Background

1. The efficacy and safety of Inhibitors of Dipeptidil Peptidase 4 (DDP-4) in the treatment of Type 2 Diabetes Mellitus – a systematic review of randomized controlled trialsAuthors:TiagoMillner, Petra Santos, Sara Figueiroa Silva, André Pereira, ElizabeteBranco, Sofia Sousa, Miriam Sousa, NatachaSousa,Vanessa Silva, João Andrade, Alice Pimentel, Filipa Sousa

2. Background • Definitionof Diabetes Mellitus (DM) DM is a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects of insulin secretion, insulin action, or a combination of both. (1) • Typesof Diabetes Mellitus - Type 1 diabetes: due to a virtually complete lack of endogenous pancreatic insulin production; - Type 2 diabetes: the rising blood glucose results from a combination of genetic predisposition, unhealthy diet, physical inactivity, and increasing weight with a central distribution resulting in complex pathophysiological processes;(2) • RA. InternationalTextbookof Diabetes Mellitus. 3rd ed. Chichester, WestSussex, Hoboken, NJ: John Wiley; 2004. • LarsRydénet al. EuropeanHeartJournal, 2007, page 4

3. Background Prevalence • Rises with age up to the seventh and eighth decades in both men and women • This suggests that the lifetime risk of diabetes in European people is 30–40%. (3) 3) The DECODE Study Group. Age- and sex-specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts. Diabetes Care 2003;26:61–69.

4. Backgroud • Treatment • Oral antidiabetic drugs: Sulfonylureas; Biguanides; Thiazolidinediones; Alpha-glucosidase inhibitors. • Insulin 6)NathanDMet al. Managementofhyperglycemiaintype 2 diabetes, DiabetesCare 2006;29: 1963–72.

5. Background • Complications • Fewer than half of the adults with type 2 diabetes reach a hemoglobin A1c (HbA1c) levelofless than 7% despite several availabletherapies. (7) • Ineffectiveimplementationofexistingpharmacotherapiesis a significant factor contributing to suboptimalcare (8) • However, efficacy of available therapies, even when used appropriately, diminishes as the disease progresses because of a steady, decline in pancreatic beta cellfunctionandcurrent therapies for type 2 diabetes are often limited by adverse effects such as weight gain, edema, or hypoglycemia (9) 7) Resnick HE Achievement of American Diabetes Association clinical practice recommendations among US adults with diabetes,1999-2002: the National Health and Nutrition ExaminationSurvey. Diabetes Care. 2006;29(3):531- 537. 8) Nathan DM et al. N Engl J Med. 2007;356(5):437-440. 9) TurnerJAMA. 1999; 281(21):2005-2012.

6. Background • Dipeptidyl peptidase-4 inhibitors (DPP-4) • DPP4 inhibitors are newdrugsthat are beingdeveloped. • Incretin therapy: • Principal types of incretins: GLP1 and GIP. • Based on the inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4) resulting on the manteinance of the incretin GLP 1 for a longer time. • Examples: vildagliptin (Januvia), sitagliptin (Galvus), saxagliptin (Onglyza). (10) 10) Barnett A et al. Int J ClinPract, November 2006, 60, 11, 1454–1470

7. ResearchquestionandAims • EfficacyandsafetyofDDP-4 inhibitorsinthetreatmentoftype 2 diabetes mellitus • Aims: • Primary • Evaluatetheefficacyof DPP4 inhibitorsinthetreatmentof DM whencomparedwith standard oral antidiabetic drugs • Evaluatethereductionofthe HbA1c, glicemicfastinglevel • Secundary • Evaluatethesafetyprofileandcomplication rates of DPP4 inhibitorsinthetreatmentof DM

8. Methods • Sistematic review of randomized controlled trials. • Data SourcesandSearches: • Databases: Pubmed, ISI Web of Knowledge and Scopus. • Bibliographic research until30/11/2009

9. Methods • Researchquery: (("Diabetes Mellitus, Type 2"[Mesh] OR diabetes mellitus OR "Diabetes Mellitus, Type 2/drugtherapy"[Mesh] OR hyperglycemia) AND ("dipeptidyl peptidase-4 inhibitor" OR "DPP-4 inhibitor“ OR "sitagliptin "[SubstanceName]) OR "3-hydroxyadamantylglycine-4,5-methanoprolinenitrile "[SubstanceName] OR linagliptin OR Alogliptin OR "vildagliptin "[SubstanceName])

10. Methods • Studyselection • Two reviewers independently screenedabstractsaccording to theinclusionandexclusioncriteria. • Full-textarticleswereretrievedand reviewed if a decision on inclusion could not be made solely basedontheabstract. • Anydiscrepancieswere resolved by a thirdreviewer.

11. Methods • Inclusioncriteria • Randomizedcontrolledclinicaltrials • Studiescomparing DPP4 inhibitor based therapy with other hipoglycemic treatment or placebo • Minimum follow up of 12 weeks • Articles with information about HbA1c or fasting glucose levels • Exclusioncriteria • Notwritteninportugueseorenglish • Studynotperformedinhumans • Reviewarticles • 11) Renee E. Amoriet al. JAMA, July 11, 2007—Vol 298, No. 2

12. Methods • Evaluationofarticlequality: • Ofthearticlesincluded, weassessedthequalityacording to thecriteriaoftheConsort. Articleswhichdidnotrespect 60 % ofthe 22 criteriastatedwereeliminated. • Inthis fase wereincluded 5 articles, beingexcluded 7 becauseofdeniedaccess.

13. Methods Figure 2: Articleflowinthestudy

14. Methods • Data were extracted according to the following 4 topics: - Methods; - Participants; - Interventions; - Outcomes and Results These criteria were used according to the Cochrane Handbook for Systematic Reviews of Interventions , 4.2.6 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of InterventiosVersion 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.

15. Methods • Data Synthesis and Analysis • For data synthesis we used a table which summarised the information about study duration, population size, drug used and dosage, HbA1c and FPG baseline levels and their differencefrom baseline and the adverse effects, represented by the hypoglycemic events. • We also used, for Data analysis, the RevMan software to create forest plots to assess the efficacy of the DPP-4 Inhibitors versus placebo. We created two forest plots, one for each of the two primary outcomes, HbA1c and FPG

16. Results • Data Extraction : • The following articles are included in the systematic review: • 1) R. Scott, M. Wu, M. Sanchez, P. Stein: Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes.Int J ClinPract , 61: 171 – 180, 2006 • 2) J. Rosenstock, M. Niggliand M. Maldonado-Lutomirsk: Long-term 2-year safety and efficacy of vildagliptin compared with rosiglitazone in drug-naïve patients with type 2 diabetes mellitus. Diabetes, ObesityandMetabolism, 11: 571-578, 2009

17. Results • 3) PabloAschner, MD; Mark S. Kipnes, MD; Jared K. Lunceford, PHD; Matilde Sanchez, PHD; CarolynMichel, MS; Debora E. Williams-Herman, MD. Effect of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy on Glycemic Control in Patients with Type 2 Diabetes. Diabetes Care, Volume 29, number 12, 2006 • 4) R. E. Pratley; S. Jauffret−Kamel; E. Galbreath; D. Holmes: Twelve−week Monotherapy with the DPP−4 Inhibitor Vildagliptin Improves Glycemic Control in Subjects withType 2 Diabetes. HormMetabRes, volume 38, pages 423 to 428, 2006 • 5) S. Dejager; S. Razac; J. E Foley; A. Schweizer: Vildagliptin in Drug-naïve Patients with Type 2 Diabetes: A 24-Week, Double-blind, Randomized, Placebo-controlled, Multiple-doseStudy. HormMetabRes , volume 39, pages 218 – 223, 2007

18. Results

19. Results

20. Results Figure 5: Comparisonof DPP-4 versus placeboconcerning HbA1c differencefrombaselineinalldrugdosages

21. Results Comparisonof DPP-4 versus placeboconcerning FPG differencefrombaselineinalldrugdosages

22. Results Comparisonof DPP-4 versus placeboconcerning HbA1c differencefrombaselineinthemostefficientdrugdosagesofeachstudy

23. Results Comparisonof DPP-4 versus placeboconcerning FPG differencefrombaselineinthebiggestdrugdosagesofeachstudy

24. Results Sitagliptin versus glipizide: • incidence of drug-related clinical adverse experiences modestly higher in the glipizide group • This difference was result of increased incidence of hypoglycaemia adverse experiences in the glipizidegroup Vildagliptin versus rosiglitazone: • overall occurrence of adverse effects similar • The majority of events were mild to moderate in severity. • Suspected study drug related adverse effects higher proportion in the rosiglitazone • A notable observation was the lower incidence of peripheral oedema in the vildagliptin treatment group compared with the rosiglitazone treatment group.

25. Results DPP-4 (sitagliptinandvildagliptin) versus placebo: • incidenceof adverse effectssimilar • majorityof adverse effectsclassified as mildandofmoderateseverity.

26. Discussion • Efficacyofthe DPP 4 inhibitorsgreaterthanofplaceboinallstudies DPP 4 vs. Otherhipoglicemicagents (glipizideandrosiglitazone): • greaterreductionofHbA1c and FPG with usual hypoglicemicagents • DPP 4 inbitorspresentbettersafetyprofile.

27. DPP 4 Inhibitors • goodsafetyprofile • Leadto a smallernumberof adverse effectsthanwithother usual hypogliceamicagents.

28. Limitations • Thelimitationsofthissystematicreview are: • Smallnumberofincludedstudies; • Studiespresentdifferentdrugdosageswhichdifficultagreggationof data; • Heterogeneityofthe data, which does notallowus to perform a metanalysis.

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