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.
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 clinicaltrials.gov 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.
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.
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.
Mukherjee S, Sharmasarkar B, Das KK, Bhattacharyya A, Deb A (2013). Compliance to anti-diabetic drugs: observations from the diabetic clinic of a medical college in Kolkata, India. J Clin Diagn Res, 7:661-665.
Rwegerera GM (2014). Adherence to anti-diabetic drugs among patients with Type 2 diabetes mellitus at Muhimbili National Hospital, Dar es Salaam, Tanzania: A cross-sectional study. Pan Afr Med J, 17:252.
Rwegerera GM, Moshomo T, Gaenamong M, Oyewo TA, Gollakota S, Mhimbira FA, et al. (2017). Antidiabetic medication adherence and associated factors among patients in Botswana: Implications for the future. Alexandria Journal of Medicine, 54:1-7.
Khotkar K, Chaudhari S, Jadhav P, A Deshmukh Y (2017). Assessment of medication adherence in type II diabetic patients: A cross-sectional study. MGM Journal of Medical Sciences, 4:65-69.
Gimenes HT, Zanetti ML, Haas VJ (2009). Factors related to patient adherence to antidiabetic drug therapy. Rev Lat Am Enfermagem, 17:46-51.
Nauck MA, Vilsboll T, Gallwitz B, Garber A, Madsbad S (2009). Incretin-based therapies: Viewpoints on the way to consensus. Diabetes Care, 32 Suppl 2:S223-231.
Tran KL, Park YI, Pandya S, Muliyil NJ, Jensen BD, Huynh K, et al. (2017). Overview of glucagon-like peptide-1 receptor agonists for the treatment of patients with type 2 diabetes. Am Health Drug Benefits, 10:178-188.
Pinelli NR, Hurren KM (2011). Efficacy and safety of long-acting glucagon-like peptide-1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: A systematic review and meta-analysis. Ann Pharmacother, 45:850-860.
Alanazi AS (2015). Systematic review and meta-analysis of efficacy and safety of combinational therapy with metformin and dipeptidyl peptidase-4 inhibitors. Saudi Pharm J, 23:603-613.
Nguyen H, Dufour R, Caldwell-Tarr A (2017). Glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy adherence for patients with type 2 diabetes in a medicare population. Adv Ther, 34:658-673.
Farr AM, Sheehan JJ, Curkendall SM, Smith DM, Johnston SS, Kalsekar I (2014). Retrospective analysis of long-term adherence to and persistence with DPP-4 inhibitors in US adults with type 2 diabetes mellitus. Adv Ther, 31:1287-1305.
Schott G, Martinez YV, Ediriweera de Silva RE, Renom-Guiteras A, Vogele A, Reeves D, et al. (2017). Effectiveness and safety of dipeptidyl peptidase 4 inhibitors in the management of type 2 diabetes in older adults: A systematic review and development of recommendations to reduce inappropriate prescribing. BMC Geriatr, 17:226.
Mannucci E, Monami M (2017). Cardiovascular safety of incretin-based therapies in type 2 diabetes: Systematic review of integrated analyses and randomized controlled trials. Adv Ther, 34:1-40.
Karagiannis T, Liakos A, Bekiari E, Athanasiadou E, Paschos P, Vasilakou D, et al. (2015). Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab, 17:1065-1074.
Filippatos TD, Panagiotopoulou TV, Elisaf MS (2014). Adverse effects of GLP-1 receptor agonists. Rev Diabet Stud, 11:202-230.
Gerrity RG, Natarajan R, Nadler JL, Kimsey T (2001). Diabetes-induced accelerated atherosclerosis in swine. Diabetes, 50:1654-1665.
Renard CB, Kramer F, Johansson F, Lamharzi N, Tannock LR, von Herrath MG, et al. (2004). Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. J Clin Invest, 114:659-668.
Cohen JM, Escasena CA (2015). Headache and Dizziness: How to differentiate vestibular migraine from other conditions. Curr Pain Headache Rep, 19:31.
Nauck M (2016). Incretin therapies: Highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab, 18:203-216.
Higgins JPT, Green S (2011). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. London: The Cochrane Collaboration. 552 pp.
Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JP (2014). Evaluating the quality of evidence from a network meta-analysis. PLoS One, 9:e99682.
Dias S, Welton NJ, Caldwell DM, Ades AE (2010). Checking consistency in mixed treatment comparison meta-analysis. Stat Med, 29:932-944.
Higgins JP, Jackson D, Barrett JK, Lu G, Ades AE, White IR (2012). Consistency and inconsistency in network meta-analysis: Concepts and models for multi-arm studies. Res Synth Methods, 3:98-110.
Wu S, Cipriani A, Yang Z, Yang J, Cai T, Xu Y, et al. (2018). The cardiovascular effect of incretin-based therapies among type 2 diabetes: A systematic review and network meta-analysis. Expert Opin Drug Saf, 17:243-249.
Su B, Sheng H, Zhang M, Bu L, Yang P, Li L, et al. (2015). Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists’ treatment: A meta-analysis of randomized controlled trials. Endocrine, 48:107-115.
Yang J, Huang C, Wu S, Xu Y, Cai T, Chai S, et al. (2017). The effects of dipeptidyl peptidase-4 inhibitors on bone fracture among patients with type 2 diabetes mellitus: A network meta-analysis of randomized controlled trials. PLoS One, 12:e0187537.
Li ZX, Wu SS, Yang ZR, Zhan SY, Sun F (2016). Impact of glucagon-like peptide-1 receptor agonists on nasopharyngitis and upper respiratory tract infection among patients with type 2 diabetes: A network meta-analysis. Journal of Peking University (Health Science), 48:454-459.
Chen H, Zhou X, Chen T, Liu B, Jin W, Gu H, et al. (2016). Incretin-Based Therapy and risk of pancreatic cancer in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. Diabetes Ther, 7:725-742.
Montilla S, Marchesini G, Sammarco A, Trotta MP, Siviero PD, Tomino C, et al. (2014). Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: Data from the Italian AIFA Anti-diabetics Monitoring Registry. Nutr Metab Cardiovasc Dis, 24:1346-1353.
Engel SS, Suryawanshi S, Stevens SR, Josse RG, Cornel JH, Jakuboniene N, et al. (2017). Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: Outcomes from TECOS. Diabetes Obes Metab, 19:1587-1593.
Pannacciulli N, Le DS, Salbe AD, Chen K, Reiman EM, Tataranni PA, et al. (2007). Postprandial glucagon-like peptide-1 (GLP-1) response is positively associated with changes in neuronal activity of brain areas implicated in satiety and food intake regulation in humans. Neuroimage, 35:511-517.
Wang B, Zhong J, Lin H, Zhao Z, Yan Z, He H, et al. (2013). Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: A meta-analysis of clinical trials. Diabetes Obes Metab, 15:737-749.
Robinson LE, Holt TA, Rees K, Randeva HS, O’Hare JP (2013). Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: Systematic review and meta-analysis. BMJ Open, 3.
Mistry GC, Maes AL, Lasseter KC, Davies MJ, Gottesdiener KM, Wagner JA, et al. (2008). Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol, 48:592-598.
Ogawa S, Ishiki M, Nako K, Okamura M, Senda M, Mori T, et al. (2011). Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes. Tohoku J Exp Med, 223:133-135.
Gutzwiller JP, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, et al. (2004). Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab, 89:3055-3061.
Katsurada K, Yada T (2016). Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist. J Diabetes Investig, 7 Suppl 1:64-69.
Kanoski SE, Fortin SM, Arnold M, Grill HJ, Hayes MR (2011). Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology, 152:3103-3112.
Baraboi ED, St-Pierre DH, Shooner J, Timofeeva E, Richard D (2011). Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4. Am J Physiol Regul Integr Comp Physiol, 301:R1011-1024.
Plamboeck A, Veedfald S, Deacon CF, Hartmann B, Wettergren A, Svendsen LB, et al. (2013). The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol, 304:G1117-1127.
Ramsey RR, Ryan JL, Hershey AD, Powers SW, Aylward BS, Hommel KA (2014). Treatment adherence in patients with headache: A systematic review. Headache, 54:795-816.