Abstract
Background Clinical trials comparing incretin-based therapies—glucagon-like peptide-1 receptor agonists (exenatide—twice daily and once weekly—and once-daily liraglutide) and dipeptidyl peptidase-4 inhibitors (vildagliptin, sitagliptin, saxagliptin and linagliptin)—with placebo and oral antidiabetic drugs show that these therapies effectively control glycaemia, with low risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists are associated with weight loss and reductions in systolic blood pressure, while dipeptidyl peptidase-4 inhibitors are weight-neutral. Based on this, the National Institute for Health and Clinical Excellence recommends using these agents in patients with type 2 diabetes for whom excess weight and/or hypoglycaemia are problematic. Aim of the review This review aims to help decision making when selecting and using incretin-based therapies in type 2 diabetes. Methods A search or MEDLINE and Cochrane clinical trials databases, limited to clinical trials in humans, was performed using the search criteria ‘exenatide or liraglutide or vildagliptin or sitagliptin, or saxagliptin or linagliptin’. Abstracts presented at recent American Diabetes Association and European Association for the Study of Diabetes meetings were also searched. Eighteen clinical trials directly comparing incretin-based therapies were identified. Results Glucagon-like peptide-1 receptor agonists achieved significantly greater reductions in glycated hemoglobin and weight than dipeptidyl peptidase-4 inhibitors, which have a neutral effect on weight. Between-treatment differences were clinically important. Gastrointestinal side effects were more frequent with glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors. Comparisons between glucagon-like peptide-1 receptor agonists and between dipeptidyl peptidase-4 inhibitors showed that differences within the available agents in the two sub-classes are small. Greater treatment satisfaction was reported with glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors. Conclusion Glucagon-like peptide-1 receptor agonists achieve greater glycated hemoglobin reductions than dipeptidyl peptidase-4 inhibitors, with concomitant weight loss. Probably due to the greater efficacy of glucagon-like peptide-1 receptor agonists, patient satisfaction is greater with these agents compared with dipeptidyl peptidase-4 inhibitors despite injectable versus oral administration and more frequent gastrointestinal side effects with the agonists.
Similar content being viewed by others
References
The International Diabetes Federation. IDF Diabetes Atlas. 4th ed. 2009. Available from: http://www.diabetesatlas.org/content/international-diabetes-federation. Accessed 9 May 2012.
Diabetes UK. Publications, reports and resources: Reports and statistics (Diabetes prevalence 2010). 2010. Available from: http://www.diabetes.org.uk/Professionals/Publications-reports-and-resources/Reports-statistics-and-case-studies/Reports/Diabetes-prevalence-2010. Accessed 9 May 2011.
Massó-González EL, Johansson S, Wallander MA, García Rodríguez LA. Trends in the prevalence and incidence of diabetes in the UK: 1996–2005. J Epidemiol Community Health. 2009;63(4):332–6.
Bergenstal RM, Kendall DM. Management of type 2 diabetes: a systematic approach to meeting the standards of care: oral agents, insulin, and management of complications. In: Degroot LJ, Jameson JL, editors. Endocrinology. Philadelphia, PA: Saunders; 2001. p. 821–35.
UK Prospective Diabetes Study Group. UK prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995;44(11):1249–58.
Lebovitz HE. Insulin secretagogues: old and new. Diabetes Rev. 1999;7(3):139–53.
Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12.
Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427–43.
Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA. 2002;287(3):360–72.
Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006;29(8):1963–72.
[No authors listed]. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–65.
Odegard PS, Capoccia K. Medication taking and diabetes: a systematic review of the literature. Diabetes Educ. 2007;33(6):1014–29.
Munshi M. Managing the’geriatric syndrome’ in patients with type 2 diabetes. Consult Pharm. 2008;23(Suppl. B):12–6.
Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076–82.
Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973;37(5):826–8.
Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci USA. 1987;84(10):3434–8.
Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia. 2004;47(3):357–66.
Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29(1):46–52.
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131–57.
Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia. 2002;45(8):1111–9.
Kieffer TJ, Habener T. The glucagon-like peptides. Endocr Rev. 1999;20(6):876–913.
During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003;9(9):1173–9.
Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–34.
Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36(8):741–4.
Meier JJ, Gethmann A, Götze O, Gallwitz B, Holst JJ, Schmidt WE, et al. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia. 2006;49(3):452–8.
Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359(9309):824–30.
Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109(8):962–5.
Nyström T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahrén B, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287(6):E1209–15.
Gutzwiller JP, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89(6):3055–61.
Vilsbøll T, Agersø H, Krarup T, Holst JJ. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab. 2003;88(1):220–4.
Amylin Pharmaceuticals, Inc. Byetta 5 μg and 10 μg for injection: summary of product characteristics. 2011. Available from: http://www.medicines.org.uk/emc/medicine/19257. Accessed 9 May 2012.
Novo Nordisk Limited. Victoza 6 mg/mL solution for injection in pre-filled pen: summary of product characteristics. 2012. Available from: http://www.medicines.org.uk/emc/medicine/21986/SPC/. Accessed 26 April 2012.
Novartis Pharmaceuticals UK Ltd. Galvus 50 mg tablets: summary of product characteristics. 2011. Available from: http://www.medicines.org.uk/emc/history/20734/SPC/Galvus. Accessed 9 May 2012.
Merck Sharp & Dohme Ltd. Januvia 100 mg film-coated tablets: summary of product characteristics. 2011. Available from: http://www.medicines.org.uk/EMC/medicine/23111/SPC/Janumet+50+mg+1000+mg+film-coated+tablets. Accessed 9 May 2012.
Bristol-Myers Squibb-AstraZeneca EEIG. Onglyza 5 mg film-coated tablets: summary of product characteristics. 2012. Available from: http://www.medicines.org.uk/EMC/medicine/22315/SPC/Onglyza+5mg+film-coated+tablets. Accessed 9 May 2012.
Eli Lilly and Company Limited. Bydureon 2 mg powder and solvent for prolonged-release suspension for injection: summary of product characteristics. 2011. Available from: http://www.medicines.org.uk/EMC/medicine/24665/SPC/BYDUREON+2+mg+powder+and+solvent+for+prolonged-release+suspension+for+injection/. Accessed 9 May 2012.
Boehringer Ingelheim Limited. Trajenta 5 mg film-coated tablets: summary of product characteristics. 2011. Available from: http://www.medicines.org.uk/emc/medicine/25000/SPC/trajenta%205%20mg%20film-coated%20tablets/. Accessed 9 May 2012.
Scottish Intercollegiate Guidelines Network. Management of diabetes: a national clinical guideline. Clinical guideline 116. 2010. Available from: http://www.sign.ac.uk/pdf/sign116.pdf. Accessed 9 May 2012.
National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes. NICE clinical guideline 87. 2009. Available from: http://www.nice.org.uk/nicemedia/pdf/CG87NICEGuideline.pdf. Accessed 9 May 2012.
National Institute for Health and Clinical Excellence. NICE technology appraisal guidance TA203: liraglutide for the treatment of type 2 diabetes mellitus. 2010. Available from: http://www.nice.org.uk/nicemedia/live/13248/51259/51259.pdf. Accessed 9 May 2012.
National Institute for Health and Clinical Excellence. NICE technology appraisal guidance TA248: exenatide prolonged-release suspension for injection in combination with oral antidiabetic therapy for the treatment of type 2 diabetes. 2012. Available from: http://www.nice.org.uk/nicemedia/live/13670/58205/58205.pdf. Accessed 20 April 2012.
Peters A. Incretin-based therapies: review of current clinical data. Am J Med. 2010;123(Suppl. 3):S28–37.
Rosenstock J, Gumprecht J, Szyprowska E, Bednarczyk-Kaluzny M, Zychma M, During M, et al. Pharmacokinetics of liraglutide vs. exenatide in type 2 diabetes: sustained vs. fluctuating concentrations over 24 hours. Diabetes. 2009;58(Suppl. 1):A150.
Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39–47.
Watson E, Jonker DM, Jacobsen LV, Ingwersen SH. Population pharmacokinetics of liraglutide, a once-daily human glucagon-like peptide-1 analog, in healthy volunteers and subjects with type 2 diabetes, and comparison to twice-daily exenatide. J Clin Pharmacol. 2010;50(8):886–94.
DeYoung MB, MacConell L, Sarin V, Trautmann M, Herbert P. Encapsulation of exenatide in poly-(D, L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther. 2011;13(11):1145–54.
Buse JB, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, et al. Switching to once-daily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care. 2010;33(6):1300–3.
Pratley R, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S. et al; 1860-LIRA-DPP-4 Study Group. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial. Int J Clin Pract. 2011;65(4):397–407.
Buse JB, Drucker DJ, Taylor KL, Kim T, Walsh B, Hu H, et al. DURATION-1 Study Group. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010;33(6):1255–61.
Russell-Jones D, Cuddihy RM, Hanefeld M, Kumar A, González JG, Chan M. et al; DURATION-4 Study Group. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012;35(2):252–8.
Wysham C, Bergenstal R, Malloy J, Yan P, Walsh B, Malone J, Taylor K. DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabet Med. 2011;28(6):705–14.
Schmidt WE, Christiansen JS, Hammer M, Zychma MJ, Buse JB. Patient-reported outcomes are superior in patients with Type 2 diabetes treated with liraglutide as compared with exenatide, when added to metformin, sulphonylurea or both: results from a randomized, open-label study. Diabet Med. 2011;28(6):715–23.
Buse JB, Nauck MA, Forst T, Sheu WH, Shenouda SK, Heilmann CR, Hoogwerf BJ, et al. Exenatide once weekly versus liraglutide once daily patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2012; doi:10.1016/S0140-6736(12)61267-7.
Eli Lilly. Press release—DURATION-6 top-line study results announed. 2011. Available from: https://investor.lilly.com/releasedetail2.cfm?ReleaseID=554248. Accessed 12 Feb 2012.
Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet. 2010;375(9724):1447–56.
Davies M, Pratley R, Hammer M, Thomsen AB, Cuddihy R. Liraglutide improves treatment satisfaction in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin. Diabet Med. 2011;28(3):333–7.
Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372(9645):1240–50.
Blevins T, Pullman J, Malloy J, Yan P, Taylor K, Schulteis C, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 dfiabetes. J Clin Endocinol Metab. 2011;96(5):1301–10.
Best JH, Boye KS, Rubin RR, Cao D, Kim TH, Peyrot M. Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily. Diabet Med. 2009;26(7):722–8.
Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010;376(9739):431–9.
Best JH, Rubin RR, Peyrot M, Li Y, Yan P, Malloy J, et al. Weight-related quality of life, health utility, psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or pioglitazone after 26 weeks of treatment. Diabetes Care. 2011;34(2):314–9.
Scheen AJ, Charpentier G, Östgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2010;26:540–9.
Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes. Systematic review and meta-analysis. JAMA. 2007;298(2):194–206.
Prospective Studies Collaboration. Body-mass index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373(9669):1083–96.
Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316(7134):823–8.
Bergenstal R, Daniels G, Mann J, Nissen S, Pocock S, Zinman B, et al. Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER™) trial: rationale and study design. Diabetes. 2011;60(Suppl. 1):A612–3.
Merck & Co. TECOS: A randomized, placebo controlled clinical trial to evaluate cardiovascular outcomes after treatment with sitagliptin in patients with type 2 diabetes mellitus and inadequate glycemic control (ClinicalTrials.gov identifier: NCT00790205). 2008. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00790205?term=TECOS&rank=1. Accessed 9 May 2012.
AstraZeneca. Does saxagliptin reduce the risk of cardiovascular events when used alone or added to other diabetes medications (SAVOR- TIMI 53). 2010. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01107886?term=saxagliptin+cardiovascular&rank=1. Accessed 9 May 2012.
Amylin Pharmaceuticals, Inc. Exenatide study of cardiovascular event lowering trial (EXSCEL): a trial to evaluate cardiovascular outcomes after treatment with exenatide once weekly in patients with type 2 diabetes mellitus. 2010. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01144338?term=EXSCEL&rank=1. Accessed 9 May 2012.
Boehringer Ingelheim Pharmaceuticals. A multicentre, international, randomised, parallel group, double blind study to evaluate cardiovascular safety of linagliptin versus glimepiride in patients with type 2 diabetes mellitus at high cardiovascular risk (CAROLINA). 2010. Available from: http://clinicaltrials.gov/ct2/show/NCT01243424?term=CAROLINA+linagliptin&rank=1. Accessed 9 May 2012.
Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased risk of acute pancreatitis and biliary disease observe din patients with type 2 diabetes. A retrospective cohort study. Diabetes Care. 2009;32:834–8.
Drucker DJ, Sherman SI, Bergenstal RM, Buse JB. The safety of incretin-based therapies–review of the scientific evidence. J Clin Endocrinol Metab. 2011;96(7):2027–31.
Blonde L, Montanya E. Comparison of liraglutide versus other incretin-related anti-hyperglycaemic agents. Diabetes Obes Metab. 2012;14(Suppl. 2):20–32.
UK Department of Health. Department of Health: quality and outcomes framework. Available from URL: http://www.dh.gov.uk/en/Healthcare/Primarycare/PMC/Quality/OutcomesFramework/index.htm. Accessed 9 May 2012.
Acknowledgments
The author would like to thank Watermeadow Medical, UK, for assistance in preparing a draft version of this manuscript.
Funding
Funding for editorial and writing support was provided by Novo Nordisk.
Conflicts of interest
SR declares that preparation of the manuscript was funded by Novo Nordisk UK. This manuscript details the views of the author and not necessarily the views of Barndoc Healthcare Ltd.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Russell, S. Incretin-based therapies for type 2 diabetes mellitus: a review of direct comparisons of efficacy, safety and patient satisfaction. Int J Clin Pharm 35, 159–172 (2013). https://doi.org/10.1007/s11096-012-9729-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11096-012-9729-9