Efficacy and Safety of Incretin Therapy in Type 2 Diabetes: Systematic Review and Meta-analysis
Abstract
ContextPharmacotherapies that augment the incretin pathway have recently become available, but their role in the management of type 2 diabetes is not well defined.ObjectiveTo assess the efficacy and safety of incretin-based therapy in adults with type 2 diabetes based on randomized controlled trials published in peer-reviewed journals or as abstracts.Data SourcesWe searched MEDLINE (1966–May 20, 2007) and the Cochrane Central Register of Controlled Trials (second quarter, 2007) for English-language randomized controlled trials involving an incretin mimetic (glucagonlike peptide 1 [GLP-1] analogue) or enhancer (dipeptidyl peptidase 4 [DPP4] inhibitor). We also searched prescribing information, relevant Web sites, reference lists and citation sections of recovered articles, and abstracts presented at recent conferences.Study SelectionRandomized controlled trials were selected if they were at least 12 weeks in duration, compared incretin therapy with placebo or other diabetes medication, and reported hemoglobin A1c data in nonpregnant adults with type 2 diabetes.Data ExtractionTwo reviewers independently assessed trials for inclusion and extracted data. Differences were resolved by consensus. Meta-analyses were conducted for several efficacy and safety outcomes.ResultsOf 355 potentially relevant articles identified, 51 were retrieved for detailed evaluation and 29 met the inclusion criteria. Incretins lowered hemoglobin A1c compared with placebo (weighted mean difference, −0.97% [95% confidence interval {CI}, −1.13% to −0.81%] for GLP-1 analogues and −0.74% [95% CI, −0.85% to −0.62%] for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. Glucagonlike peptide 1 analogues resulted in weight loss (1.4 kg and 4.8 kg vs placebo and insulin, respectively) while DPP4 inhibitors were weight neutral. Glucagonlike peptide 1 analogues had more gastrointestinal side effects (risk ratio, 2.9 [95% CI, 2.0-4.2] for nausea and 3.2 [95% CI, 2.5-4.4] for vomiting). Dipeptidyl peptidase 4 inhibitors had an increased risk of infection (risk ratio, 1.2 [95% CI, 1.0-1.4] for nasopharyngitis and 1.5 [95% CI, 1.0-2.2] for urinary tract infection) and headache (risk ratio, 1.4 [95% CI, 1.1-1.7]). All but 3 trials had a 30-week or shorter duration; thus, long-term efficacy and safety could not be evaluated.ConclusionsIncretin therapy offers an alternative option to currently available hypoglycemic agents for nonpregnant adults with type 2 diabetes, with modest efficacy and a favorable weight-change profile. Careful postmarketing surveillance for adverse effects, especially among the DPP4 inhibitors, and continued evaluation in longer-term studies and in clinical practice are required to determine the role of this new class among current pharmacotherapies for type 2 diabetes.
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DPP-4 inhibitors are consistently weight-neutral.
“Consistently weight-neutral. A pooled sitagliptin analysis confirmed no significant weight change [43].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [43]
Gastrointestinal adverse events associated with GLP-1 receptor agonists are dose dependent and decline over time.
“This result corresponded to a research showing that the gastrointestinal AEs associated with GLP-1RAs were dose dependent and decline over time (45).”
From Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system (2022) · cites this paper as [45]
DPP-4 inhibitors are effective in treating obesity and diabetes.
“dipeptidyl peptidase-4 (DPP-4) inhibitors were developed to stabilize endogenous GLP-1, an approach which is effective in treating obesity and diabetes [2].”
From Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models (2013) · cites this paper as [2]
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- Authors
- Amori, R. E., Lau, J., & Pittas, A. G.
- Affiliations
- Tufts Medical Center (US)
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2007-07-11
- Volume
- 298
- Issue
- 2
- Pages
- 194
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W100598291
- Cited by
- 12
- References
- 40
- Citations by year
- 2020: 1 · 2012: 4
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK 61506)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- type 2 diabetes, incretin-based therapy, GLP-1 receptor agonists, DPP-4 inhibitors, glycemic control, HbA1c, weight loss, gastrointestinal adverse effects, infection risk, drug safety, hypoglycemia, randomized controlled trials meta-analysis
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