH - Evolution of Targeted Therapies for C difficile
Sahil Khanna, MBBS, MS, FACG, AGAF - Harnessing the Power of AI to Enhance Endoscopy: Promises and Pitfalls
Eugenia Uche-Anya, MD, MPH - The Evolving Role of Surgery for IBD
Julie K.M. Thacker, MD, FACS, FASCRS
GI&Hepatology News and the American Gastroenterological Association present the 2023 issue of Gastroenterology Data Trends, a special report on hot topics in gastroenterology told through original infographics and visual storytelling.
In this issue:
- Gastroenterology and Climate Change: Assessing and Mitigating Impacts
Swapna Gayam, MD, FACG - MASLD/MASH and Weight Loss
Arpan Mohanty, MD, MSc - Digital Tools in the Management of IBS/Functional GI Disorders
Eric D. Shah, MD, MBA, FACG - Long COVID and the Gastrointestinal System: Emerging Evidence
Daniel E. Freedberg, MD, MS, and Lin Chang, MD, AGAF - Germline Genetic Testing in CRC: Implications for Familial and Population-Based Testing
Fay Kastrinos, MD, MPH - Evolution of Targeted Therapies for C difficile
Sahil Khanna, MBBS, MS, FACG, AGAF - Harnessing the Power of AI to Enhance Endoscopy: Promises and Pitfalls
Eugenia Uche-Anya, MD, MPH - The Evolving Role of Surgery for IBD
Julie K.M. Thacker, MD, FACS, FASCRS
The ‘triple-G’ agonist for obesity management: Five things to know
The complex pathophysiology of obesity requires a multidisciplinary approach that includes lifestyle and medical interventions for successful management. Antiobesity medications (AOMs) have emerged as a powerful and life-changing tool for many individuals with obesity who are unable to sustain long-term weight loss through lifestyle changes alone. As with other chronic diseases such as hypertension and hyperlipidemia, the goal of decades of research has been to develop antiobesity medications with long-term efficacy and safety. Recent groundbreaking findings from a phase 2 trial show immense potential for a new AOM.
1. Gut hormone physiology informs the development of AOMs.
The three hormones associated with obesity or diabetes are glucagonlike peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. GLP-1, a peptide released from the intestines in response to food ingestion, increases insulin production, reduces gut motility, and suppresses appetite. GIP is also an intestinal hormone that increases meal-stimulated insulin production and additionally facilitates lipolysis. Glucagon is known to increase hepatic glucose output but will also increase insulin secretion in the setting of hyperglycemia. Glucagon also promotes lipolysis.
Though these hormones are more commonly thought of as incretins, gut hormones that stimulate postprandial insulin secretion, their role in energy physiology is more diverse. Because of multiple mechanisms of action, incretins are increasingly referred to as nutrient-stimulated hormones (NuSH), a term which encompasses other peptides with therapeutic potential (e.g., amylin, oxyntomodulin, peptide tyrosine–tyrosine).
2. Studies have shown that NuSH therapies are highly effective AOMs.
In 2021 the Food and Drug Administration approved subcutaneous semaglutide 2.4 mg, a GLP-1 receptor agonist, for the treatment of obesity. Clinical trials demonstrating an average weight loss of 15% in patients taking semaglutide ushered in a new era of AOMs associated with significant weight loss that not only improve disease activity but also have the potential to achieve diabetes remission. Recent findings from the OASIS I trial demonstrated an average weight loss of 15.1% from baseline in patients treated with oral semaglutide for 68 weeks. Medical societies, including the American Diabetes Association and the American Association for the Study of Liver Diseases, recommend 10%-15% weight loss to fully treat weight-related comorbidities like type 2 diabetes and nonalcoholic fatty liver disease. In 2022, tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated an average weight loss of 22.5% in phase 3 of the SURMOUNT-1 trial for obesity – a weight loss approaching that of some bariatric surgeries.
3. Clinical trial data show that the novel triple agonist retatrutide induces significant weight loss.
Preclinical studies on the newest NuSH therapy, triple GLP-1–GIP–glucagon receptor agonist retatrutide, showed predominant activity at the GIP receptor, with less GLP-1– and glucagon-receptor agonism than that of endogenous GLP-1 and GIP. Results from a phase 2 trial published in June 2023 showed a weight loss of 24% at 48 weeks in adults with obesity treated with retatrutide, which is the greatest weight loss reported in an obesity trial so far. Moreover, for the first time in obesity pharmacotherapy research, 100% of participants achieved clinically significant weight loss (defined as ≥ 5% of baseline weight).
4. Retatrutide may improve lipid metabolism.
In the phase 2 trial, retatrutide reduced low-density lipoprotein cholesterol levels by approximately 20%. This degree of reduced plasma LDL-C is dramatic in weight loss studies. Typically, weight loss significantly reduces triglyceride levels, increases high-density lipoprotein cholesterol levels, and has a modest effect on LDL-C reduction of about 5%.
A 20% reduction in LDL-C with retatrutide is hypothesis generating. Preclinical studies have shown glucagon to be an important regulator of proprotein convertase subtilisin/kexin type 9 degradation, with the lack of glucagon resulting in increased PCSK9 levels, decreased LDL receptors, and increased plasma LDL; conversely, treatment with glucagon decreased plasma LDL.
5. The long-term safety of retatrutide still needs to be determined.
In the 48-week phase 2 trial, retatrutide was observed to have a side-effect profile largely similar to other NuSH therapies (e.g., semaglutide 2.4 mg, tirzepatide), with a predominance of gastrointestinal symptoms including nausea, diarrhea, vomiting, and constipation. However, side effects potentially unique to retatrutide also emerged. Cutaneous hyperesthesia and skin sensitivity were reported in 7% of participants in the retatrutide group vs. 1% in the placebo group; none of these effects were associated with physical skin findings. Of note, 17 out of 198 (9%) participants in the retatrutide group developed cardiac arrhythmia vs. two out of 70 (3%) in the placebo group. There was no consistent pattern of arrhythmia type (e.g., supraventricular, ventricular) observed, and some of these events were reported as “palpitations” or “increased heart rate” without further detail. Phase 3 clinical trial data will provide further insight into the long-term safety of retatrutide.
Dr. Tchang is assistant professor of clinical medicine, division of endocrinology, Weill Cornell Medicine and physician, department of medicine, New York-Presbyterian/Weill Cornell Medical Center, both in New York. She has disclosed ties with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
The complex pathophysiology of obesity requires a multidisciplinary approach that includes lifestyle and medical interventions for successful management. Antiobesity medications (AOMs) have emerged as a powerful and life-changing tool for many individuals with obesity who are unable to sustain long-term weight loss through lifestyle changes alone. As with other chronic diseases such as hypertension and hyperlipidemia, the goal of decades of research has been to develop antiobesity medications with long-term efficacy and safety. Recent groundbreaking findings from a phase 2 trial show immense potential for a new AOM.
1. Gut hormone physiology informs the development of AOMs.
The three hormones associated with obesity or diabetes are glucagonlike peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. GLP-1, a peptide released from the intestines in response to food ingestion, increases insulin production, reduces gut motility, and suppresses appetite. GIP is also an intestinal hormone that increases meal-stimulated insulin production and additionally facilitates lipolysis. Glucagon is known to increase hepatic glucose output but will also increase insulin secretion in the setting of hyperglycemia. Glucagon also promotes lipolysis.
Though these hormones are more commonly thought of as incretins, gut hormones that stimulate postprandial insulin secretion, their role in energy physiology is more diverse. Because of multiple mechanisms of action, incretins are increasingly referred to as nutrient-stimulated hormones (NuSH), a term which encompasses other peptides with therapeutic potential (e.g., amylin, oxyntomodulin, peptide tyrosine–tyrosine).
2. Studies have shown that NuSH therapies are highly effective AOMs.
In 2021 the Food and Drug Administration approved subcutaneous semaglutide 2.4 mg, a GLP-1 receptor agonist, for the treatment of obesity. Clinical trials demonstrating an average weight loss of 15% in patients taking semaglutide ushered in a new era of AOMs associated with significant weight loss that not only improve disease activity but also have the potential to achieve diabetes remission. Recent findings from the OASIS I trial demonstrated an average weight loss of 15.1% from baseline in patients treated with oral semaglutide for 68 weeks. Medical societies, including the American Diabetes Association and the American Association for the Study of Liver Diseases, recommend 10%-15% weight loss to fully treat weight-related comorbidities like type 2 diabetes and nonalcoholic fatty liver disease. In 2022, tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated an average weight loss of 22.5% in phase 3 of the SURMOUNT-1 trial for obesity – a weight loss approaching that of some bariatric surgeries.
3. Clinical trial data show that the novel triple agonist retatrutide induces significant weight loss.
Preclinical studies on the newest NuSH therapy, triple GLP-1–GIP–glucagon receptor agonist retatrutide, showed predominant activity at the GIP receptor, with less GLP-1– and glucagon-receptor agonism than that of endogenous GLP-1 and GIP. Results from a phase 2 trial published in June 2023 showed a weight loss of 24% at 48 weeks in adults with obesity treated with retatrutide, which is the greatest weight loss reported in an obesity trial so far. Moreover, for the first time in obesity pharmacotherapy research, 100% of participants achieved clinically significant weight loss (defined as ≥ 5% of baseline weight).
4. Retatrutide may improve lipid metabolism.
In the phase 2 trial, retatrutide reduced low-density lipoprotein cholesterol levels by approximately 20%. This degree of reduced plasma LDL-C is dramatic in weight loss studies. Typically, weight loss significantly reduces triglyceride levels, increases high-density lipoprotein cholesterol levels, and has a modest effect on LDL-C reduction of about 5%.
A 20% reduction in LDL-C with retatrutide is hypothesis generating. Preclinical studies have shown glucagon to be an important regulator of proprotein convertase subtilisin/kexin type 9 degradation, with the lack of glucagon resulting in increased PCSK9 levels, decreased LDL receptors, and increased plasma LDL; conversely, treatment with glucagon decreased plasma LDL.
5. The long-term safety of retatrutide still needs to be determined.
In the 48-week phase 2 trial, retatrutide was observed to have a side-effect profile largely similar to other NuSH therapies (e.g., semaglutide 2.4 mg, tirzepatide), with a predominance of gastrointestinal symptoms including nausea, diarrhea, vomiting, and constipation. However, side effects potentially unique to retatrutide also emerged. Cutaneous hyperesthesia and skin sensitivity were reported in 7% of participants in the retatrutide group vs. 1% in the placebo group; none of these effects were associated with physical skin findings. Of note, 17 out of 198 (9%) participants in the retatrutide group developed cardiac arrhythmia vs. two out of 70 (3%) in the placebo group. There was no consistent pattern of arrhythmia type (e.g., supraventricular, ventricular) observed, and some of these events were reported as “palpitations” or “increased heart rate” without further detail. Phase 3 clinical trial data will provide further insight into the long-term safety of retatrutide.
Dr. Tchang is assistant professor of clinical medicine, division of endocrinology, Weill Cornell Medicine and physician, department of medicine, New York-Presbyterian/Weill Cornell Medical Center, both in New York. She has disclosed ties with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
The complex pathophysiology of obesity requires a multidisciplinary approach that includes lifestyle and medical interventions for successful management. Antiobesity medications (AOMs) have emerged as a powerful and life-changing tool for many individuals with obesity who are unable to sustain long-term weight loss through lifestyle changes alone. As with other chronic diseases such as hypertension and hyperlipidemia, the goal of decades of research has been to develop antiobesity medications with long-term efficacy and safety. Recent groundbreaking findings from a phase 2 trial show immense potential for a new AOM.
1. Gut hormone physiology informs the development of AOMs.
The three hormones associated with obesity or diabetes are glucagonlike peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. GLP-1, a peptide released from the intestines in response to food ingestion, increases insulin production, reduces gut motility, and suppresses appetite. GIP is also an intestinal hormone that increases meal-stimulated insulin production and additionally facilitates lipolysis. Glucagon is known to increase hepatic glucose output but will also increase insulin secretion in the setting of hyperglycemia. Glucagon also promotes lipolysis.
Though these hormones are more commonly thought of as incretins, gut hormones that stimulate postprandial insulin secretion, their role in energy physiology is more diverse. Because of multiple mechanisms of action, incretins are increasingly referred to as nutrient-stimulated hormones (NuSH), a term which encompasses other peptides with therapeutic potential (e.g., amylin, oxyntomodulin, peptide tyrosine–tyrosine).
2. Studies have shown that NuSH therapies are highly effective AOMs.
In 2021 the Food and Drug Administration approved subcutaneous semaglutide 2.4 mg, a GLP-1 receptor agonist, for the treatment of obesity. Clinical trials demonstrating an average weight loss of 15% in patients taking semaglutide ushered in a new era of AOMs associated with significant weight loss that not only improve disease activity but also have the potential to achieve diabetes remission. Recent findings from the OASIS I trial demonstrated an average weight loss of 15.1% from baseline in patients treated with oral semaglutide for 68 weeks. Medical societies, including the American Diabetes Association and the American Association for the Study of Liver Diseases, recommend 10%-15% weight loss to fully treat weight-related comorbidities like type 2 diabetes and nonalcoholic fatty liver disease. In 2022, tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated an average weight loss of 22.5% in phase 3 of the SURMOUNT-1 trial for obesity – a weight loss approaching that of some bariatric surgeries.
3. Clinical trial data show that the novel triple agonist retatrutide induces significant weight loss.
Preclinical studies on the newest NuSH therapy, triple GLP-1–GIP–glucagon receptor agonist retatrutide, showed predominant activity at the GIP receptor, with less GLP-1– and glucagon-receptor agonism than that of endogenous GLP-1 and GIP. Results from a phase 2 trial published in June 2023 showed a weight loss of 24% at 48 weeks in adults with obesity treated with retatrutide, which is the greatest weight loss reported in an obesity trial so far. Moreover, for the first time in obesity pharmacotherapy research, 100% of participants achieved clinically significant weight loss (defined as ≥ 5% of baseline weight).
4. Retatrutide may improve lipid metabolism.
In the phase 2 trial, retatrutide reduced low-density lipoprotein cholesterol levels by approximately 20%. This degree of reduced plasma LDL-C is dramatic in weight loss studies. Typically, weight loss significantly reduces triglyceride levels, increases high-density lipoprotein cholesterol levels, and has a modest effect on LDL-C reduction of about 5%.
A 20% reduction in LDL-C with retatrutide is hypothesis generating. Preclinical studies have shown glucagon to be an important regulator of proprotein convertase subtilisin/kexin type 9 degradation, with the lack of glucagon resulting in increased PCSK9 levels, decreased LDL receptors, and increased plasma LDL; conversely, treatment with glucagon decreased plasma LDL.
5. The long-term safety of retatrutide still needs to be determined.
In the 48-week phase 2 trial, retatrutide was observed to have a side-effect profile largely similar to other NuSH therapies (e.g., semaglutide 2.4 mg, tirzepatide), with a predominance of gastrointestinal symptoms including nausea, diarrhea, vomiting, and constipation. However, side effects potentially unique to retatrutide also emerged. Cutaneous hyperesthesia and skin sensitivity were reported in 7% of participants in the retatrutide group vs. 1% in the placebo group; none of these effects were associated with physical skin findings. Of note, 17 out of 198 (9%) participants in the retatrutide group developed cardiac arrhythmia vs. two out of 70 (3%) in the placebo group. There was no consistent pattern of arrhythmia type (e.g., supraventricular, ventricular) observed, and some of these events were reported as “palpitations” or “increased heart rate” without further detail. Phase 3 clinical trial data will provide further insight into the long-term safety of retatrutide.
Dr. Tchang is assistant professor of clinical medicine, division of endocrinology, Weill Cornell Medicine and physician, department of medicine, New York-Presbyterian/Weill Cornell Medical Center, both in New York. She has disclosed ties with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
Tirzepatide superior to semaglutide for A1c control, weight loss
, results from a meta-analysis of 22 randomized controlled trials show.
“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.
“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.
The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.
While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.
For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.
Overall, 18,472 participants were included in the studies.
All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
Blood glucose reduction
Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).
All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.
Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
Body weight reduction comparisons
The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).
In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
Adverse events: Increased GI events with highest tirzepatide dose
Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.
There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).
In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).
There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
Real-world applications, comparisons
Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.
“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.
Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.
Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.
Among other issues of comparison with the two drugs is cost.
In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.
Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.
Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.
Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.
Dr. Karagiannis reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, results from a meta-analysis of 22 randomized controlled trials show.
“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.
“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.
The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.
While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.
For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.
Overall, 18,472 participants were included in the studies.
All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
Blood glucose reduction
Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).
All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.
Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
Body weight reduction comparisons
The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).
In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
Adverse events: Increased GI events with highest tirzepatide dose
Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.
There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).
In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).
There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
Real-world applications, comparisons
Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.
“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.
Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.
Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.
Among other issues of comparison with the two drugs is cost.
In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.
Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.
Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.
Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.
Dr. Karagiannis reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, results from a meta-analysis of 22 randomized controlled trials show.
“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.
“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.
The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.
While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.
For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.
Overall, 18,472 participants were included in the studies.
All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
Blood glucose reduction
Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).
All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.
Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
Body weight reduction comparisons
The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).
In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
Adverse events: Increased GI events with highest tirzepatide dose
Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.
There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).
In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).
There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
Real-world applications, comparisons
Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.
“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.
Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.
Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.
Among other issues of comparison with the two drugs is cost.
In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.
Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.
Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.
Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.
Dr. Karagiannis reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EASD 2023
Waist-hip ratio a stronger mortality predictor than BMI
TOPLINE:
Compared with body mass index, waist-hip ratio (WHR) had the strongest and most consistent association with all-cause mortality and was the only measurement unaffected by BMI.
METHODOLOGY:
- Cohort study of incident deaths from the U.K. Biobank (2006-2022), including data from 22 centers across the United Kingdom.
- A total of 387,672 participants were divided into a discovery cohort (n = 337,078) and validation cohort (n = 50,594), with the latter consisting of 25,297 deaths and 2,297 controls.
- The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses.
- Exposure-outcome associations were analyzed through observational and mendelian randomization analyses.
TAKEAWAY:
- In adjusted analysis, a J-shaped association was found for both measured BMI and fat mass index (FMI), whereas the association with WHR was linear (hazard ratio 1.41 per standard deviation increase).
- There was a significant association between all three adiposity measures and all-cause mortality, with odds ratio 1.29 per SD change in genetically determined BMI (P = 1.44×10-13), 1.45 per SD change in genetically determined FMI, 1.45 (P = 6.27×10-30), and 1.51 per SD change in genetically determined WHR (P = 2.11×10-9).
- Compared with BMI, WHR had the stronger association with all-cause mortality, although it was not significantly stronger than FMI.
- The association of genetically determined BMI and FMI with all-cause mortality varied across quantiles of observed BMI, but WHR did not (P = .04, P = .02, and P = .58, for BMI, FMI, and WHR, respectively).
IN PRACTICE:
“Current World Health Organization recommendations for optimal BMI range are inaccurate across individuals with various body compositions and therefore suboptimal for clinical guidelines.”
SOURCE:
Study by Irfan Khan, MSc, of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton, Ont., and colleagues. Published online in JAMA Network Open.
LIMITATIONS:
Study population was genetically homogeneous, White, and British, so results may not be representative of other racial or ethnic groups.
DISCLOSURES:
Study was funded by, and Irfan Khan received support from, the Ontario Graduate Scholarship–Masters Scholarship, awarded by the government of Ontario.
A version of this article first appeared on Medscape.com.
TOPLINE:
Compared with body mass index, waist-hip ratio (WHR) had the strongest and most consistent association with all-cause mortality and was the only measurement unaffected by BMI.
METHODOLOGY:
- Cohort study of incident deaths from the U.K. Biobank (2006-2022), including data from 22 centers across the United Kingdom.
- A total of 387,672 participants were divided into a discovery cohort (n = 337,078) and validation cohort (n = 50,594), with the latter consisting of 25,297 deaths and 2,297 controls.
- The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses.
- Exposure-outcome associations were analyzed through observational and mendelian randomization analyses.
TAKEAWAY:
- In adjusted analysis, a J-shaped association was found for both measured BMI and fat mass index (FMI), whereas the association with WHR was linear (hazard ratio 1.41 per standard deviation increase).
- There was a significant association between all three adiposity measures and all-cause mortality, with odds ratio 1.29 per SD change in genetically determined BMI (P = 1.44×10-13), 1.45 per SD change in genetically determined FMI, 1.45 (P = 6.27×10-30), and 1.51 per SD change in genetically determined WHR (P = 2.11×10-9).
- Compared with BMI, WHR had the stronger association with all-cause mortality, although it was not significantly stronger than FMI.
- The association of genetically determined BMI and FMI with all-cause mortality varied across quantiles of observed BMI, but WHR did not (P = .04, P = .02, and P = .58, for BMI, FMI, and WHR, respectively).
IN PRACTICE:
“Current World Health Organization recommendations for optimal BMI range are inaccurate across individuals with various body compositions and therefore suboptimal for clinical guidelines.”
SOURCE:
Study by Irfan Khan, MSc, of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton, Ont., and colleagues. Published online in JAMA Network Open.
LIMITATIONS:
Study population was genetically homogeneous, White, and British, so results may not be representative of other racial or ethnic groups.
DISCLOSURES:
Study was funded by, and Irfan Khan received support from, the Ontario Graduate Scholarship–Masters Scholarship, awarded by the government of Ontario.
A version of this article first appeared on Medscape.com.
TOPLINE:
Compared with body mass index, waist-hip ratio (WHR) had the strongest and most consistent association with all-cause mortality and was the only measurement unaffected by BMI.
METHODOLOGY:
- Cohort study of incident deaths from the U.K. Biobank (2006-2022), including data from 22 centers across the United Kingdom.
- A total of 387,672 participants were divided into a discovery cohort (n = 337,078) and validation cohort (n = 50,594), with the latter consisting of 25,297 deaths and 2,297 controls.
- The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses.
- Exposure-outcome associations were analyzed through observational and mendelian randomization analyses.
TAKEAWAY:
- In adjusted analysis, a J-shaped association was found for both measured BMI and fat mass index (FMI), whereas the association with WHR was linear (hazard ratio 1.41 per standard deviation increase).
- There was a significant association between all three adiposity measures and all-cause mortality, with odds ratio 1.29 per SD change in genetically determined BMI (P = 1.44×10-13), 1.45 per SD change in genetically determined FMI, 1.45 (P = 6.27×10-30), and 1.51 per SD change in genetically determined WHR (P = 2.11×10-9).
- Compared with BMI, WHR had the stronger association with all-cause mortality, although it was not significantly stronger than FMI.
- The association of genetically determined BMI and FMI with all-cause mortality varied across quantiles of observed BMI, but WHR did not (P = .04, P = .02, and P = .58, for BMI, FMI, and WHR, respectively).
IN PRACTICE:
“Current World Health Organization recommendations for optimal BMI range are inaccurate across individuals with various body compositions and therefore suboptimal for clinical guidelines.”
SOURCE:
Study by Irfan Khan, MSc, of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton, Ont., and colleagues. Published online in JAMA Network Open.
LIMITATIONS:
Study population was genetically homogeneous, White, and British, so results may not be representative of other racial or ethnic groups.
DISCLOSURES:
Study was funded by, and Irfan Khan received support from, the Ontario Graduate Scholarship–Masters Scholarship, awarded by the government of Ontario.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Landmark obesity legislation reintroduced in Congress
(TROA) (H.R. 4818/S. 2407). This legislation is a vital first step in expanding access to obesity treatment as it would expand Medicare coverage to include screening and treatment of obesity by a diverse range of health care providers who provide obesity care. The bill also includes coverage of behavioral counseling, prescription drugs for long-term weight management, and other prevention and treatment options.
The passage of TROA could lead to improved obesity care options because many private insurance companies model their covered health benefits to reflect Medicare.
You can help lawmakers understand the urgent need for expanded access to affordable, effective obesity treatments and how greater access to these tools will equip you to better care for your patients.
Use the new obesity advocacy toolkit to find the tools and resources you need, including an email template, sample phone script, op-ed template, and more, to assist you in reaching out to your elected officials and urging them to support the passage of TROA.
(TROA) (H.R. 4818/S. 2407). This legislation is a vital first step in expanding access to obesity treatment as it would expand Medicare coverage to include screening and treatment of obesity by a diverse range of health care providers who provide obesity care. The bill also includes coverage of behavioral counseling, prescription drugs for long-term weight management, and other prevention and treatment options.
The passage of TROA could lead to improved obesity care options because many private insurance companies model their covered health benefits to reflect Medicare.
You can help lawmakers understand the urgent need for expanded access to affordable, effective obesity treatments and how greater access to these tools will equip you to better care for your patients.
Use the new obesity advocacy toolkit to find the tools and resources you need, including an email template, sample phone script, op-ed template, and more, to assist you in reaching out to your elected officials and urging them to support the passage of TROA.
(TROA) (H.R. 4818/S. 2407). This legislation is a vital first step in expanding access to obesity treatment as it would expand Medicare coverage to include screening and treatment of obesity by a diverse range of health care providers who provide obesity care. The bill also includes coverage of behavioral counseling, prescription drugs for long-term weight management, and other prevention and treatment options.
The passage of TROA could lead to improved obesity care options because many private insurance companies model their covered health benefits to reflect Medicare.
You can help lawmakers understand the urgent need for expanded access to affordable, effective obesity treatments and how greater access to these tools will equip you to better care for your patients.
Use the new obesity advocacy toolkit to find the tools and resources you need, including an email template, sample phone script, op-ed template, and more, to assist you in reaching out to your elected officials and urging them to support the passage of TROA.
‘New dawn’ for aldosterone as drug target in hypertension?
Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.
Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.
“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”
Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
Aldosterone’s contribution ‘vastly underappreciated’
Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome.
“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.
Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).
The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.
The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.
Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).
In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.
Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.
Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.
Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.
A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat.
No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.
The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”
A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
‘New dawn’ for therapies targeting aldosterone
The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”
“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.
The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.
A version of this article first appeared on Medscape.com.
Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.
Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.
“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”
Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
Aldosterone’s contribution ‘vastly underappreciated’
Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome.
“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.
Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).
The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.
The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.
Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).
In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.
Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.
Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.
Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.
A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat.
No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.
The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”
A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
‘New dawn’ for therapies targeting aldosterone
The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”
“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.
The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.
A version of this article first appeared on Medscape.com.
Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.
Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.
“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”
Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
Aldosterone’s contribution ‘vastly underappreciated’
Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome.
“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.
Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).
The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.
The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.
Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).
In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.
Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.
Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.
Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.
A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat.
No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.
The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”
A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
‘New dawn’ for therapies targeting aldosterone
The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”
“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.
The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.
A version of this article first appeared on Medscape.com.
FROM HYPERTENSION 2023
Willpower and obesity
A few months ago I wrote a column in which I reluctantly supported designating obesity as a disease. My rationale was that in the more than 50 years that I have been watching the ebb and flow of medicine in this country I have seen very little, if any, evidence of success in our attempts to prevent obesity. Given this abysmal track record, the pragmatic side of my brain says why not label it a disease and begin to focus on treatment. However, I closed the column urging that we not lose sight of our core values and completely abandon any attempts at prevention.
As the months have rolled by, I have become increasingly concerned that preventing obesity is slipping further down the slippery slope to oblivion, greased by the success of semaglutide and the prospect of similar drugs in the pipeline. Before turning in our credentials as card-carrying preventionists, we need to step back and take another look at how we approach obesity from the pediatric side.
The majority of Americans believe that obesity occurs when an individual consumes more calories than he or she burns by being active. Some nutritionists criticize this “energy balance” model view as too simplistic and prefer a carbohydrate insulin model, which considers obesity as a metabolic disorder that is better managed by adjusting what the individual eats with less focus on amounts and the role of exercise. However, while the public may acknowledge that there are some individuals to whom genetics has dealt a more difficult hand, it continues to put a high priority on the dual roles of willpower and exercise.
But, what about children? At what point, if ever, does willpower enter the obesity discussion? A child may be able to exert some control over his or her diet by eating selectively. But, until the child acquires a certain level of resources and maturity it is parents who should be dictating the volume and variety of available food from which the child can choose. And, on the other side of the energy equation, parents should be playing a significant role in how much or how little physical activity their children engage in.
Of course there are many children whose genes predispose them to obesity when food is cheap and abundant. And, there are numerous families for whom socioeconomic factors limit their ability to control their children’s diet and activity options. However, we mustn’t lose sight of the fact that the majority of families may be making choices for their children that are contributing to the obesity problem in this country.
For example, a recent study published in Pediatrics has found that mean television viewing time during childhood and adolescence was associated with metabolic syndrome at age 45. Is this a failure on our part to anticipate this finding when for decades we as physicians have already seen anecdotal evidence to support it? Or is this another example of a willpower deficit by parents who likewise must have had an inkling that sitting on the couch watching television wasn’t healthy for their children?
Or is this just more evidence that as a nation we lack the political will to enact laws and develop programs aimed at heading off obesity in early childhood before it reaches the point that we have learned, from sad experience, is beyond the reach of dietary change, increased physical activity, and the fragility of normal human willpower. Here I’m talking about the disappearance of meaningful physical education in the schools, the failure to effectively prevent the marketing of poor nutritional foods and beverages to children, and the failure to aggressively promote universal breastfeeding-friendly workplaces and schedules, to name just a few.
As individuals we know all too well the limits of our own willpower. But, collectively as a nation we should be able to pool those fragmentary resources into a force for positive change. We may have thrown in the towel when we have opted to treat obesity as a disease in adults. Let’s find the will to work on prevention in early childhood when the window for change is still open.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
A few months ago I wrote a column in which I reluctantly supported designating obesity as a disease. My rationale was that in the more than 50 years that I have been watching the ebb and flow of medicine in this country I have seen very little, if any, evidence of success in our attempts to prevent obesity. Given this abysmal track record, the pragmatic side of my brain says why not label it a disease and begin to focus on treatment. However, I closed the column urging that we not lose sight of our core values and completely abandon any attempts at prevention.
As the months have rolled by, I have become increasingly concerned that preventing obesity is slipping further down the slippery slope to oblivion, greased by the success of semaglutide and the prospect of similar drugs in the pipeline. Before turning in our credentials as card-carrying preventionists, we need to step back and take another look at how we approach obesity from the pediatric side.
The majority of Americans believe that obesity occurs when an individual consumes more calories than he or she burns by being active. Some nutritionists criticize this “energy balance” model view as too simplistic and prefer a carbohydrate insulin model, which considers obesity as a metabolic disorder that is better managed by adjusting what the individual eats with less focus on amounts and the role of exercise. However, while the public may acknowledge that there are some individuals to whom genetics has dealt a more difficult hand, it continues to put a high priority on the dual roles of willpower and exercise.
But, what about children? At what point, if ever, does willpower enter the obesity discussion? A child may be able to exert some control over his or her diet by eating selectively. But, until the child acquires a certain level of resources and maturity it is parents who should be dictating the volume and variety of available food from which the child can choose. And, on the other side of the energy equation, parents should be playing a significant role in how much or how little physical activity their children engage in.
Of course there are many children whose genes predispose them to obesity when food is cheap and abundant. And, there are numerous families for whom socioeconomic factors limit their ability to control their children’s diet and activity options. However, we mustn’t lose sight of the fact that the majority of families may be making choices for their children that are contributing to the obesity problem in this country.
For example, a recent study published in Pediatrics has found that mean television viewing time during childhood and adolescence was associated with metabolic syndrome at age 45. Is this a failure on our part to anticipate this finding when for decades we as physicians have already seen anecdotal evidence to support it? Or is this another example of a willpower deficit by parents who likewise must have had an inkling that sitting on the couch watching television wasn’t healthy for their children?
Or is this just more evidence that as a nation we lack the political will to enact laws and develop programs aimed at heading off obesity in early childhood before it reaches the point that we have learned, from sad experience, is beyond the reach of dietary change, increased physical activity, and the fragility of normal human willpower. Here I’m talking about the disappearance of meaningful physical education in the schools, the failure to effectively prevent the marketing of poor nutritional foods and beverages to children, and the failure to aggressively promote universal breastfeeding-friendly workplaces and schedules, to name just a few.
As individuals we know all too well the limits of our own willpower. But, collectively as a nation we should be able to pool those fragmentary resources into a force for positive change. We may have thrown in the towel when we have opted to treat obesity as a disease in adults. Let’s find the will to work on prevention in early childhood when the window for change is still open.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
A few months ago I wrote a column in which I reluctantly supported designating obesity as a disease. My rationale was that in the more than 50 years that I have been watching the ebb and flow of medicine in this country I have seen very little, if any, evidence of success in our attempts to prevent obesity. Given this abysmal track record, the pragmatic side of my brain says why not label it a disease and begin to focus on treatment. However, I closed the column urging that we not lose sight of our core values and completely abandon any attempts at prevention.
As the months have rolled by, I have become increasingly concerned that preventing obesity is slipping further down the slippery slope to oblivion, greased by the success of semaglutide and the prospect of similar drugs in the pipeline. Before turning in our credentials as card-carrying preventionists, we need to step back and take another look at how we approach obesity from the pediatric side.
The majority of Americans believe that obesity occurs when an individual consumes more calories than he or she burns by being active. Some nutritionists criticize this “energy balance” model view as too simplistic and prefer a carbohydrate insulin model, which considers obesity as a metabolic disorder that is better managed by adjusting what the individual eats with less focus on amounts and the role of exercise. However, while the public may acknowledge that there are some individuals to whom genetics has dealt a more difficult hand, it continues to put a high priority on the dual roles of willpower and exercise.
But, what about children? At what point, if ever, does willpower enter the obesity discussion? A child may be able to exert some control over his or her diet by eating selectively. But, until the child acquires a certain level of resources and maturity it is parents who should be dictating the volume and variety of available food from which the child can choose. And, on the other side of the energy equation, parents should be playing a significant role in how much or how little physical activity their children engage in.
Of course there are many children whose genes predispose them to obesity when food is cheap and abundant. And, there are numerous families for whom socioeconomic factors limit their ability to control their children’s diet and activity options. However, we mustn’t lose sight of the fact that the majority of families may be making choices for their children that are contributing to the obesity problem in this country.
For example, a recent study published in Pediatrics has found that mean television viewing time during childhood and adolescence was associated with metabolic syndrome at age 45. Is this a failure on our part to anticipate this finding when for decades we as physicians have already seen anecdotal evidence to support it? Or is this another example of a willpower deficit by parents who likewise must have had an inkling that sitting on the couch watching television wasn’t healthy for their children?
Or is this just more evidence that as a nation we lack the political will to enact laws and develop programs aimed at heading off obesity in early childhood before it reaches the point that we have learned, from sad experience, is beyond the reach of dietary change, increased physical activity, and the fragility of normal human willpower. Here I’m talking about the disappearance of meaningful physical education in the schools, the failure to effectively prevent the marketing of poor nutritional foods and beverages to children, and the failure to aggressively promote universal breastfeeding-friendly workplaces and schedules, to name just a few.
As individuals we know all too well the limits of our own willpower. But, collectively as a nation we should be able to pool those fragmentary resources into a force for positive change. We may have thrown in the towel when we have opted to treat obesity as a disease in adults. Let’s find the will to work on prevention in early childhood when the window for change is still open.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].