Abstract Background Considerable clinical data on the treatment of type 2 diabetes with incretin-based therapies (glucagon-like peptide 1 receptor agonists GLP-1RAs and dipeptidyl-peptidase IV DPP-4 ...inhibitors) are available. Objective This meta-analysis was performed to support the understanding of the overall evidence by summarizing the findings from studies of the incretin-based therapies. Methods The MEDLINE, EMBASE, BIOSIS, and BIOSIS trial databases were searched for relevant literature published between January 1, 1990, and June 30, 2011. Search terms included GLP-1, DPP-4, the names of drugs that have been approved by the US Food and Drug Administration for the treatment of diabetes, and the names of drugs that have not been approved but are in late-stage research. Studies were included if they were randomized controlled trials of 12 to 52 weeks' duration and having change from baseline in hemoglobin (Hb) A1c as the primary end point. The random effects meta-analyses models examined HbA1c , fasting plasma glucose (FPG), and body weight for individual therapies, but did not compare effects between therapies. Results The reviewers identified 362 unique clinical studies, of which 80 were eligible for inclusion in the present meta-analysis. Mean baseline HbA1c values ranged from 7.4% to 10.3% (GLP-1RA studies) and 7.2% to 9.3% (DPP-4 inhibitor studies). The highest maintenance doses of the GLP-1RAs and the DPP-4 inhibitors were associated with changes from baseline in mean HbA1c of −1.1% to −1.6% and −0.6% to −1.1%, respectively. Mean reductions in FPG with exenatide once weekly (QW) or liraglutide once daily were apparently greater than those with exenatide twice daily (BID) and the DPP-4 inhibitors, with the exception of vildagliptin. Mean weight losses with the GLP-1RAs and the DPP-4 inhibitors were >–2.0 and −0.2 to −0.6 kg, respectively. The limitations of the present analysis included a lack of adjustment for placebo use and interstudy heterogeneity associated with differences in methodology (eg, management of concurrent medications, blinding, criteria for treatment discontinuation). Conclusions All of the incretin-based therapies in the present meta-analysis were associated with significant reductions from baseline in HbA1c and FPG. Further direct comparative studies between the GLP-1RAs and the DPP-4 inhibitors and within the GLP-1RA class are justified.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Context:
Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use.
Objective:
To assess the risk of B12 deficiency with metformin use in the ...Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS).
Design:
Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years.
Setting:
Twenty-seven study centers in the United States.
Patients:
DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively.
Interventions:
Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS).
Main Outcome Measures:
B12 deficiency, anemia, and peripheral neuropathy.
Results:
Low B12 (≤ 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06–1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels.
Conclusions:
Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.
Participants from DPP/DPPOS were assigned to placebo (n=1082) or metformin (n=1073) for 3.2 years, followed by metformin in the metformin group for 9 years. Metformin use was associated with increased risk of vitamin B12 deficiency.
To compare the efficacy and safety of once-weekly semaglutide 1.0 mg s.c. with exenatide extended release (ER) 2.0 mg s.c. in subjects with type 2 diabetes.
In this phase 3a, open-label, ...parallel-group, randomized controlled trial, 813 subjects with type 2 diabetes taking oral antidiabetic drugs were randomized (1:1) to semaglutide 1.0 mg or exenatide ER 2.0 mg for 56 weeks. The primary end point was change from baseline in HbA
at week 56.
Mean HbA
(8.3% 67.7 mmol/mol at baseline) was reduced by 1.5% (16.8 mmol/mol) with semaglutide and 0.9% (10.0 mmol/mol) with exenatide ER (estimated treatment difference vs. exenatide ER ETD -0.62% 95% CI -0.80, -0.44 -6.78 mmol/mol (95% CI -8.70, -4.86);
< 0.0001 for noninferiority and superiority). Mean body weight (95.8 kg at baseline) was reduced by 5.6 kg with semaglutide and 1.9 kg with exenatide ER (ETD -3.78 kg 95% CI -4.58, -2.98;
< 0.0001). Significantly more subjects treated with semaglutide (67%) achieved HbA
<7.0% (<53 mmol/mol) versus those taking exenatide ER (40%). Both treatments had similar safety profiles, but gastrointestinal adverse events were more common in semaglutide-treated subjects (41.8%) than in exenatide ER-treated subjects (33.3%); injection-site reactions were more frequent with exenatide ER (22.0%) than with semaglutide (1.2%).
Semaglutide 1.0 mg was superior to exenatide ER 2.0 mg in improving glycemic control and reducing body weight after 56 weeks of treatment; the drugs had comparable safety profiles. These results indicate that semaglutide treatment is highly effective for subjects with type 2 diabetes who are inadequately controlled on oral antidiabetic drugs.
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, ...general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, ...general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
Regulatory guidelines describe the use of estimands in designing and conducting clinical trials. Estimands ensure alignment of the objectives with the design, conduct and analysis of a trial. An ...estimand is defined by four inter‐related attributes: the population of interest, the variable (endpoint) of interest, the way intercurrent events are handled and the population level summary. A trial may employ multiple estimands to evaluate treatment effects from different perspectives in order to address different scientific questions. As estimands may be an unfamiliar concept for many clinicians treating diabetes, this paper reviews the estimand concept and uses the PIONEER 1 phase 3a clinical trial, which investigated the efficacy and safety of oral semaglutide vs placebo, as an example of the way in which estimands can be implemented and interpreted. In the PIONEER 1 trial, two estimands were employed for each efficacy endpoint and were labelled as: (a) the treatment policy estimand, used to assess the treatment effect regardless of use of rescue medication or discontinuation of trial product, and provides a broad perspective of the treatment effect in the population of patients with type 2 diabetes in clinical practice; and (b) the trial product estimand, used to assess the treatment effect if all patients had continued to use trial product for the planned duration of the trial without rescue medication, thereby providing information on the anticipated treatment effect of the medication. Both approaches are complementary to understanding the effect of the studied treatments.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed ...by diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients.
This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93 sites in nine countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA
. The confirmatory secondary end point was change from baseline to week 26 in body weight.
In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA
8.0% 64 mmol/mol), oral semaglutide reduced HbA
(placebo-adjusted treatment differences at week 26: treatment policy estimand, -0.6% 3 mg, -0.9% 7 mg, and -1.1% 14 mg; trial product estimand, -0.7% 3 mg, -1.2% 7 mg, and -1.4% 14 mg;
< 0.001 for all) and body weight (treatment policy, -0.1 kg 3 mg, -0.9 kg 7 mg, and -2.3 kg 14 mg,
< 0.001; trial product, -0.2 kg 3 mg, -1.0 kg 7 mg,
= 0.01, and -2.6 kg 14 mg,
< 0.001). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3-7.4% with oral semaglutide and 2.2% with placebo.
In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA
(all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, ...general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, ...general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
PDF
