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To the Editor: The risk of hypoglycemia in patients who are receiving glucagon-like peptide-1 (GLP-1) analogues as monotherapy is considered to be insignificant. In the recent phase 3 Semaglutide Treatment Effect in People with Obesity 1 (STEP 1) trial by Wilding et al. (March 18 issue),1 the incidence of hypoglycemia that was associated with the GLP-1 analogue semaglutide was only 0.6% in adults with overweight or obesity. However, in a similar trial of another GLP-1 analogue (liraglutide),2 investigators found a higher incidence of hypoglycemia with liraglutide than with placebo (11.9% vs. 3.3%). In that trial, the majority of cases of . . .
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Eugen Javor, M.Pharm.
General Hospital Bjelovar, Bjelovar, Croatia ([email protected])
Marko Lucijanić, M.D., Ph.D.
Dubrava University Hospital, Zagreb, Croatia
Marko Skelin, Ph.D.
University of Rijeka, Rijeka, Croatia
To the Editor: The risk of hypoglycemia in patients who are receiving glucagon-like peptide-1 (GLP-1) analogues as monotherapy is considered to be insignificant. In the recent phase 3 Semaglutide Treatment Effect in People with Obesity 1 (STEP 1) trial by Wilding et al. (March 18 issue),1 the incidence of hypoglycemia that was associated with the GLP-1 analogue semaglutide was only 0.6% in adults with overweight or obesity. However, in a similar trial of another GLP-1 analogue (liraglutide),2 investigators found a higher incidence of hypoglycemia with liraglutide than with placebo (11.9% vs. 3.3%). In that trial, the majority of cases of hypoglycemia were recorded at visits to monitor fasting glucose levels or oral glucose tolerance, and most results were associated with a blood glucose measurement of more than 56 mg per deciliter.
In another trial of semaglutide involving patients with diabetes,3 the hypoglycemic effect was more pronounced than it was among the patients without diabetes in the STEP 1 trial (13.5% vs. 0.6%). Furthermore, in the Evaluation of Liraglutide in Pediatrics with Diabetes (Ellipse) trial involving children and adolescents with type 2 diabetes,4 hypoglycemia occurred in patients who received a GLP-1 analogue regardless of their background antihyperglycemic treatment.5 Since patients with diabetes have a blunted inverse relationship between pulsatile insulin and compensatory glucagon secretion, the use of GLP-1 analogues may put them at an increased risk for hypoglycemia.6 Therefore, to better understand the risk of hypoglycemia associated with GLP-1 analogues in actual practice, it would be helpful if the authors of the STEP 1 report could provide data from blood glucose measurements obtained during trial visits.
No potential conflict of interest relevant to this letter was reported.
References
1 Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med (2021); 384:989-1002. PMID: 33567185
2 Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med (2015); 373:11-22. PMID: 26132939
3 Lingvay I, Catarig A-M, Frias JP, et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol (2019); 7:834-844. PMID: 31540867
4 Tamborlane WV, Barrientos-Pérez M, Fainberg U, et al. Liraglutide in children and adolescents with type 2 diabetes. N Engl J Med (2019); 381:637-646. PMID: 31034184
5 Javor E, Skelin M, Lucijanić M. Liraglutide in children and teens with type 2 diabetes. N Engl J Med (2019); 381:1786-1787. PMID: 31665591
6 Menge BA, Grüber L, Jørgensen SM, et al. Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes. Diabetes (2011); 60:2160-2168. PMID: 21677283
Teck K. Khoo, M.D., and Jack Lin, D.O.
MercyOne Des Moines, Des Moines, IA ([email protected])
To the Editor: In light of the current obesity epidemic and the lack of effective long-term pharmacotherapy, the findings of the STEP 1 trial are indeed exciting and show much promise. However, since semaglutide was first approved by the Food and Drug Administration (FDA) for use in patients with type 2 diabetes,1 it would have been helpful to include a subgroup of patients who had diabetes rather than specifically excluding them. Such inclusion would have provided a more real-world application to patients with obesity who are at risk for type 2 diabetes. In addition, we wonder whether the study included patients who had undergone bariatric surgery and, if so, whether data are available regarding weight loss in this specific population. Gastric bypass surgery is known to raise levels of endogenous GLP-1,2,3 so we question whether the use of an exogenous GLP-1 such as semaglutide would have resulted in lower weight-loss effects in this population than in patients who had not undergone this surgery.
No potential conflict of interest relevant to this letter was reported.
References
1 Ozempic (semaglutide) injection prescribing information.
2 Rhee NA, Wahlgren CD, Pedersen J, et al. Effect of Roux-en-Y gastric bypass on the distribution and hormone expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes. Diabetologia (2015); 58:2254-2258. PMID: 26186884
3 Jirapinyo P, Jin DX, Qazi T, Mishra N, Thompson CC. A meta-analysis of GLP-1 after Roux-en-Y gastric bypass: impact of surgical technique and measurement strategy. Obes Surg (2018); 28:615-626. PMID: 28871519
Karl Z. Nadolsky, D.O.
Michigan State University College of Human Medicine, Grand Rapids, MI ([email protected])
Monica Agarwal, M.D.
University of Alabama at Birmingham, Birmingham, AL
To the Editor: The STEP 1 trial of semaglutide was met with excitement as we enter a new era in pharmacology to combat obesity. However, the accompanying editorial by Ingelfinger and Rosen1 came across as more tempered. The editorial stressed the occurrence of gastrointestinal side effects, which were transiently mild or moderate in severity, and noted a concern about potential pancreatitis, which has not been supported by meta-analyses.2 The editorialists suggest that oral semaglutide may be more appealing to patients, despite its similar gastrointestinal effects to the subcutaneous formulation yet lower efficacy,3 not to mention the burden of daily dosing with restrictions that could be a deterrent to adherence. They also question the efficacy of semaglutide in the majority of patients without prediabetes (an issue that was addressed in the phase 2 dosing trial4) and question the long-term efficacy in the face of data regarding liraglutide.5 Finally, the editorialists express concern regarding the underrepresentation of certain groups in this trial, a factor that is an unfortunate reality in many clinical trials. For example, women are historically more likely than men to seek participation in antiobesity trials.
Despite these stated concerns, we think that the results of the STEP 1 trial spur more optimism than pessimism for the treatment of obesity and adiposity-based chronic disease. One step for weight loss, one giant leap for obesity.
No potential conflict of interest relevant to this letter was reported.
References
1 Ingelfinger JR, Rosen CJ. STEP 1 for effective weight control — another first step? N Engl J Med (2021); 384:1066-1067. PMID: 33567184
2 Singh AK, Gangopadhyay KK, Singh R. Risk of acute pancreatitis with incretin-based therapy: a systematic review and updated meta-analysis of cardiovascular outcomes trials. Expert Rev Clin Pharmacol (2020); 13:461-468. PMID: 32129106
3 Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA (2017); 318:1460-1470. PMID: 29049653
4 O’Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet (2018); 392:637-649. PMID: 30122305
5 le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet (2017); 389:1399-1409. PMID: 28237263
Gitanjali Srivastava, M.D.
Vanderbilt University School of Medicine, Nashville, TN ([email protected])
Rekha B. Kumar, M.D.
Weill Cornell Medical College, New York, NY
To the Editor: We thank the authors of the editorial for highlighting the findings of the STEP 1 trial. However, we disagree with several issues in the editorial. First, as a drug class, the GLP-1 agonists are labeled to preclude their use in persons who have a personal or family history of multiple endocrine neoplasia type 2, not type 1, as stated. Second, phentermine–topiramate,1 orlistat,2 and the single GLP-1 that is FDA-approved for obesity (liraglutide,3 which was not included in the table accompanying the editorial) have all been shown to prevent diabetes, contrary to the information in the editorial. Third, we disagree with the suggestion that existing diabetes medications, such as inhibitors of sodium–glucose cotransporter 2 (SGLT2), can be used to treat patients with obesity. In this drug class, only canagliflozin has been shown to be associated with weight loss (with modest results), and the use of this drug for weight loss would be an off-label recommendation. Fourth, we do not agree that the injectable formulation of semaglutide is a burdensome intervention on the basis of its evident clinical acceptance and side-effect profile. Semaglutide is the only GLP-1 agonist with an oral formulation, which is not approved for use in persons with obesity and is associated with less weight loss than the injectable formulation. Therefore, oral semaglutide cannot be compared with injectable formulations. Fifth, although antiobesity medications have been associated with a mean weight loss of 5 to 7%, the 14.9% loss reported in the STEP 1 trial is a remarkable advancement in a field in which treating to target may be an attainable goal.
Dr. Srivastava reports receiving consulting fees from Novo Nordisk and Rhythm Pharmaceuticals. Dr. Kumar reports receiving lecture fees from Novo Nordisk and Janssen Pharmaceuticals, receiving consulting fees from Gelesis, Pfizer, and Eli Lilly, and having an equity interest in Vivus. No other potential conflict of interest relevant to this letter was reported.
References
1 Garvey WT, Ryan DH, Henry R, et al. Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care (2014); 37:912-921. PMID: 24103901
2 Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care (2004); 27:155-161. PMID: 14693982
3 le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet (2017); 389:1399-1409. PMID: 28237263
John P.H. Wilding, D.M.
University of Liverpool, Liverpool, United Kingdom
Salvatore Calanna, M.D., Ph.D.
Novo Nordisk, Soborg, Denmark
Robert F. Kushner, M.D.
Northwestern University Feinberg School of Medicine, Chicago, IL ([email protected])
The authors reply: Javor and colleagues question the risk of hypoglycemia associated with GLP-1 agonists. Extensive clinical data regarding GLP-1 agonists in general among patients with type 2 diabetes and regarding liraglutide in particular among patients with obesity have shown that severe hypoglycemia is rare with these agents. In patients with type 2 diabetes, the majority of hypoglycemic events occur in those who are taking concomitant sulfonylurea or insulin therapy. Since no patients with diabetes were included in the STEP 1 trial, this issue was not relevant among the trial patients. The suggestion of measuring fasting blood glucose during study visits is reasonable. However, in the Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals (SCALE) Obesity and Prediabetes trial,1 most of the hypoglycemic events that were reported were asymptomatic glucose readings of less than 3.9 mmol per liter during fasting study visits, and there were no severe episodes of hypoglycemia; similar results were seen in the phase 2 trial with semaglutide.2 Thus, frequent monitoring for hypoglycemia was not considered to be essential for the safety of the STEP 1 trial patients.
Khoo and Lin ask about the efficacy of semaglutide in patients with type 2 diabetes. This issue is indeed an important one and has been addressed in the separate STEP 2 trial.3 Their question about the use of GLP-1 agonists as an adjunct to bariatric surgery is an area that would be of interest for future research with semaglutide; we did not include patients who had undergone bariatric surgery in the STEP 1 trial. However, a number of ongoing trials (including the BARIOPTIMISE trial; ClinicalTrials.gov number,
Since publication of their article, the authors report no further potential conflict of interest.
References
1 Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med (2015); 373:11-22. PMID: 26132939
2 O’Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet (2018); 392:637-649. PMID: 30122305
3 Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet (2021); 397:971-984. PMID: 33667417
4 ClinicalTrials.gov. Evaluation of liraglutide 3.0mg in patients with poor weight-loss and a suboptimal glucagon-like peptide-1 response (BARIOPTIMISE), 2017 (https://clinicaltrials.gov/ct2/show/NCT03341429).
Clifford J. Rosen, M.D.
Maine Medical Center Research Institute, Scarborough, ME
Julie R. Ingelfinger, M.D.
The editorialists reply: We thank the readers who noted two important errors in our editorial — one regarding the randomization ratio, which was 1:1, and the other regarding the contraindication of semaglutide in patients with multiple endocrine neoplasia type 2. Both these errors have been corrected.
We also thank Nadolsky and Agarwal, along with Srivastava and Kumar, for their comments. In our editorial, we thought it was important to consider the potential weight-loss benefits of oral glucose-lowering drugs that are not approved for weight management (e.g., SGLT2 inhibitors and oral semaglutide) and to note the reported effects of these drugs in comparison with subcutaneous semaglutide. We also noted that the effect of semaglutide in persons with obesity who have normal glucose tolerance remains to be studied further.
With respect to the lack of mention of liraglutide in our table of medications, that list was intended to include examples of GLP-1 agonists and SGLT2 inhibitors rather than to present a complete listing of all the drugs that are currently available. However, we have now expanded the table entries in response to requests to do so.
Since publication of their editorial, the authors report no further potential conflict of interest.
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