Dataset Information

Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

ABSTRACT:

Importance

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.

Objectives

To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.

Design, setting, and patients

Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use.

Interventions

Once-daily oral semaglutide of 2.5 mg (n?=?70), 5 mg (n?=?70), 10 mg (n?=?70), 20 mg (n?=?70), 40-mg 4-week dose escalation (standard escalation; n?=?71), 40-mg 8-week dose escalation (slow escalation; n?=?70), 40-mg 2-week dose escalation (fast escalation, n?=?70), oral placebo (n?=?71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n?=?70) for 26 weeks.

Main outcomes and measures

The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events.

Results

Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P?=?.01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P?Conclusions and relevanceAmong patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.

Trial registration

clinicaltrials.gov Identifier: NCT01923181.

SUBMITTER: Davies M

PROVIDER: S-EPMC5817971 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Davies Melanie M Pieber Thomas R TR Hartoft-Nielsen Marie-Louise ML Hansen Oluf K H OKH Jabbour Serge S Rosenstock Julio J

JAMA 20171001 15

<h4>Importance</h4>Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.<h4>Objectives</h4>To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.<h4>Design, setting, and patients</h4>Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 10 ...[more]

PMID: 29049653

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Project description:ImportanceThe effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described.ObjectiveTo assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control.Design, setting, and participantsRandomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin.InterventionsPatients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved.Main outcomes and measuresThe primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels.ResultsAmong 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001 for both). Mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]). Mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, -8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%).Conclusions and relevanceAmong patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks.Trial registrationClinicalTrials.gov Identifier: NCT04039503.

Project description:Importance:Intermittent energy restriction is an alternative weight loss method that is becoming popular; however, to date, there are no long-term clinical trials of intermittent energy restriction in patients with type 2 diabetes. Objective:To compare the effects of intermittent energy restriction (2 days per week) with those of continuous energy restriction on glycemic control and weight loss in patients with type 2 diabetes during a 12-month period. Design, Setting, and Participants:Adult participants (N?=?137) with type 2 diabetes were randomized 1:1 to parallel diet groups (intermittent energy restriction [n?=?70] or continuous energy restriction [n?=?67]) between April 7, 2015, and September 7, 2017, at the University of South Australia. Medications likely to cause hypoglycemia were reduced at baseline according to the medication management protocol. Interventions:An intermittent energy restriction diet (500-600 kcal/d) followed for 2 nonconsecutive days per week (participants followed their usual diet for the other 5 days) or a continuous energy restriction diet (1200-1500 kcal/d) followed for 7 days per week for 12 months. Main Outcomes and Measures:The primary outcome was change in hemoglobin A1c (HbA1c) level, with equivalence prespecified by a 90% CI margin of ±0.5%. The secondary outcome was weight loss with equivalence set at ±2.5 kg (±1.75 kg for fat mass loss and ±0.75 kg for fat-free mass loss). All other outcomes were tested for superiority. Results:Of the 137 randomized participants (77 women and 60 men; mean [SD] age, 61.0 [9.1] years; mean [SD] body mass index, 36.0 [5.8] [calculated as weight in kilograms divided by height in meters squared]; and mean [SD] HbA1c level, 7.3% [1.3%]), 97 completed the trial. Intention-to-treat analysis showed similar reductions in mean (SEM) HbA1c level between the continuous and intermittent energy restriction groups (-0.5% [0.2%] vs -0.3% [0.1%]; P?=?.65), with a between-group difference of 0.2% (90% CI, -0.2% to 0.5%) meeting the criteria for equivalence. Mean (SEM) weight change was similar between the continuous and intermittent energy restriction groups (-5.0 [0.8] kg vs -6.8 [0.8] kg; P?=?.25), but the between-group difference did not meet the criteria for equivalence (-1.8 kg; 90% CI, -3.7 to 0.07 kg), nor did the between-group difference in fat mass (-1.3 kg; 90% CI, -2.8 to 0.2 kg) or fat-free mass (-0.5 kg; 90% CI, -1.4 to 0.4 kg). There were no significant differences between groups in final step count, fasting glucose levels, lipid levels, or total medication effect score at 12 months. Effects did not differ using completers analysis. Hypoglycemic or hyperglycemic events in the first 2 weeks of treatment were similar between the continuous and intermittent energy restriction groups (mean number [SEM] of events, 3.2 [0.7] vs 4.9 [1.4]; P?=?.28), affecting 35% of participants (16 of 46) using sulfonylureas and/or insulin. Conclusions and Relevance:Intermittent energy restriction is an effective alternative diet strategy for the reduction of HbA1c and is comparable with continuous energy restriction in patients with type 2 diabetes. Trial Registration:anzctr.org.au Identifier: ACTRN12615000383561.

Project description:ImportanceThe effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.ObjectiveTo compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly.Design, setting, and participantsRandomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes.InterventionsA total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups.Main outcomes and measuresThe primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]).ResultsAmong 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).Conclusions and relevanceAmong adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks.Trial registrationClinicalTrials.gov Identifier: NCT03548987.

Project description:Background: This meta-analysis aimed to combine the data available from clinical trials to assess the effects of subcutaneous and oral semaglutide administration on glycemic control, weight management, and safety outcomes in patients with type 2 diabetes (T2D). Methods: We systematically searched for phase 3 randomized controlled trials (RCTs) that compared semaglutide with placebo or other anti-diabetic drugs in T2D patients. The primary outcome was the change from baseline in glycated hemoglobin (HbA1c) levels. Secondary efficacy endpoints included the change from baseline in body weight, achievement of HbA1c targets, and clinically significant weight loss. Key safety outcomes were also assessed. Results: In this meta-analysis, 24 trials with a total of 22185 patients were included. Subcutaneous semaglutide administration reduced HbA1c levels (weighted mean difference [WMD]: -1.14% and -1.37%, for 0.5 mg and 1 mg, respectively) and body weight (WMD: -2.73 kg and -4.09 kg, for 0.5 mg and 1 mg, respectively) when compared with placebo; its efficacy was also superior to other anti-diabetic drugs in reducing HbA1c levels (WMD: -0.71% and -0.86%, for 0.5 mg and 1 mg, respectively) and body weight (WMD: -2.65 kg and -3.78 kg, for 0.5 mg and 1 mg, respectively). Oral semaglutide administration was superior to placebo in decreasing HbA1c levels (WMD: -0.96% and -1.02%, for 7 mg and 14 mg, respectively). Moreover, oral administration of 14 mg of semaglutide also showed a significant reduction in HbA1c levels (WMD: -0.36%) compared with other anti-diabetic drugs. Furthermore, oral semaglutide administration resulted in substantial weight loss compared with other anti-diabetic drugs (WMD: -1.53 kg and -1.73 kg, for 7 mg and 14 mg, respectively). Notably, subcutaneous and oral semaglutide administration also resulted in higher numbers of patients achieving the targets of HbA1c levels and weight loss than placebo and other anti-diabetic drugs. Overall, we noted no clear evidence of detrimental effects on safety endpoints due to semaglutide treatment, except for some gastrointestinal adverse events. Conclusion: Both subcutaneous and oral semaglutide administration could enable the achievement of sufficient glycemic control and weight management without increasing the risk of hypoglycemia, which were effective and safe for the treatment of T2D.

Project description:Early and effective glycemic control can prevent or delay the complications associated with type 2 diabetes (T2D). The benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly recognized and they now feature prominently in international T2D treatment recommendations and guidelines across the disease continuum. However, despite providing effective glycemic control, weight loss, and a low risk of hypoglycemia, GLP-1RAs are currently underutilized in clinical practice. The long-acting GLP-1RA, semaglutide, is available for once-weekly injection and in a new once-daily oral formulation. Semaglutide is an advantageous choice for the treatment of T2D since it has greater efficacy in reducing glycated hemoglobin and body weight compared with other GLP-1RAs, has demonstrated benefits in reducing major adverse cardiovascular events, and has a favorable profile in special populations (e.g., patients with hepatic impairment or renal impairment). The oral formulation represents a useful option to help improve acceptance and adherence compared with injectable formulations for patients with a preference for oral therapy, and may lead to earlier and broader use of GLP-1RAs in the T2D treatment trajectory. Oral semaglutide should be taken on an empty stomach, which may influence the choice of formulation. As with most GLP-1RAs, initial dose escalation of semaglutide is required for both formulations to mitigate gastrointestinal adverse events. There are also specific dose instructions to follow with oral semaglutide to ensure sufficient gastric absorption. The evidence base surrounding the clinical use of semaglutide is being further expanded with trials investigating effects on diabetic retinopathy, cardiovascular outcomes, and on the common T2D comorbidities of obesity, chronic kidney disease, and non-alcoholic steatohepatitis. These will provide further information about whether the benefits of semaglutide extend to these other indications.

Project description:Introduction: Oral semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that improves glycated hemoglobin levels and body weight in patients with type 2 diabetes (T2DM). We aim to evaluate the cost-effectiveness of once-daily oral semaglutide in comparison to placebo and injectable GLP-1 RAs in Chinese patients with T2DM inadequately controlled on basal insulin. Methods: The United Kingdom Prospective Diabetes Study Outcomes Model (UKPDS OM2.1) was used to estimate the cost-effectiveness by calculating the incremental cost-effectiveness ratio (ICER). Baseline characteristics of the simulation cohort were obtained from the PIONEER 8 trial. Utility and safety inputs were derived from a network meta-analysis of 12 trials. Direct medical costs were retrieved from published literature and discounted at an annual rate of 5%. We used a willingness-to-pay (WTP) threshold of $36,528.3 per quality-adjusted life-year (QALY) gained. Scenario analysis, and one-way and probabilistic sensitivity analysis were performed. Results: The effectiveness of oral semaglutide was 10.39 QALYs with a total cost of $30,223.10, while placebo provided 10.13 QALYs at a lower total cost of $20,039.19. Oral semaglutide was not cost-effective at an ICER of $39,853.22 and $88,776.61 per QALY compared to placebo and exenatide at the WTP. However, at an annual price of $1,871.9, it was cost-effective compared with dulaglutide, liraglutide, and lixisenatide. The model was most sensitive to the discount rate and annual cost of oral semaglutide. The price of oral semaglutide needed to be reduced to $1,711.03 per year to be cost-effective compared to placebo and other injectable GLP-1 RAs except for exenatide and semaglutide injection. Conclusion: We found that once-daily oral semaglutide, at a comparable price of semaglutide injection, proves to be a cost-effective add-on therapy to insulin for Chinese patients with T2DM, especially when compared to subcutaneous GLP-1 RAs other than injectable semaglutide and exenatide. However, to achieve cost-effectiveness in comparison to placebo, further cost reduction of oral semaglutide is necessary. The estimated annual cost of $1,711.03 for oral semaglutide demonstrates a more cost-effective option than placebo, highlighting its potential value in the management of T2DM.

Project description:Medical nutrition therapy is recognized as an important treatment option in type 2 diabetes. Most guidelines recommend eating a diet with a high intake of fiber-rich food including fruit. This is based on the many positive effects of fruit on human health. However some health professionals have concerns that fruit intake has a negative impact on glycemic control and therefore recommend restricting the fruit intake. We found no studies addressing this important clinical question. The objective was to investigate whether an advice to reduce the intake of fruit to patients with type 2 diabetes affects HbA1c, bodyweight, waist circumference and fruit intake.This was an open randomized controlled trial with two parallel groups. The primary outcome was a change in HbA1c during 12 weeks of intervention. Participants were randomized to one of two interventions; medical nutrition therapy + advice to consume at least two pieces of fruit a day (high-fruit) or medical nutrition therapy + advice to consume no more than two pieces of fruit a day (low-fruit). All participants had two consultations with a registered dietitian. Fruit intake was self-reported using 3-day fruit records and dietary recalls. All assessments were made by the "intention to treat" principle.The study population consisted of 63 men and women with newly diagnosed type 2 diabetes. All patients completed the trial. The high-fruit group increased fruit intake with 125 grams (CI 95%; 78 to 172) and the low-fruit group reduced intake with 51 grams (CI 95%; -18 to -83). HbA1c decreased in both groups with no difference between the groups (diff.: 0.19%, CI 95%; -0.23 to 0.62). Both groups reduced body weight and waist circumference, however there was no difference between the groups.A recommendation to reduce fruit intake as part of standard medical nutrition therapy in overweight patients with newly diagnosed type 2 diabetes resulted in eating less fruit. It had however no effect on HbA1c, weight loss or waist circumference. We recommend that the intake of fruit should not be restricted in patients with type 2 diabetes.http://www.clinicaltrials.gov; Identifier: NCT01010594.

Project description:ImportancePhase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.ObjectiveTo compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity.Design, setting, and participantsRandomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338).InterventionsParticipants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85).Main outcomes and measuresThe primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points.ResultsOf 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.Conclusions and relevanceAmong adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.Trial registrationClinicalTrials.gov Identifier: NCT04074161.

Dataset Information

Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance

Objectives

Design, setting, and patients

Interventions

Main outcomes and measures

Results

Trial registration

Publications

Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

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