Type 2 Diabetes review – ToR 4 COMPARATIVE SAFETY AND EFFECTIVENESS OF TYPE 2 DIABETES MEDICINES FINAL REPORT SEPTEMBER 2014 A report by the Centre for Applied Health Economics (CAHE), Griffith University Type 2 Diabetes review – ToR 4 This report was commissioned by the Pharmaceutical Evaluation Branch, Department of Health, the Australian Government. Researchers: Erika Turkstra Senior research fellow, health technology assessment Martin Downes Research fellow, health technology assessment Emilie Bettington Senior research assistant Tracy Comans Senior research fellow, health technology assessment Paul Scuffham Professor and chair in health economics The assistance of Sanjeewa Kularatna with the data extraction and Gabor Mihala with the statistical analyses is appreciated. The advice provided by the Post-Market Review Section, Pharmaceutical Evaluation Branch, Department of Health and the Reference Group is also appreciated. Type 2 Diabetes review – ToR 4 CONTENTS ACRONYMS ............................................................................................................. III EXECUTIVE SUMMARY ............................................................................................ 1 PURPOSE OF THE REVIEW ........................................................................................... 1 BACKGROUND ............................................................................................................ 1 REVIEW OF CLINICAL GUIDELINES ................................................................................ 2 SYSTEMATIC LITERATURE REVIEW ................................................................................ 3 RESULTS ................................................................................................................... 4 CONCLUSION ........................................................................................................... 16 BACKGROUND ....................................................................................................... 18 SECTION A: REVIEW CLINICAL TREATMENT ALGORITHMS FOR TYPE 2 DIABETES ............................................................................................................... 20 A.1 AUSTRALIAN GUIDELINES ............................................................................... 21 A.1.1 RACGP and Diabetes Australia ..................................................................... 21 ''''''''''''' '''''''''''''''''''''''' '''''''''''''''''''''' '''''''''''''''' ........................................................................... 21 A.2 INTERNATIONAL GUIDELINES ........................................................................... 22 A.2.1 Canada .......................................................................................................... 23 A.2.2 England and Wales ........................................................................................ 23 A.2.3 New Zealand.................................................................................................. 26 A.2.4 United States of America ............................................................................... 26 A.3 SUMMARY OF CLINICAL GUIDELINES ................................................................ 27 SECTION B: LITERATURE REVIEW AND META-ANALYSES OF THE COMPARATIVE CLINICAL SAFETY AND EFFICACY OF TYPE 2 DIABETES MEDICATION ........................................................................................................... 29 B.1 METHODS FOR THE SYSTEMATIC LITERATURE REVIEW ..................................... 30 B.1.1 Stage 1: Identifying systematic reviews.......................................................... 30 B.1.2 Stage 2: Systematic literature review – update from identified reviews .......... 32 B.1.3 Stage 3: Identifying relevant RCTs ................................................................. 32 B.1.4 Stage 4: Identifying additional triple therapy trials .......................................... 33 B.1.5 Data extraction ............................................................................................... 34 B.1.6 Clinical outcomes included............................................................................. 34 B.1.7 Statistical analysis.......................................................................................... 34 B.2 RESULTS – MONOTHERAPY ............................................................................ 35 B.2.1 List of included trials - MONOTHERAPY ........................................................ 35 B.3 RESULTS – DUAL THERAPY ............................................................................ 38 B.3.1 List of included trials – DUAL THERAPY ....................................................... 38 B.3.2 Risk of bias – DUAL THERAPY ..................................................................... 41 B.3.3 Trial characteristics – DUAL THERAPY ......................................................... 42 B.3.4 Baseline characteristics – DUAL THERAPY .................................................. 42 B.3.5 Methods of analysis – DUAL THERAPY ........................................................ 42 B.3.6 Results – DUAL THERAPY ............................................................................ 42 B.3.7 Discussion – DUAL THERAPY ...................................................................... 43 B.4 RESULTS – TRIPLE THERAPY .......................................................................... 43 B.4.1 List of included trials – TRIPLE THERAPY .................................................... 43 B.4.2 Risk of bias – TRIPLE THERAPY .................................................................. 46 B.4.3 Trial characteristics – TRIPLE THERAPY ...................................................... 47 B.4.4 Baseline characteristics – TRIPLE THERAPY ............................................... 47 B.4.5 Methods of analysis – TRIPLE THERAPY ..................................................... 48 B.4.6 Results – TRIPLE THERAPY ......................................................................... 49 B.4.7 Discussion – TRIPLE THERAPY ................................................................... 63 B.5 RESULTS – THERAPY ADDED TO EXISTING MEDICATION .................................... 64 B.5.1 List of included trials – EXISITING MEDICATION .......................................... 64 B.5.2 Risk of bias – EXISTING MEDICATION ......................................................... 66 i Type 2 Diabetes review – ToR 4 B.5.3 Trial characteristics – EXISTING MEDICATION ............................................ 66 B.5.4 Baseline characteristics – EXISTING MEDICATION ...................................... 67 B.5.5 Methods of analysis – EXISTING MEDICATION ............................................ 67 B.5.6 Results – EXISTING MEDICATION ............................................................... 68 B.5.7 Discussion – EXISTING MEDICATION .......................................................... 74 SECTION C: SUMMARY AND DISCUSSION ............................................................ 75 REFERENCES ......................................................................................................... 78 ATTACHMENT TO SECTION B: SYSTEMATIC LITERATURE REVIEW ................... 85 B.1 METHODS ..................................................................................................... 85 B.1.1 Literature search for RCTs ............................................................................. 85 B.1.2 Full details of searches and terms .................................................................. 88 B.1.7 Statistical Analyses ........................................................................................ 91 B.3 RESULTS – DUAL THERAPY ............................................................................ 92 B.3.2 Assessment of bias – DUAL THERAPY ......................................................... 92 B.3.3 Trial characteristics – DUAL THERAPY ......................................................... 92 B.3.4 Baseline characteristics – DUAL THERAPY .................................................. 93 B.4 RESULTS – TRIPLE THERAPY .......................................................................... 94 B.4.2 Risk of bias – TRIPLE THERAPY .................................................................. 94 B.4.3 Trial characteristics – TRIPLE THERAPY ...................................................... 96 B.4.4 Baseline characteristics – TRIPLE THERAPY ............................................. 101 B.4.6 Results of the included trials – TRIPLE THERAPY ...................................... 106 B.5 RESULTS – THERAPY ADDED TO EXISTING MEDICATION .................................. 115 B.5.2 Risk of bias – EXISTING MEDICATION ....................................................... 115 B.5.3 Trial characteristics – EXISTING MEDICATION .......................................... 116 B.5.4 Baseline characteristics – EXISTING MEDICATION .................................... 119 B.5.6 Results of trials with a duration of less than one year – EXISTING MEDICATION ............................................................................................................. 120 ii Type 2 Diabetes review – ToR 4 ACRONYMS ACA = acarbose MI = myocardial infarction ACE = angiotensin converting enzyme Mor = mortality AE = adverse event MTC = mixed treatment comparison ALO = alogliptin MVD = microvascular disease Asp = aspart N = North bid = twice