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Aging and disease    2019, Vol. 10 Issue (6) : 1311-1319     DOI: 10.14336/AD.2019.0303
Review |
Neurological Manifestation of Incretin-Based Therapies in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis
Le Gao1, Shuqing Yu1, Andrea Cipriani2, Shanshan Wu3, Yi Huang4, Zilu Zhang5, Jun Yang1, Yixin Sun1, Zhirong Yang6, Sanbao Chai7, Yuan Zhang8, Linong Ji9, Siyan Zhan1,*, Feng Sun1,*
1Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
2Department of Psychiatry, University of Oxford, Oxford, OX3 7JX, UK.
3National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
4Department of Mathematics and Statistics, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
5Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA.
6Primary Care Unit, School of Clinical Medicine, University of Cambridge, Cambridge, CB1 8RN, UK.
7Department of Endocrinology and Metabolism, Peking University International Hospital, Beijing, China.
8Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
9Department of Endocrinology and Metabolism, People’s Hospital, Peking University, Beijing, China.
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As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.

Keywords Incretin-based therapies      type 2 diabetes      network meta-analysis      dizziness      headache     
Corresponding Authors: Zhan Siyan,Sun Feng   
About author: These are co-senior authors.
Just Accepted Date: 23 March 2019   Issue Date: 16 November 2019
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Gao Le
Yu Shuqing
Cipriani Andrea
Wu Shanshan
Huang Yi
Zhang Zilu
Yang Jun
Sun Yixin
Yang Zhirong
Chai Sanbao
Zhang Yuan
Ji Linong
Zhan Siyan
Sun Feng
Cite this article:   
Gao Le,Yu Shuqing,Cipriani Andrea, et al. Neurological Manifestation of Incretin-Based Therapies in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis[J]. Aging and disease, 2019, 10(6): 1311-1319.
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Figure 1.  Flow chart of studies considered for inclusion.
Figure 2.  Odds ratios (ORs) with 95%CIs of NMA. For dizziness (A) and headache (B), results of direct comparisons were listed in the upper triangle, and the estimation was calculated as the row-defining treatment compared with the column-defining treatment. Results of NMA were listed in the lower triangle, the estimation was calculated as the column-defining treatment compared with the row-defining treatment. The statistically significant results were bolded in red. NA: not available. DPP-4Is: dipeptidyl peptidase-4 inhibitors; GLP-1 RAs: glucagon-like peptide-1 receptor agonists; SGLT-2: sodium-glucose co-transporter 2; TZD: thiazolidinediones; AGI: alpha-glucosidase inhibitor.
Figure 3.  Two-dimensional graphs about risk on dizziness and headache. ORs in comparison with placebo (reference) of NMA (A) and direct comparisons (B) were used. Error bars are 95% CIs. Different drugs are represented by di?erent colored nodes. Metformin and AGI were not included in direct comparisons because no trials focus on these drugs compared with placebo. DPP-4Is: dipeptidyl peptidase-4 inhibitors; GLP-1 RAs: glucagon-like peptide-1 receptor agonists; SGLT-2: sodium-glucose co-transporter 2; TZD: thiazolidinediones; AGI: alpha-glucosidase inhibitor.
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