Aims
To review the evolution and advancement of GLP‐1 receptor agonist (GLP‐1RA) therapy, through the lens of randomised controlled trials, from differentiating characteristics, efficacy, safety, ...tolerability, and cardiovascular outcomes, to evidence gaps and next steps.
Methods
Clinical review of published phase 3 or later RCT data studying efficacy, safety, and outcomes of approved GLP‐1 RA therapies.
Results
Through a wealth of studies, including both placebo‐controlled and active‐controlled studies, GLP‐1 RAs have demonstrated high glycemic efficacy and ability to facilitate weight loss, with minimal risk of hypoglycemia, potential to restore beta cell function, and evidence for improved cardiovascular outcomes in those at risk.
Conclusions
Over a decade of clinical studies have established the unique contributions of GLP‐1 RAs in the treatment of diabetes. Individual differences between the different GLP‐1 RAs, in delivery, pharmacokinetic and clinical effects, exist, allowing for tailored approaches to clinical care. The strength of evidence generated through RCTs, both short‐term and long‐term studies, will continue to evolve and inform our current paradigms in diabetes care.
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycemia in type 2 ...diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional health care team providing diabetes care in the U.S. and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the health care system, and physical activity behaviors, including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.
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.
This study was conducted to demonstrate the efficacy and safety of LixiLan (iGlarLixi), a novel, titratable, fixed-ratio combination of insulin glargine (iGlar) (100 units) and lixisenatide, compared ...with iGlar in patients with type 2 diabetes inadequately controlled on basal insulin with or without up to two oral glucose-lowering agents.
After a 6-week run-in when iGlar was introduced and/or further titrated, and oral antidiabetic drugs other than metformin were stopped, 736 basal insulin-treated patients (mean diabetes duration 12 years, BMI 31 kg/m
) were randomized 1:1 to open-label, once-daily iGlarLixi or iGlar, both titrated to fasting plasma glucose <100 mg/dL (<5.6 mmol/L) up to a maximum dose of 60 units/day. The primary outcome was change in HbA
levels at 30 weeks.
HbA
decreased from 8.5% (69 mmol/mol) to 8.1% (65 mmol/mol) during the run-in period. After randomization, iGlarLixi showed greater reductions in HbA
from baseline compared with iGlar (-1.1% vs. -0.6%, P < 0.0001), reaching a mean final HbA
of 6.9% (52 mmol/mol) compared with 7.5% (58 mmol/mol) for iGlar. HbA
<7.0% (53 mmol/mol) was achieved in 55% of iGlarLixi patients compared with 30% on iGlar. Mean body weight decreased by 0.7 kg with iGlarLixi and increased by 0.7 kg with iGlar (1.4 kg difference, P < 0.0001). Documented symptomatic hypoglycemia (≤70 mg/dL) was comparable between groups. Mild gastrointestinal adverse effects were very low but more frequent with iGlarLixi.
Compared with iGlar, a substantially higher proportion of iGlarLixi-treated patients achieved glycemic targets with a beneficial effect on body weight, no additional risk of hypoglycemia, and low levels of gastrointestinal adverse effects in inadequately controlled, basal insulin-treated, long-standing type 2 diabetes.
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.
Despite common mechanisms of actions, glucagon-like peptide-1 receptor agonists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial compared semaglutide with ...dulaglutide in patients with inadequately controlled type 2 diabetes.
This was an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA
7·0-10·5% (53·0-91·0 mmol/mol) on metformin monotherapy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either semaglutide 0·5 mg, dulaglutide 0·75 mg, semaglutide 1·0 mg, or dulaglutide 1·5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA
; the confirmatory secondary endpoint was change in bodyweight, both at week 40. The primary analysis population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was powered for HbA
non-inferiority (margin 0·4%) and bodyweight superiority. This trial is registered with ClinicalTrials.gov, number NCT02648204.
Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to semaglutide 0·5 mg, 299 to dulaglutide 0·75 mg, 300 to semaglutide 1·0 mg, and 299 to dulaglutide 1·5 mg. 72 (6%) patients withdrew from the trial (22 receiving semaglutide 0·5 mg, 13 receiving dulaglutide 0·75 mg, 21 receiving semaglutide 1·0 mg, and 16 receiving dulaglutide 1·5 mg). From overall baseline mean, mean percentage HbA
was reduced by 1·5 (SE 0·06) percentage points with semaglutide 0·5 mg versus 1·1 (0·05) percentage points with dulaglutide 0·75 mg (estimated treatment difference ETD -0·40 percentage points 95% CI -0·55 to -0·25; p<0·0001) and by 1·8 (0·06) percentage points with semaglutide 1·0 mg versus 1·4 (0·06) percentage points with dulaglutide 1·5 mg (ETD -0·41 percentage points -0·57 to -0·25; p<0·0001). From overall baseline mean, mean bodyweight was reduced by 4·6 kg (SE 0·28) with semaglutide 0·5 mg compared with 2·3 kg (0·27) with dulaglutide 0·75 mg (ETD -2·26 kg -3·02 to -1·51; p<0·0001) and by 6·5 kg (0·28) with semaglutide 1·0 mg compared with 3·0 kg (0·27) with dulaglutide 1·5 mg (ETD -3·55 kg -4·32 to -2·78; p<0·0001). Gastrointestinal disorders were the most frequently reported adverse event, occurring in 129 (43%) of 301 patients receiving semaglutide 0·5 mg, 133 (44%) of 300 patients receiving semaglutide 1·0 mg, 100 (33%) of 299 patients receiving dulaglutide 0·75 mg, and in 143 (48%) of 299 patients receiving dulaglutide 1·5 mg. Gastrointestinal disorders were also the most common reason for discontinuing treatment with semaglutide and dulaglutide. There were six fatalities: one in each semaglutide group and two in each dulaglutide group.
At low and high doses, semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clinically meaningful glycaemic targets and weight loss, with a similar safety profile.
Novo Nordisk.
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycaemia in type 2 ...diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the healthcare system and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.
Graphical abstract
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