The role of incretin-based therapies in prediabetes: A review

  • Author Footnotes
    1 Tel.: +1 961 70 209 135; fax: +1 961 1 365 189.
    Hala Ahmadieh
    Footnotes
    1 Tel.: +1 961 70 209 135; fax: +1 961 1 365 189.
    Affiliations
    Department of Internal Medicine, Division of Endocrinology and Metabolism, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, United States
    Search for articles by this author
  • Sami T. Azar
    Correspondence
    Corresponding author. Tel.: +1 961 3 234 250; fax: +1 961 1 365 189.
    Affiliations
    Department of Internal Medicine, Division of Endocrinology and Metabolism, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, United States
    Search for articles by this author
  • Author Footnotes
    1 Tel.: +1 961 70 209 135; fax: +1 961 1 365 189.
Published:March 24, 2014DOI:https://doi.org/10.1016/j.pcd.2014.02.005

      Abstract

      Prediabetes, a high-risk state for future development of diabetes, is prevalent globally. Abnormalities in the incretin axis are important in the progression of B-cell failure in type 2 diabetes. Incretin based therapy was found to improve B cell mass and glycaemic control in addition to having multiple beneficial effects on the systolic and diastolic blood pressure, weight loss in addition to their other beneficial effects on the liver and cardiovascular system. In prediabetes, several well-designed preventive trials have shown that lifestyle and pharmacologic interventions such as metformin, thiazolidinediones (TZD), acarbose and, nateglinide and orlistat, are effective in reducing diabetes development. In recent small studies, incretin based therapy (DPP IV inhibitors and GLP-1 agonists) have also been extended to patients with prediabetes since it was shown to better preserve B-cell function and mass in animal studies and in clinical trials and it was also shown to help maintain good long term metabolic control. Because of the limited studies and clinical experience, their side effects and costs currently guidelines do not recommend incretin-based therapies as an option for treatment in patients with prediabetes. With future clinical trials and studies they may be recommended for patients with impaired fasting glucose or impaired glucose tolerance.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Primary Care Diabetes
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • American Diabetes Association
        Standards of medical care in diabetes-2013.
        Diabetes Care. 2013; 35: S11-S63
        • The International Expert Committee
        International expert committee report on the role of the A1c assay in the diagnosis of diabetes.
        Diabetes Care. 2009; 32: 1327-1334
        • WHO
        Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus.
        Diabetes Res. Clin. Pract. 2011; 93: 299-309
      1. Report of a WHO/IDF Consultation: Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia.
        WHO, Geneva2006 (http://whqlibdoc.who.int/publications/2006/924159 4934_eng.pdf)
      2. IDF DIABETES ATLAS Sixth edition. Online version of IDF Diabetes Atlas: www.idf.org/diabetesatlas. ISBN: 2-930229-85-3.

        • Tábak A.G.
        • Herder C.
        • Rathmann W.
        • et al.
        Prediabetes: a high-risk state for diabetes development.
        Lancet. 2012; : 60283-60289https://doi.org/10.1016/S0140-6736
        • Kahn S.E.
        • Cooper M.E.
        • Del S.
        • Prato
        Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.
        Lancet. 2013; : 62154-62156https://doi.org/10.1016/S0140-6736
        • DeFronzo R.A.
        Current issues in the treatment of type 2 diabetes. Overview of newer agents: where treatment is going.
        Am J Med. 2010; 123: S38-S48
        • Wajchenberg B.L.
        Beta-cell failure in diabetes and preservation by clinical treatment.
        Endocr. Rev. 2007; 28: 187-218
        • Weir G.
        • Bonner-Weir S.
        Five stages of evolving b-cell dysfunction during progression to diabetes.
        Diabetes. 2004; 53: S16-S21
        • Abdul-Ghani M.A.M.A.
        • DeFronzo T.D.
        Contributions of B-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose.
        Diabetes Care. 2006; 29: 1130-1139
        • Nathan D.M.
        • Davidson M.B.
        • Defronzo R.A.
        • Heine R.J.
        • Henry R.R.
        • Pratley R.
        • Zinman B.
        Impaired fasting glucose and impaired glucose tolerance.
        Diabetes Care. 2007; 30: 753-759
        • Buchanan T.A.
        • Xiang A.H.
        • Peters R.K.
        • Kjos S.L.
        • Marroguin A.
        • Goico J.
        • Ochoa C.
        • Tan S.
        • Berkowitz K.
        • Hodis H.N.
        • Azzen S.P.
        Preservation of pancreatic–cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women.
        Diabetes. 2002; 51: 2796-2803
        • Pan X.R.
        • Li G.W.
        • Hu Y.H.
        • Wang J.X.
        • Yang W.Y.
        • AN Z.X.
        • Hu Z.X.
        • Lin J.
        • Xiao J.Z.
        • Cao H.B.
        • Liu P.A.
        • Jiang X.G.
        • Jiang Y.Y.
        • Wang J.P.
        • Zheng H.
        • Bennett P.H.
        • Howard B.V.
        Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study.
        Diabetes Care. 1997; 20: 537-544
        • Rask E.
        • Olsson T.
        • Soderberg S.
        • Holst J.J.
        • Tura A.
        • Pacini G.
        Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance.
        Metabolism. 2004; 53: 624-631
        • Laakso M.
        • Zilinskaite J.
        • Hansen T.
        • Boesgaard T.W.
        • Vanttinen M.
        • Stancakova A.A.
        Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study.
        Diabetologia. 2008; 51: 502-511
        • Fritsche A.
        • Stefan N.
        • Hardt E.
        • Haring H.
        • Stumvoll M.
        Characterisation of beta-cell dysfunction of impaired glucose tolerance: evidence for impairment of incretin-induced insulin secretion.
        Diabetologia. 2000; 43: 852-858
        • Bock G.
        • Dalla Man C.
        • Campioni M.
        • Chittilapilly E.
        • Basu R.
        • Toffolo G.G.
        Pathogenesis of prediabetes: mechanisms of fasting and postprandial hyperglycemia in people with impaired fasting glucose and/or impaired glucose tolerance.
        Diabetes. 2006; 55: 3536-3549
        • Abu-Hamdah R.
        • Rabiee A.
        • Meneilly G.S.
        • et al.
        Clinical review: the extrapancreatic effects of glucagon-like peptide-1 and related peptides.
        J. Clin. Endocrinol. Metab. 2009; 94: 1843-1852
        • Vella A.
        Mechanism of action of DPP-4 inhibitors-new insights.
        J. Clin. Endocrinol. Metab. 2012; 97: 2626-2628
        • Holst J.
        On the physiology of GIP and GLP-1.
        Horm. Metab. Res. 2004; 36: 747-754
        • Baggio L.L.
        • Drucker D.J.
        Biology of incretins: GLP-1 and GIP.
        Gastroenterology. 2007; 132: 2131-2157
        • Buse J.B.
        • Klonoff D.C.
        • Nielsen L.L.
        • Guan X.
        • Bowlus C.L.
        • Holcombe J.H.
        • Maggs D.G.
        M. E. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials.
        Clin. Ther. 2007; 29: 139-153
        • Vilsbøll T.
        • Brock B.
        • Perrild H.
        • Levin K.
        • Lervang H.H.
        • Kolendorf K.
        • Krarup T.
        • Schmitz O.
        • Zdravkovic M.
        • Le-Thi T.
        • Madsbad S.
        Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with type 2 diabetes mellitus.
        Diabet. Med. 2008; 25: 152-156
        • Ban K.
        • Noyan-Ashraf M.H.
        • Hoefer J.
        • Bolz S.S.
        • Drucker D.J.
        • Husain M.M.
        Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways.
        Circulation. 2008; 117: 2340-2350
        • Nauck A.
        • Michael A.
        • Vilsbøll T.
        • Gallwitz B.
        • Garber A.
        • Madsbad S.
        Incretin-based therapies.
        Diabetes Care. 2009; 32: S223-S231
        • Fontana J.
        • Červinková Z.
        • Anděl M.
        Effects of GLP-1 (glucagon-like peptide 1) on liver.
        Vnitr Lek. 2013; 59: 551-558
        • Svegliati-Baroni G.
        • Saccomanno S.
        • Rychlicki C.
        • Agostinelli L.
        • De Minicis S.
        • Candelaresi C.
        • Faraci G.
        • Pacetti D.
        • Vivarelli M.
        • Nicolini D.
        • Garelli P.
        • Casini A.
        • Manco M.
        • Mingrone G.
        • Risaliti A.
        • Frega G.N.
        • Benedetti A.
        • Gastaldelli A.
        Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis.
        Liver Int. 2011; 31: 1285-1297
        • Deacon C.F.
        • Marx N.
        Potential cardiovascular effects of incretin-based therapies.
        Expert Rev. Cardiovascular Therapy. 2003; 10: 337-351
        • Anagnostis P.
        • Athyros V.G.
        • Adamidou F.
        • Panagiotou A.
        • Kita M.
        • Karagiannis A.
        • Mikhailidis D.P.
        Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control.
        Diab. Obes. Metab. 2011; 13: 302-312
        • Ban K.
        • Noyan-Ashraf M.H.
        • Hoefer J.
        • Bolz S.S.
        • Drucker D.J.
        • Husain M.
        Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways.
        Circulation. 2008; 117: 2340-2350
        • Nyström T.
        • Gutniak M.K.
        • Zhang Q.
        • Zhang F.
        • Holst J.J.
        • Ahrén B.
        • Sjöholm A.
        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: E1209-E1215
        • Petrie J.
        The cardiovascular safety of incretin-based therapies: a review of the evidence.
        Cardiovasc. Diabetol. 2013; 12: 130
        • Bergenstal R.
        • Daniels G.
        • Mann J.
        • Nissen S.
        • Pocock S.
        • Zinman B.
        Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADERTM) trial: rationale and study design.
        Diabetes. 2011; 60: A612-A613
      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.

      4. 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.

      5. 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.

      6. 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.

        • Vilsbøll T.
        • Christensen M.
        • Junker A.E.
        • Knop F.K.
        • Gluud L.L.
        Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials.
        BMJ. 2012; 344 (doi: http://dx.doi.org/10.1136/bmj.d7771)
        • Buse J.B.
        • Rosenstock J.
        • Sesti G.G.
        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: 39-47
        • Buse J.B.
        • Sesti G.
        • W.E. Schmidt W.E.
        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: 1300-1303
        • Drucker D.J.
        • Buse J.B.
        • Taylor K.
        Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study.
        Lancet. 2008; 372: 1240-1250
        • Hadjiyanni I.
        Exendin-4 modulates diabetes onset in nonobese diabetic mice.
        Endocrinology. 2008; 149: 1338-1349
        • Pan X.R.
        • Li G.W.
        • Hu Y.H.
        • et al.
        Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerances. The Da Qing IGT and Diabetes Study.
        Diabetes Care. 1997; 20: 537-544
        • Sherry N.A.
        Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells.
        Endocrinology. 2007; 148: 5136-5144
      7. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
        N Engl J Med. 2002; 346: 393-403
        • Sheffield C.A.
        Off-label use of exenatide for the management of insulinresistant type 1 diabetes mellitus in an obese patient with human immunodeficiency virus infection.
        Pharmacotherapy. 2007; 27: 1449-1455
        • Lindstrom J.
        • Eriksson J.G.
        • Valle T.T.
        • et al.
        Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial.
        J. Am. Soc. Nephrol. 2003; 14: S108-S113
        • Paisley A.N.
        Stabilizing effect of exenatide in a patient with C-peptidenegative diabetes mellitus.
        Diabet. Med. 2009; 26: 935-938
        • Buchanan T.A.
        • Xiang A.H.
        • Peters R.K.
        • et al.
        Preservation of pancreatic–cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high risk Hispanic women.
        Diabetes. 2002; 51: 2796-2803
        • Creutzfeldt W.O.
        Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I (7-36) amide in type 1 diabetic patients.
        Diabetes Care. 1996; 19: 580-586
        • Gerstein H.C.
        • Yusuf S.
        • Bosch J.
        • et al.
        Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
        Lancet. 2006; 368: 1096-1105
        • Suarez-Pinzon W.L.
        Combination therapy with a dipeptidyl peptidase-4 inhibitor and a proton pump inhibitor restores normoglycaemia in non-obese diabetic mice.
        Diabetologia. 2009; 52: 1680-1682
        • Bosch J.
        • Yusuf S.
        • Gerstein H.C.
        • et al.
        Effect of ramipril on the incidence of diabetes.
        N. Engl. J. Med. 2006; 355: 1551-1562
        • Tian L.
        Reversal of new-onset diabetes through modulating inflammation and stimulating beta-cell replication in nonobese diabetic mice by a dipeptidyl peptidase IV inhibitor.
        Endocrinology. 2010; 151: 3049-3060
        • Chiasson J.L.
        • Josse R.G.
        • Gomis R.
        • et al.
        Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. The STOP-NIDDM trial.
        JAMA. 2003; 290: 486-494
        • Pan C.Y.
        • Gao U.
        • Chen J.W.
        • et al.
        Efficacy of acarbose in Chinese subjects with impaired glucose tolerance.
        Diabetes Res. Clin. Pract. 2003; 61: 183-190
        • Torgerson J.S.
        • Hauptman J.
        • Boldrin M.N.
        • Sjöström L.
        Xenical in the prevention of Diabetes in Obese Subjects (XENDOS) study.
        Diabetes Care. 2004; 27: 155-161
        • McMurray J.J.
        • Holman R.R.
        • Haffner S.M.
        • et al.
        Effect of valsartan on the incidence of diabetes and cardiovascular events.
        N. Engl. J. Med. 2010; 362: 1477-1490
        • Holman R.R.
        • Haffner S.M.
        • McMurray J.J.
        • et al.
        Effect of nateglinide on the incidence of diabetes and cardiovascular events.
        N. Engl. J. Med. 2010; 362: 1463-1476
        • Scheen A.J.
        NAVIGATOR: a trial of prevention of cardiovascular complications and type 2 diabetes with valsartan and/or nateglinide.
        Rev. Med. Liege. 2010; 65: 217-223
        • Kirman M.S.
        • Shankar R.R.
        • Shankar S.
        • Shen C.
        • Brizendine E.
        • Baron A.
        • Mcgill J.
        Treating postprandial hyperglycemia does not appear to delay progression of early type 2 diabetes.
        Diabetes Care. 2006; 29: 2095-2101
        • Sudre B.
        • Broqua P.
        • White R.B.
        • et al.
        Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male zucker diabetic fatty rats.
        Diabetes. 2002; 51: 1461-1469
        • Moritoh Y.
        • Takeuchi K.
        • Hazama M.
        Combination treatment with alogliptin and voglibose increases active GLP-1 circulation, prevents the development of diabetes and preserves pancreatic beta-cells in prediabetic db/db mice.
        Diabetes Obes. Metab. 2010; 12: 224-233
        • Utzschneider K.M.
        • Tong J.
        • Montgomery B.
        • et al.
        The dipeptidyl peptidase-4 inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose.
        Diabetes Care. 2008; 31: 108-113
        • Rosenstock J.
        • Foley J.
        • Rendell M.
        • et al.
        Effects of the dipeptidyl peptidase-IV inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia in subjects with impaired glucose tolerance.
        Diabetes Care. 2008; 31: 30-35
        • Bock G.
        • Dalla Man C.
        • Micheletto F.
        • et al.
        The effect of DPP-4 inhibition with sitagliptin on incretin secretion and on fasting and postprandial glucose turnover in subjects with impaired fasting glucose.
        Clin. Endocrinol. (Oxf.). 2010; 73: 189-196
        • Perreault L.
        • Man C.D.
        • Hunerdosse D.M.
        • et al.
        Incretin action maintains insulin secretion, but not hepatic insulin action, in people with impaired fasting glucose.
        Diabetes Res. Clin. Pract. 2010; 90: 87-94
        • Astrup A.
        • Rossner S.
        • Van G.L.
        • Rissanen A.
        • et al.
        Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study.
        Lancet. 2009; 374: 1606-1616
        • DeFronzo R.
        • Abdul-Ghani M.
        Preservation of b-cell function: the key to diabetes prevention.
        J. Clin. Endocrinol. Metab. 2011; 96: 2354-2366
        • Rosenstock J.
        • Klaff L.J.
        • Schwartz S.
        • et al.
        Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without prediabetes.
        Diabetes Care. 2010; 33: 1173-1175
      8. Byetta [Package Insert].
        Amylin Pharmaceuticals, Inc., San Diego, CA2007
        • Crespel A.
        • De B.F.
        • Gros L.L.
        Effects of glucagon and glucagon-like peptide-1- (7-36) amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line.
        Endocrinology. 1996; 137: 3674-3680
        • Lamari y.
        • Boissard C.
        • Moukhtar M.S.
        Expression of glucagon-like peptide 1 receptor in a murine C cell line: regulation of calcitonin gene by glucagon-like peptide 1.
        FEBS Lett. 1996; 393: 248-252
        • Parks M.
        • Rosebraugh C.
        Weighing risks and benefits of liraglutide – the FDA's review of a new antidiabetic therapy.
        N. Engl. J. Med. 2010; 362: 774-777
        • Food U.S.
        Drug Administration, Center for Drug Evaluation and Research. Exenatide (marketed as BYETTA): acute pancreatitis.
        FDA Drug Safety Newsletter Silver Spring, MD: US Department of Health and Human Services, 2008: 1 (http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNews letter/ucm109165.htm [4 May 2011])
      9. Food and Drug Administration. Information for healthcare professionals: exenatide (marketed as BYETTA) – 8/2008 update. 2008; http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm124713.htm [4 May 2011].

        • Dore D.D.
        • Seeger J.D.
        • Arnold C.K.C.K.
        Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide.
        Curr. Med. Res. Opin. 2009; 25: 1019-1027
        • Engel S.S.
        • Williams-Herman D.E.
        • Golm G.T.
        Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis.
        Int. J. Clin. Pract. 2010; 64: 984-990
        • Nathan D.M.
        • Buse J.B.
        • Davidson M.B.
        Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.
        Diabetes Care. 2009; 32: 193-203
        • Buse J.B.
        • Henry R.R.
        • Han J.
        Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylureatreated patients with type 2 diabetes.
        Diabetes Care. 2004; 27: 2628-2635
        • DeFronzo R.A.
        • Ratner R.E.
        • Han J.
        Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.
        Diabetes Care. 2005; 28: 1092-1100
        • Nauck M.
        • Fri A.
        • Hermansen K. K.
        Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (Liraglutide Effect and Action in Diabetes)-2 study.
        Diabetes Care. 2009; 32: 84-90
        • Aroda V.R.
        The safety and tolerability of GLP-1 receptor agonists in the treatment of type 2 diabetes: a review.
        Diabetes Metab. Res. Rev. 2011; 27: 528-542