APPENDIX 1: Literature Search Strategy for Clinical Effectiveness Studies

Transcription

1 APPENDIX 1: Literature Search Strategy for Clinical Effectiveness Studies Guide to Search Syntax (DIALOG )! " " () (l) (n) (w) ab de dt id rn ti tn tw Explode the search term. Retrieve the search concept plus all narrower terms. Truncation symbol, single character. Retrieve plural and variant ending of search terms. Search phrases. Proximity operator. Words must be adjacent. Proximity operator. Links descriptors and subheadings. Proximity operator. Words must be near each other in any order. Proximity operator. Words must be adjacent. Search in article abstract. Descriptor i.e., subject heading ( a controlled, thesaurus term). Document type. Identifier (includes CAS Registry Number and natural language indexing terms). CAS Registry Number. Search in titles. Brand name. Text word. DATABASES DATES / LIMITS DIALOG OneSearch Human MEDLINE BIOSIS Previews EMBASE PASCAL SUBJECT HEADINGS/KEYWORDS Insulin Long-Acting(l)aa/de [MeSH heading for MEDLINE ] OR (Insulin Glargine OR Insulin Detemir)/de [EMTREE terms for EMBASE ] OR TN=(Lantus OR Levemir) [Brand names in EMBASE ] OR (glargine OR Lantus OR HOE()901 OR ()95()1)/ti,ab,id OR RN= OR (detemir OR Levemir OR NN()304 OR ()63()4)/ti,ab,id OR RN= [Textwords searched in title, abstract, identifier, registry number] OR (long()acting()insulin? OR slow?()acting()insulin? OR long()acting()analog? OR slow?()acting()analog?)/ti,ab [Textwords searched in title, abstract] OR Insulin(l)aa/de [MeSH heading for MEDLINE ] OR (Insulin Derivative OR Insulin Aspart OR A-1

2 Insulin()B28()Lysine()B29()Proline)/de [EMTREE terms for EMBASE ] OR TN=(Humalog OR NovoLog OR NovoRapid OR NovoMix OR Apidra) [Brand names in EMBASE ] OR Insulin Lispro/de [BIOSIS Previews thesaurus term] OR (insulin?(1n)analog? OR insulin?(1n)derivat? OR new()insulin? OR novel()insulin?)/ti,ab OR (133107()64()9 OR insulin?(2n)(lys?()28()b) OR (28()B()Lys?()29()B)(2n)insulin? OR Lispro? OR Humalog? OR B28 OR 28()B()lysine()29()B()prolineinsulin?)/ti,ab,id OR Lyspro?/ti,ab OR insulin()lys()b28()pro()b29/id OR RN= OR (116094()23()6 OR insulin?()aspart? OR B28()asp? OR Asp()B28 OR NovoLog OR NovoRapid OR NovoMix?)/ti,ab OR insulin()asp()b28/id OR RN= OR (insulin()glulisine OR apidra OR ()29()6 OR insulin()lys()b3()glu()b29 OR insulin()lysyl()b3()glutamyl()b29 OR B3()lysyl()B29()glutamylinsulin)/ti,ab,id OR RN= OR (quick()acting()insulin? OR rapid()acting()insulin? OR rapidly()acting()insulin? OR short()acting()insulin? OR fast()acting()insulin? OR quick()acting()analog? OR rapid()acting()analog? OR rapidly()acting()analog? OR short()acting()analog? OR fast()acting()analog?)/ti,ab AND Diabetes Mellitus!/de [MeSH heading for MEDLINE ] OR (Insulin-Dependent Diabetes OR Insulin-Dependent Diabetes Mellitus OR Diabetes OR Diabetes Insipidus OR Diabetes Mellitus OR "Maturity-Onset Diabetes of the Young" OR Non-Insulin-Dependent Diabetes Mellitus OR "Gestational Diabetes" OR "Gestational Diabetes Mellitus")/de [BIOSIS Previews thesaurus terms] OR (Diabetes Control OR Diabetes Insipidus! OR Diabetes Mellitus! OR A-2

3 Experimental Diabetes Mellitus! OR Pregnancy Diabetes Mellitus!)/de [EMTREE terms for EMBASE ] OR (diabet? OR IDDM OR NIDDM OR MODY OR "type 1" OR "type I" OR "type 2" OR "type II" OR insulin()depend?()dm OR matur?()onset()dm OR late()life()dm OR gestational()dm OR juvenile()onset()dm OR juvenile()dm OR ketosis()prone()dm OR sudden()onset()dm OR non()insulin()depend?()dm OR adult()onset()dm)/ti,ab AND (Controlled Clinical Trials OR Multicenter Studies OR Randomized Controlled Trials OR Double-Blind Method OR Random Allocation OR Single-Blind Method OR Placebos)/de [MeSH headings for MEDLINE ] OR dt=(multicenter Study OR Randomized Controlled Trial OR Controlled Clinical Trial) [Document type in MEDLINE ] OR (Multicenter Study OR Randomized Controlled Trial OR Randomized Clinical Trial OR Randomized Trial OR Evidence-Based Medicine)/de [BIOSIS Previews thesaurus terms] OR (Major Clinical Study OR Multicenter Study OR Controlled Study! OR Randomized Controlled Trial)/de [EMTREE terms for EMBASE ] OR (random? OR sham? OR placebo? OR singl?()(blind? OR dumm? OR mask?) OR doubl?()(blind? OR dumm? OR mask?) OR tripl?()(blind? OR dumm? OR mask?) OR trebl?()(blind? OR dumm? OR mask?) OR control?()(study OR studies OR trial?) OR RCT?? OR (multicent? OR multi()cent?)()(study OR studies OR trial?))/ti,ab OR (Meta-Analysis OR Technology Assessment, Biomedical)/de [MeSH headings for MEDLINE ] OR dt=meta-analysis [Document type in MEDLINE ] OR Meta-Analysis/de [BIOSIS Previews thesaurus term] OR (Meta Analysis OR Systematic Review OR Biomedical Technology A-3

4 Assessment)/de [EMTREE terms for EMBASE ] OR (meta()analy? OR metaanaly? OR met()analy? OR metanaly? OR health()technology()assessment? OR meta()regression? OR metaregression? OR mega()regression? OR systematic?()(literature()review? OR review? OR overview?) OR methodologic?()(literature()review? OR review? OR overview?) OR quantitative()(review? OR overview? OR synthes?) OR research()(integration? OR overview?) OR integrative(2w)(review? OR overview?) OR collaborative()(review? OR overview?) OR pool?()analy? OR data()synthes? OR data()extraction? OR data()abstraction? OR handsearch? OR hand()search? OR mantel()haenszel OR peto OR der()simonian OR dersimonian OR fixed()effect? OR latin()square?)/ti,ab Search performed on 3 August 2005; monthly alerts set up on MEDLINE, EMBASE and BIOSIS Previews and were ongoing until Jan/1/2006. Cochrane Library Issue Total Hits = 850 Records (817 clinical results + 33 sys. review /metaanalysis results), 442 Unique Records after comparison with PubMed records (423 clinical results + 19 sys. review /meta-analysis results) Same MeSH and keywords as per MEDLINE search, excluding study design filter. Appropriate syntax used. PubMed Websites of health technology assessment (HTA) and related agencies; trial registries; other databases Human Initial search performed on 2 August 2005 and updated with subsequent database updates. Last update performed on Feb/6/2006. Total Hits = Cochrane Database of Systematic Reviews = 2 Records, 1 Unique DARE = 2 Records, 0 Unique CENTRAL = 276 Records, 13 Unique Abstracts by INAHTA and other HTAs = 6 Records, 3 Unique Same MeSH and keywords as per MEDLINE search. Appropriate syntax used. Total Hits = 407 Unique Records AHRQ; National Research Register; University of York NHS Centre for Reviews and Dissemination to CRD databases; LILACS etc. A-4

5 APPENDIX 2: Data Extraction Form Reviewer s initials Reference (Ref ID, author, year, source, publication status) Trial characteristics Study design Number of centres Country Sponsor Number of patients Type of diabetes Disease state Investigator s definition of hypoglycemia Procedure Other Patients characteristics Category Unit Control All s Combined Comment Age Male or female Duration of diabetes HbA1c BMI Race or ethnicity Withdrawals or lost to follow-up Other Outcomes and Cost Data Category Units Control Comment HbA1c BG Diabetic complications AE Mortality QoL Cost Other A-5

6 APPENDIX 3: Trial Quality Assessment Form Reference Reviewer Number Category 1 Randomization Was the study described as randomized (i.e., including words such as randomly, random, randomization)? A trial reporting that it is randomized receives one point, yes=1, no=0 Trials describing an appropriate method of randomization (table of random numbers, computergenerated) receive an additional point, appropriate=1, not appropriate=0 If the report describes the trial as randomized and uses an inappropriate method of randomization (e.g., date of birth, hospital numbers), a point is deducted, inappropriate= 1 2 Double-blinding Was the study described as double-blind? A trial reporting that it is double-blind receives one point, yes=1, no=0 Trials describing an appropriate method of double-blinding (identical placebo: colour, shape, taste) receive an additional point, yes=1, no=0 If the report describes a trial as double-blind and uses an inappropriate method (e.g., comparison of tablets versus injection with no dummy), a point is deducted, inappropriate= 1 3 Withdrawals and dropouts Was there a description of withdrawals and dropouts? A trial reporting the number and reasons for withdrawals or dropouts receives one point. If there is no description, no point is given, yes=1, no=0 Total score (for above three categories) 4 Adequacy of allocation concealment: Central randomization; numbered or coded bottles or containers; drugs prepared by a pharmacy; serially numbered, opaque, sealed envelopes=adequate Alternation; reference to case-record number or date of birth=inadequate Allocation concealment not reported or fits neither category=unclear Score Adequacy Level A-6

7 APPENDIX 4A: Characteristics of RCTs Involving Type 1 DM Patients Study Anderson 1 Annuzzi 2 Arslanian 3 (poster) Study Period Sponsor Countries Number of Centres Study Type some 17 countries multi-centre open-label, investigators crossover, from Eli no wash-out Lilly period Eli Lilly Italy 8 open-label, crossover, no wash-out period reported 24 weeks US 64 open-label, parallel Bode 4 7 weeks author associated with Novo Nordisk Bode 5 16 weeks Novo Nordisk Bott 6 6 Novo Nordisk Caixàs Ciofetta 8 3 B.B. and Colombel US 1 open-label, parallel US 13 open-label, parallel Germany, Austria, Switzerland 36 open-label, parallel Eli Lilly Spain 1 open-label, crossover, no washout period reported Italy 1 open-label, Sons parallel France 1 open-label, crossover, no washout period Comparison ILis+NPH or UL versus HI+NPH or UL [NPH or UL 1 time(s) daily] ILis+NPH versus HI+NPH [NPH 1 time(s) daily] IAsp+NPH versus ILis+NPH versus HI+NPH IAsp+basal versus HI+basal, CSII IAsp+basal versus ILis+basal versus HI+basal, CSII IAsp+NPH versus HI+NPH ILis+UL versus HI+UL (UL before breakfast and dinner) ILis+NPH versus HI+NPH (NPH: bedtime) ILis+NPH versus HI+NPH (with ILis, NPH given at pre-meal and bedtime) (with HI, NPH Number of Withdrawals Patients 1, (4.8%), no difference in discontinuation between 2 treatment groups 85 5 (5.9%) total: 3 during HI, 2 during ILis (21%) 29 (IAsp=19, HI=10) 1 (3.4%) in IAsp group (moved away) (9.6%) 424 (IAsp=283, HI=141) (treatments only compared on 1st crossover period) A-7

8 Study Danne, 10 (abstract) Deeb 11 Del Sindaco 12 Study Period 6 weeks Sponsor Countries Number of Centres Study Type reported Germany multi-centre open-label, crossover, no washout period reported 1 author from Eli Lilly Canada, US 6 open-label, 3-period crossover, no washout period reported Italy 1 open-label, crossover, no washout period reported DeVries weeks Novo Nordisk multinational 43 open-label, parallel Ferguson weeks Eli Lilly UK 1 open-label, 2 crossover, no washout period reported Ford-Adams 15 Gale Eli Lilly UK open-label, crossover, no washout period reported Eli Lilly UK 10 (patients recruited from 10 clinics) doubleblind, crossover, no washout Comparison given at bedtime) IAsp+NPH versus HI+NPH ILis (before meal) versus ILis (after meal) versus HI; basal: NPH, L, or UL group 1: ILis versus HI (both with 1 or 2 NPH); group 2: ILis+3 or 4 NPH versus HI+1 or 2 NPH; group 3: ILis versus HI (both with 3 or 4 NPH); group 4: HI 5 minutes pre-meal versus HI 10 to 40 minutes pre-meal IAsp+NPH versus HI+NPH ILis+NPH versus HI+NPH ILis+NPH versus HI+NPH (NPH: prebreakfast and pre-bed) ILis+NPH versus HI+NPH Number of Patients (60 randomized) 69 type 1 (15, 18, 12, 24 in groups 1, 2, 3, 4 respectively) Withdrawals 2 (3.3%) (1 before randomization, 1 during treatment) (10.3%) 39 type 1 (33 in analysis) 23 type 1 none 5 (12.8%) 93 type 1 6 (6.5%) A-8

9 Study Study Period Garg, weeks Sanofi- Aventis Sponsor Countries Number of Centres multinational multi-centre Study Type period reported open-label, parallel Garg Eli Lilly US open-label, parallel Hedman 19 6 weeks 2 Heller 20 Heller 21 Herz 22 Holcombe weeks 2 12 weeks Swedish Medical Research Council, Swedish Diabetes Association and University Sweden 1 open-label, crossover, no washout period reported Eli Lilly UK 11 open-label, crossover, no washout period reported Novo Nordisk Eli Lilly UK, Denmark, Norway, Australia, the Netherlands Europe, South Africa 19 doubleblind, crossover with 4-week washout 10 open-label, crossover, no washout period reported Eli Lilly 15 countries 53 open-label, crossover, no washout period reported Comparison IGlu (pre-meal)+iglar versus IGlu (post-meal) +IGlar versus HI+IGlar ILis+NPH or UL versus HI+NPH or UL ILis+basal versus HI+basal ILis+NPH versus HI+NPH (NPH: bedtime) IAsp+NPH versus HI+NPH (NPH: bedtime and pre-breakfast) Mix50+NPH versus HI+NPH (NPH: bedtime) ILis+NPH versus HI+NPH (NPH: 1 to 3 times daily) Number of Patients Withdrawals (7.3%) 39 2 (5.1%) 12 none (0.7%) (10.3%) withdrew before treatment, 19 (17.4%) discontinued 481 (463 randomized) 18 (3.7%) discontinued before randomization A-9

10 Study Holleman 24 Home 25 Study Period 12 weeks 2 4 weeks 2 Sponsor Countries Number of Centres Study Type Eli Lilly UK, 19 open-label, Belgium, crossover, the no washout Netherlands period reported Novo Nordisk Home 26 6 Novo Nordisk Home 27 (extension study of Home 26 ) 30 Novo Nordisk UK 11 doubleblind, crossover, no washout period reported 8 European countries 8 European countries 88 open-label, parallel 79 open-label, parallel Iwamoto weeks Japan open-label, parallel Jacobs 29 Janes 30 (abstract) 4 weeks Eli Lilly the Netherlands Janssen to 14 weeks Jansson 32 4 Eli Lilly Sweden, Finland, Spain, Italy 1 open-label, crossover, no washout period reported Eli Lilly UK multi-centre open-label, crossover, no washout period reported Eli Lilly the open-label, Netherlands parallel multi-centre open-label, parallel Comparison ILis+NPH versus HI+NPH (NPH: premeals) IAsp+NPH versus HI+NPH (NPH: bedtime) IAsp+NPH versus HI+NPH (NPH: 1 to 2 times daily) IAsp+NPH versus HI+NPH IAsp+basal versus HI+basal ILis+NPH versus HI+NPH (NPH: bedtime) Number of Patients 199 randomized 104 randomized Withdrawals 10 (5.0%) 14 (13.5%) 1, (5.5%) 753; IAsp 155 (2.1%) 84% (567/676); HI 56% (186/335) (7.1%) randomized; 205 evaluated 12 randomized ILis versus HI, basal 97 Mix75+NPL versus HI+NPH ILis+NPH versus HI+NPH 35 randomized 84 A-10

11 Study Study Period Sponsor Countries Number of Centres Study Type Johansson 33 2 Eli Lilly Sweden 4 open-label, 2 crossover, no washout period reported Lalli 34 1 year Italy 1 open-label, parallel Linkeschova 35 (abstract) Melki 36 Mortensen 37 (abstract) weeks ; 1 investigator from Novo Nordisk Germany doubleblind, crossover, no washout period reported Eli Lilly France 5 open-label, crossover, no washout period reported open-label, parallel Persson 38 6 Sweden 4 open-label, parallel Provenzano 39 1 year Italy open-label, crossover, no washout period reported Raskin weeks 2 Eli Lilly US 3 open-label, crossover, no washout Comparison ILis+NPH versus HI+NPH; CSII ILis+NPH versus HI+NPH (ILis given with NPH pre-meals and bedtime) (HI given with NPH at bedtime) ILis versus HI; CSII; basal ILis+basal versus HI+basal; CSII BIAsp30 versus HI+BHI (NPH allowed if required) ILis+NPH versus HI+NPH (NPH: bedtime and pre-breakfast if needed) ILis+basal versus HI+basal ILis+basal versus HI+basal Number of Withdrawals Patients 41 randomized 0 56 randomized randomized 1 (2.5%) (6.9%) A-11

12 Study Raskin 41 Study Period 12 (6 with voluntary 6-month extension) Sponsor Countries Number of Centres Novo Nordisk Study Type period reported US, Canada 59 open-label, parallel Recasens 42 1 year Spain, Italy open-label, parallel Renner 43 Schmauss 44 Tamás 45 Tubiana- Rufi 46 Tupola weeks; 12 weekperiod analyzed in article 16 weeks Eli Lilly Germany open-label, crossover, no washout period reported Eli Lilly Germany 1 open-label, crossover, no washout period reported Novo Nordisk 11 countries 48 open-label, parallel Eli Lilly France 2 open-label, crossover, no washout period reported Eli Lilly Finland 2 open-label, crossover, no washout period reported Comparison IAsp+NPH versus HI+NPH (NPH: bedtime and pre-breakfast if needed) ILis+NPH versus HI+NPH (NPH: predinner or bedtime) ILis+basal versus HI+basal ILis+basal versus HI+basal IAsp+NPH versus HI+NPH ILis+basal versus HI+basal ILis+NPH versus HI+NPH (NPH: twice daily) Number of Patients Withdrawals (7.6%) after 6 ; additional 39 after 2nd 6- month period (3.5%) 29 randomized, 27 completed and evaluated 2 (6.9%) 24 2 (8.3%) Valle 48 3 Eli Lilly Italy 143 open-label, ILis+NPH versus 1,184 A-12

13 Study Zinman 49 Study Period 3 2 Sponsor Countries Number of Centres Eli Lilly Canada doubleblind, crossover, no washout period reported Study Comparison Type parallel HI+NPH (NPH: 1 to 3 times daily) ILis+basal versus HI+basal Number of Patients 30 0 Withdrawals A-13

14 APPENDIX 4B: Characteristics of RCTs Involving Type 2 DM Patients Study Study Sponsor Countries Number of Study Type Comparison Number of Withdrawals period Centres Patients Abrahamian weeks Novo Austria multi-centre open-label, BIAsp30 versus (10.7%) Nordisk parallel BHI 30 Altuntas 51 6 Turkey open-label, parallel ILis+NPH versus ILis+Metf versus HI+NPH 60 0 Anderson some investigators from Eli Lilly 16 countries (UK, Europe, US, Australia) 80 open-label, crossover, no washout period Bastyr 53 2 Eli Lilly 11 countries 58 open-label, parallel Bastyr 54 3 Eli Lilly US 22 open-label, parallel Boehm month extension Novo Nordisk Bretzel 56 3 Novo Nordisk Dailey 57 up to 26 weeks some authors have industry connections Germany, Ireland, UK 30 open-label, parallel Germany 30 open-label, parallel US, Canada, Australia multi-centre open-label, parallel ILis+basal insulin versus HI+basal insulin (multipledose therapy; basal insulin 1 or 2 times daily) ILis+NPH versus ILis+Sfu versus NPH+Sfu ILis+Glyb versus Metf+Glyb versus NPH+Glyb BIAsp30 versus BHI 30 IAsp+NPH versus HI+NPH versus BHI 30 (NPH: bedtime) IGlu+NPH versus HI+NPH; MDI (NH: 2 times daily) (5.0%) (6.4%) (12.6%) randomized; 131 evaluated (24.0%) randomized; 121 evaluated (AE including 125) (11.7%) (7.3%) A-14

15 Study Study Sponsor Countries Number of Study Type Comparison Number of Withdrawals period Centres Patients Forst weeks Eli Lilly Germany, Sweden, Switzerland 19 open-label, parallel ILis versus Glib 143 Gallagher 59 6 weeks Novo 21 3 (14.3%) 2 Nordisk Herz 60 Herz 61 4 weeks outpatient, followed by 2- to 3- day inpatient exercise study 2 4 weeks outpatient + 3-day inpatient 2 Herz weeks Eli Lilly Czech Republic, Hungary, Slovenia, Croatia, Poland, Sweden, Australia, New Zealand Iwamoto 63 (abstract) UK 1 double-blind, crossover, no washout period reported Eli Lilly Croatia 1 open-label, crossover, no washout period reported Eli Lilly South Africa open-label, crossover, no washout period reported multi-centre open-label, parallel 48 weeks Japan multi-centre open-label, parallel Kilo weeks Novo Nordisk US 25 open-label, parallel IAsp+NPH versus HI+NPH (NPH: bedtime) Mix25 versus BHI 30 Mix25 versus BHI (10.8%) 25 4 (16.0%) Mix25 versus Glyb (11.2%) BIAsp30 versus BHI 30 BIAsp30+Metf versus BHI 30+ Metf versus NPH (bedtime)+metf 437 randomized; 428 evaluated (6.4%) A-15

16 Study Study Sponsor Countries Number of Study Type Comparison Number of Withdrawals period Centres Patients Kokić 65 3 Croatia 1 open-label, parallel ILis+Metf versus BHI 30+NPH versus Metf+Glim 87 Lourens 66 3 Eli Lilly South Africa 3 open-label, Mix25 versus BHI 45 5 (11.1%) 2 crossover, no 30 washout period reported Malone weeks Eli Lilly 14 countries including US, Austria, Canada, Brazil, Romania, Australia Raskin 68 (abstract) Rayman 69 (abstract) 56 open-label, parallel 6 multi-centre open-label, parallel 26 weeks Sanofi- multinational open-label, Aventis parallel Raz 70 6 weeks Novo Nordisk Raz weeks Novo Nordisk Roach weeks Eli Lilly Romania, Russia Roach Ross Eli Lilly 2 investigators from Eli Lilly (Europe) Israel 5 open-label, parallel 8 countries 27 open-label, parallel Spain, South Africa, UK 6 open-label, parallel 12 open-label, crossover, no washout period reported Canada open-label, parallel Mix25+Metf versus Glib+Metf (Metf 2 times daily) IAsp+NPH versus HI+NPH IGlu+NPH versus HI+NPH BIAsp30+Ros versus Glib+Ros BIAsp versus BIAsp+Pio versus Glib+Pio Mix25 versus Glyb (maximum dose) Mix25 versus BHI 30 ILis+NPH versus HI+NPH (ILis, HI, NPH: pre-breakfast and pre-supper) (9.0%) (10.2%) (12.8%) (10.3%) randomized; 172 evaluated 89 9 (10.1%) (3.4%) A-16

17 Study Study period Sponsor Countries Number of Centres Study Type Comparison Number of Patients Sargin 75 6 Turkey 2 open-label, ILis+NPH versus 60 parallel HI+NPH (ILis randomized; NPH at lunch and 55 evaluated bedtime) (HI NPH at bedtime) Schernthaner 76 ~12 weeks 2 Eli Lilly Austria 1 open-label, crossover, no washout period reported Mix50 versus BHI randomized; 35 evaluated Withdrawals 5 (8.3%) 5 (12.5%) ~=approximately A-17

18 APPENDIX 4C: Characteristics of RCTs Involving Type 1 and 2 Patients Study Study Period Sponsor Countries Number of Centres Anderson some 11 countries, multi-centre investigators including from Eli South Africa, Lilly US Boehm weeks Novo Nordisk Chan 79 Howorka 80 Kotsanos 81 Laube weeks Germany, Austria, UK, Ireland 36 open-label, parallel China open-label, crossover, no washout period reported Austria 1 open-label, crossover, no washout period reported Eli Lilly Canada, France, Germany, US multi-centre Study Type Comparison Number of Patients open-label, ILis+basal versus 336 type 1 DM, parallel HI+basal 295 type 2 DM open-label, crossover, no washout period reported Germany 1 open-label, crossover, no washout period reported Roach Eli Lilly Canada, Australia, New Zealand, Germany, Italy Roach Eli Lilly Germany, Hungary, the Netherlands, Switzerland, UK multi-centre open-label, parallel 20 open-label, crossover, no washout period reported BIAsp30 versus BHI 30 ILis+NPH versus HI+NPH ILis versus HI; basal: NPH, UL or L ILis versus HI; basal: NPH or UL ILis+NPH versus HI+NPH ILis+NPL versus HI+NPH Mix50 (morning) +Mix25 (afternoon) versus BHI 50 (morning)+bhi 30 (afternoon) 294 (type 1 and type 2 DM) randomized; 291 evaluated 30 (12 type 1, 18 type 2) Withdrawals type 1 DM: 25 (7.4%) type 2 DM: 15 (5.1%) 23 (7.8%) total: IAsp 14, HI type 1, 474 type 2 7 type 1, 7 type type 1, 63 type 2 26 (2.8%) 3 (3.0%) A-18

19 Study Skrha 85 Vignati 86 Study Period Sponsor Countries Number of Centres several Czech investigators Republic, from Eli Slovenia, Lilly Slovak Eli Lilly Republic 16 countries including South Africa, US Study Type Comparison Number of Patients Withdrawals ILis+NPH versus 62 HI+NPH 8 open-label, crossover, no washout period reported open-label, crossover, no washout period reported ILis+NPH versus HI+NPH 379 type 1; 328 type 2 29 (4.1%) A-19

20 APPENDIX 4D: Characteristics of RCTs Involving GDM Patients Study Study Period Sponsor Countries Number of Centres Study Type Comparison Number of Patients Withdrawals Ilic 87 (abstract) US parallel ILis versus HI 41 Jovanovic 88 as early as 14- week gestation to delivery Eli Lilly US 1 open-label, parallel ILis+NPH versus HI+NPH 42 1 (2.4%) Mecacci 89 from 25-week gestation to delivery Italy 1 parallel ILis versus HI versus no treatment (normal pregnancy) 99 with GDM; 65 normal pregnancy A-20

21 APPENDIX 5A: Characteristics of Patients in RCTs Involving Type 1 DM Study Number of Patients Anderson 1 all 1, ± Annuzzi 2 all ± Arslanian 3 (poster) IAsp+NPH ± ILis+NPH ± HI+NPH ± Age, Male/ years female, number (%) 585/ b (58/42) 37/ a (44/56) 86/ a (46/54) 52/ a (55/45) 54/ a (56/44) Bode 4 IAsp 19 38± 13/ a (68/32) HI 10 34± 5/ a (50/50) Bode 5 IAsp+basal ± 23/ a (39/61) ILis+basal ± 9/ a (32/68) HI+basal ± 19/ a (32/68) Bott 6 all /193 (16.9) f (54/45) 143/140 88/53 2/8 IAsp (18.5) f (51/49) HI (15.3) f (62/38) Caixàs 7 all ± 6.5 a (20/80) Ciofetta 8 all 24 33±4 a 17/7 (71/29) Race or ethnicity Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) Rate of (patient/ 30 days) 12.0±0.3 b 8.5±0.1 b 24.2±0.1 b, (71.2±0.4 b ) 12.1±7.6 a 8.67± 23.2±2.5 a 0.72 a per patient 76% 4.8±3.3 a 8.3±1.2 a 21.4±4.8 a Caucasian 77% 4.4±3.1 a 8.4±1.2 a 21.4±5.3 a Caucasian 72% 4.6±3.1 a 8.3±1.3 a 20.8±3.6 a Caucasian Caucasian 2 to ±0.8 a 26±2.4 a (82±13.6 a ) Caucasian 2 to ±0.9 a 24±2.0 a (73±9.6 a ) 58 (98%) ±0.7 a 26.7±3.8 a Caucasian 26 (93%) ±0.7 a 26.3±3.2 a Caucasian 58 (98%) ±0.8 a 25.9±3.8 a Caucasian 12.5 (15.2) f 7.6 (1.6) f 24.2 (4.0) f (Germanspeaking) 13.0 (14.5) f 7.5 (1.7) f 24.2 (3.5) f 11.3 (16.2) f 7.6 (1.4) f 24.4 (5.0) f 5.5±5.0 a 7.13±1.2 a 24.1±2.6 a 13±2.1 a 6.84± 0.20 a 23.5±1.1 a A-21

22 Study Number of Patients Age, years Male/ female, number (%) Race or ethnicity Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) Rate of (patient/ 30 days) Colombel 9 all ± 15.2± ± ± Danne 10 all 26 (2.4 to 17/9 ~7.7% (abstract) 6.9) d (65/35) Deeb 11 all 61 prepubertal 7.6 (2.9 29/ (1 to 8) d 8.4±1.0 a children to 11.4) d (48/52) (5.8 to 10.2) d Del Sindaco 12 group 1: ILis versus HI (both with 1 or 2 NPH) 15 33±6.9 a 7/8 (47/53) 15.2±11.6 a 6.43±0.58 a 22.1±2.3 a 5.7±4.9 a (patient-month; BG <3.3 mm) group 2: ILis+3 or 4 NPH versus HI+1 or 2 NPH group 3: ILis versus HI (both with 3 or 4 NPH) group 4: HI 5 minutes pre-meal versus HI 10 to 40 minutes premeal 18 34±7.2 a 9/9 (50/50) 12 32±5.2 a 6/6 (50/50) 24 30±8.8 a 13/11 (54/46) DeVries 13 IAsp+NPH (28.8 to 46.7) d HI+NPH (28.8 to 46.7) d 116/71 (62/38) 111/70 (61/39) 14.1±8.9 a 6.67±0.4 a 21.8±1.6 a 6.2±4.7 a (patient-month; BG <3.3 mm) 23.0±3.1 a 6.5±3.8 a 13±8.6 a 6.35± 0.62 a (patient-month; BG <3.3 mm) 22.3±2.4 a 7.0±2.9 a 14±10.2 a 6.51± 0.58 a (patient-month; BG <3.3 mm) 169 (91%) Caucasian 166 (92%) Caucasian 14.2 (8.3 to 8.36± 25.3±3.2 a 20.7) d 0.76 a 15.6 (9.4 to 8.40± 25.8±3.4 a 23.8) d 0.77 a A-22

23 Study Number of Patients Age, years Male/ female, number (%) Ferguson 14 all 33 46±11 a 18/15 (55/45) Ford-Adams 15 all 23 prepubertal 9.4 (7 16/7 to 11) d (70/30) children Gale 16 all (18 49/44 to 63) g (53/47) Garg 17 IGlu (premeal) ± 159/ a (55.6/44.4 ) ± 157/ a (53/47) 139/ a (50/50) IGlu (postmeal) HI ± 19/20 Garg 18 all ± 4.6 a (49/51) ILis+NPH ± or UL HI+NPH or ± UL Race or ethnicity Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 25.8±9.8 a 9.0±1.1 a 25.4±2.6 a >1 8.4±0.24 b 13.1 (1 to 51) g 25.2 (20.0 to 33.7 ) g 20.0±11.4 a 7.7± 27.0±4.3 a b 27.3±4.7 a 27.0±5.0 a 20.2±11.5 a 7.7± b 19.4±11.2 a 7.6± b 10.9±7.8 a 4/8 30.5±3.2 b 6.7±0.9 b 26.5± 1.0 b 4.5 a (74.8±9.7 a ) 11.6±8.4 a 9.1±1.4 a 24.8±2.3 a 4.8 a (74.7±11.1 a ) 10.3±7.5 a 8.4±2.1 a 25.8±3.7 a Hedman 19 all ± 2.4 b Heller 20 all ±11 b 71/ ±9.2 b 6.3±1.0 b 25.3±3 b Heller 21 all ± 9.4 a (18 to 65) d Herz 22 all 109 (22 to 43) d 53/56 (49/51) (53/47) 2 8.6±1.1 a 24.0±2.6 a 108 Caucasian 1 African 11.2±7.3 a 1.75 upper limit of nondiabetic range Rate of (patient/ 30 days) 3.7±0.8 b events/patient/2 weeks 5.3±1.0 b events/patient/2 weeks 24.8±3.3 a <2 episodes within preceding 3 A-23

24 Study Number of Patients Holcombe 23 all ± Age, Male/ years female, number (%) 214/ a (45/55) 126/73 58/38 68/35 104/0 Holleman 24 All ± 9.6 a (63/37) ILis+NPH ± 9.6 a (60/40) HI+NPH ± 9.7 a (66/34) Home 25 all ± 8.6 a (100/0) Home 26 IAsp+NPH ±11 a 389/318 (55/45) HI+NPH ±12 a 200/158 (56/44) Home 27 (extension study of Home 26 ) IAsp+NPH ± 327/ a (58/43) Race or ethnicity Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 6.1±3.7 a 8.61±1.5 a 13.1±9.1 a 7.3±1.1 a 25.0±3.1 a 5.7±5.8 a 14.2±9.9 a 7.4±1.2 a 25.2±3.1 a 5.7±6.2 a 12.0±8.1 a 7.3±1.0 a 24.8±3.2 a 5.7±5.5 a 14.8±8.7 a 7.1±1.0 a 25.3±2.3 a 99% Europid 99% Europid 99% Europid 15±10 a 7.96± 25.1± 3.1 a 1.16 a 15±10 a 7.98± 24.9±3.0 a 1.17 a 14.8±10.2 a 7.88 ± 25.1±3.0 a 0.03 b 110/ ±2.9 a 7.52± 21.96±2.39 a 7.49± 21.94±2.50 a 22.00±2.13 a HI+NPH ± 98% 15.6±11.0 a 8.00± 12.4 a (59/41) Europid 0.04 b Iwamoto 28 all ± 80/125 Japanese 10.61±6.77 a 14.8 a (12 to 78) d (39/61) (2.0 to 40.7) d 1.11 a IAsp+basal ± 59/84 Japanese 10.60±7.03 a ( a (12 to 78) d (41/58) to 40.7) d 1.12 a HI+basal ± 21/41 Japanese 10.65±6.16 a 7.57± 13.2 a (12 to 68) d (34/66) (2.6 to 33.7) d 1.09 a Jacobs 29 all ±0.9 a <30 Janes 30 (abstract) all 97 Rate of (patient/ 30 days) A-24

25 Study Number of Patients Age, years Male/ female, number (%) Race or ethnicity Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) Rate of (patient/ 30 days) 11/6 11/7 23.7±0.4 b 24.1±0.4 b 2.70±0.45 b 22/19 Janssen 31 Mix ± 15.7±7.7 a 7.2±0.5 a 24.9±3.1 a NPL 8.5 a (65/35) HI+NPH ± 11.9±8.5 a 7.0±0.7 a 23.0±2.8 a 8.7 a (61/39) Jansson 32 ILis+NPH 44 35±1 b 15.6±1.2 b 7.98± 4.14±0.53 b 0.11 b HI+NPL 40 35±1 b 15.5±1.1 b 7.84± 0.14 b Johansson 33 all ± 21.0±11 a 7.7±0.8 a 24.3±3.0 a 10.0 a (54/46) Lalli 34 all 56 34±1.3 a 31/25 (55/45) 15.2±2 a 6.67±0.1 a 22.5±0.7 a 9.9±0.8 a patient/month Lalli 34 ILis+NPH 28 35±2.2 a 15/ ±2.8 a 6.6±0.23 a 22.6±1 a 10±1.5 a (54/46) HI+NPH 28 33±3 a 16/12 16±2.6 a 6.7±0.2 a 22.5±0.9 a 9.8±1.3 a (57/43) Linkeschova 35 all 27 40±13 a 14/13 18±9 a (52/48) Melki 36 all ± 1.5 b 22/17 (56/44) 22.5±1.6 b 7.84± 0.12 b 24.4±0.4 b Mortensen 37 (abstract) IAsp and/or BIAsp30+ NPH (if necessary HI and/or BHI 30+ NPH (if necessary) to both arms 17 g 80/87 (48/52) to both arms 17 g 80/87 (48/52) Persson 38 ILis+NPH (25 to 33) g 0/16 (0/100) pregnant women HI+NPH (21 to 34) g 0/17 (0/100) 9.7±1.5 a 21.1±3.8 a 9.55±1.6 a 21.1±2.9 a 15 (1 to 25) g 6.5 (4.8 to 8.6) g 24.8 (22.2 to 32.6) g 12 (2 to 29) g 6.6 (4.5 to 8.6) g 23.7 (19.0 to 29.1) g A-25

26 Study Number of Patients Age, years Male/ female, number (%) pregnant women Race or ethnicity Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 7/ ±3.2 a 16/12 14/16 Provenzano 39 all ( ± to 44) d (58/42) 0.47 a Raskin 40 ILis+basal ± 18.8±7.6 a 7.9± a (57/43) HI+basal ± 17.4±8.5 a 7.6± a (47/53) Raskin 41 all to / Caucasian IAsp+NPH ± 306/ (94%) 15.7±9.7 a 7.90± 25.6±3.6 a 10.5 a (51/49) Caucasian 1.13 a HI+NPH ± 152/ (93%) 15.8±9.3 a 7.95± 25.7± a (53/47) Caucasian 1.25 a Recasens 42 ILis+NPH ± 5.7 a 14/8 (64/36) newly diagnosed (8.0 ±3.8 weeks) 10.5±2.4 a 21.8±0.9 a HI+NPH ± 5.1 a 14/9 (61/39) 60/53 Renner 43 all ± 11.6 a (53/47) Schmauss 44 all 11 30±2.5 5/6 (45/55) Tamás 45 IAsp+NPH ± 124/ a (58/42) HI+NPH ± 117/ a (55/45) Tubiana-Rufi 46 all ± 18/9 2.2 a (67/33) (1.8 to 9) d Tupola 47 all (3.9 12/12 to 9.9) g (50/50) newly diagnosed (8.1 ±8.0 weeks) 11.4±1.9 a 20.6±2.8 a 19.1±9.2 a 7.24±1.0 a 24.7±1.1 a 14±1.0 <10 24± ±9.1 a 8.36± 24.2±2.9 a 0.05 b (71.2±12.3 a ) 14.2±9.2 a 8.29± 24.0±2.9 a 0.05 b (69.9±11.3 a ) 2.2±1.8 a (0.3 to 8) d, CSII 8.02± 0.67 a (7.2 to 10.3) d 3.1 (1.0 to 8.1±0.9 a 5.0) g 16.3±1.1 a (14.2 to 19.1) d (18.8±4.4 a ) Rate of (patient/ 30 days) A-26

27 Study Number of Patients Valle 48 all 1, ± Zinman 49 all ± 1.5 Age, Male/ years female, number (%) 663/ a (56/44) 13/17 (43/57) Race or ethnicity Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 14±9 a 8.7±1.8 a 24.3±3.2 a 4.6±3.6 a 17.5± ± ±0.5 (72.7±1.8) Rate of (patient/ 30 days) 12.7±1.6 per 30 day ~=approximately; a =mean ± SD (standard deviation); b =mean ± SE; d =mean (range); f =median (interquartile range); g =median (range) A-27

28 APPENDIX 5B: Characteristics of Patients in RCTs Involving Type 2 DM Patients Study Number of Patients Age, Years Male/ female (%) Race or ethnicity (%) Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) Rate of (patient/ 30 days) ±1.5 b ±1.5 b ±1.4 b 86/101 52/43 54/42 Altuntas 51 ILis+NPH ± 31.2±7.8 b 7.5 b ILis+Metf ± 31.8±2.7 b 3.1 b HI+NPH ± 31.3±3.8 b 7.7 b Arslanian 3 IAsp+NPH ± 76% 4.8±3.3 a 8.3±1.2 a 21.4±4.8 a (poster) 3.1 a (46/54) Caucasian ILis+NPH ± 77% 4.4±3.1 a 8.4±1.2 a 21.4±5.3 a 2.9 a (55/45) Caucasian HI+NPH ± 72% 4.6±3.1 a 8.3±1.3 a 20.8±3.6 a 2.7 a (56/44) Caucasian Anderson 52 all ±1 b 390/332 (54/46) 12.4±0.3 b 8.9±0.1 b 28.1±0.2 b 3.13±0.20 b 30 days Bastyr 53 all /203 (52/48) 385/38 (91%) Caucasian ILis+NPH /63 (58/42) ILis+Sfu /78 (44/56) NPH+Sfu /62 (54/45) Bastyr 54 all /52 (60/40) ILis+Glyb /14 (66/34) 131/18 (87.9%) Caucasian 130/9 (93.5%) Caucasian 124/11 (91.9%) Caucasian 82/49 (62.6%) Caucasian 29/12 (70.7%) ±1.68 a ±1.67 a ±1.66 a A-28

29 Study Number of Patients Age, Years Male/ female (%) Metf+Glyb /18 (55/45) NPH+Glyb /20 (60/40) Race or ethnicity (%) Caucasian 24/16 (60.0%) Caucasian 29/21 (58.0%) Caucasian Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) Rate of (patient/ 30 days) 32/26 34/33 Boehm 55 BIAsp ± 8.0 a (55/45) BHI ± 8.6 a (51/49) Bretzel 56 IAsp+NPH ±9 a 44/31 (59/41) HI+NPH 80 62±3.3 a 40/40 (50/50) BHI ± 46/30 NPH 8.9 a (61/39) Dailey 57 IGlu+NPH ± 244/ a (56/44) HI+NPH ± 219/ a (50/50) 15.5± ±1.22 a 29.1± ± ±1.22 a 27.2± ±0.13 a 29.2±3.7 a 7.83±0.13 a 29.3±3.3 a 7.78±0.13 a 29.2±4 a white/black/ Asian/multiracial/ Hispanic =372/48/8/7 /34 (85.5/11/1.8 /1.6/7.8) white/black/ Asian/ multi-racial/ Hispanic =376/51/9/5 7/26 (85.3/11.6/2. 0/1.1/5.9) 14.7±8.12 a 7.58±0.937 a 34.60±6.88 a 13.4±7.55 a 7.52±0.959 a 34.51±7.02 a A-29

30 Study Number of Patients Age, Years Male/ female (%) Forst 58 ILis ± 7.3 a 51/24 (68/32) Glib ± 8.6 a 39/29 (57/43) Gallagher 59 all 24 66±5 a 16/5 (76/24) Garg, IGlu (premeal) ± 159/ a (56/44) IGlu (postmeal) ± 157/ a (53/47) HI ± 139/ a (50/50) Herz 61 all to 70 17/8 (68/32) Mix ± 10/ b (77/23) BHI ± 7/ b (58/42) Herz 60 all ± 19/ b (51/49) Mix ± 12/ b (63/37) BHI ± 6/ b (33/67) Herz 62 Mix ± 37/ a (52/47) Glyb ± 4.9 a 32/40 (44/55) Race or ethnicity (%) Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 74 Caucasian, 1 western Asian 4.4±2.9 a 7.5±1.0 a 29.7±3.6 a ±3.4 a 7.7±1.2 a 28.7±3.9 a Caucasian, 1 African 11±4 a 7.60±0.12 a 30±2 a 20.0 ± 11.4 a 7.7 ± b 27.0±4.3 a 20.2±11.5 a 7.7±0.055 b 27.3±4.7 a 19.4±11.2 a 7.6±0.057 b 27.0±5.0 a <10 < ±0.33 b 29.2±1.2 b 7.60±0.33 b 29.3±1.2 b <10 <35 8.9±1.28 b 27.0±0.73 b (76.0±2.61 b ) 7.5±1.30 b 26.3±0.80 b (75.8±2.23 b ) 11.4±7.9 a 9.82±1.51 a 28.0±3.3 a (78.7±11.5 a ; 78.65±1.36 b ) 12.4±7.3 a 9.90±1.30 a 27.8±3.9 a (77.3±12.0 a ; 77.34±1.53 b ) Rate of (patient/ 30 days) 0.14 ± 0.14 b 0.01 ± 0.01 b A-30

31 Study Home 27 (extension study of Home 26 ) Iwamoto 63 (abstract) Kilo 64 Number of Patients Age, Years Male/ female (%) IAsp+NPH ± 327/ a (58/42) Race or ethnicity (%) 99% Europid Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 14.8±10.2 a 7.88±0.03 b 25.1±3.0 a 110/76 HI+NPH ± 98% 15.6±11.0 a 8.00±0.04 b 24.8±2.9 a 12.4 a (59/41) Europid BIAsp BHI BIAsp ± 25/21 black/ 10.4±8.6 a 9.5±1.8 a 30.4±4.4 a Metf 12.6 a (54/46) Caucasian/ Hispanic/ other =4/33/0/9 BHI 30+ Metf ± 11.0 a 29/18 (62/38) NPH+Metf ± 12.6 a 19/28 (40/60) Kokić 65 ILis+Metf ± /17 (41/59) BHI ± 10/19 NPH 4.8 (35/66) Metf+Glim ± 13/ (45/55) Lourens 66 ILis+NPL ± 12/ b (55/45) black/ Caucasian/ Hispanic/ other =6/35/1/5 8.4±4.9 a 9.3±1.4 a 30.6±4.3 a black/ 10.7±7.3 a 9.5±1.6 a 30.4±3.9 a Caucasian/ Hispanic/ other =9/30/1/7 9.5± ± ± ± ± ± ± ± ±3.6 Caucasian/ other/ African= 12/9/1 (55/41/5) 12.28±1.94 b 26.79±0.91 b (75.26±3.48 b ) Rate of (patient/ 30 days) A-31

32 Study Malone 67 Number of Patients Age, Years Male/ female (%) HI+NPH ± 2.38 b 10/13 (43/57) ILis+NPL+ Metf ±8.8 a 169/127 (57/43) Glib+Metf ±9.3 a 146/155 (49/51) Rayman 69 (abstract) all ± 9.3 Raz 70 all ± 8.9 a (43 to 77) BIAsp30+ Ros ± 9.7 a (43 to 77) Glib+Ros ± 7.9 a (43 to 71) Race or ethnicity (%) Caucasian/ other/ African= 13/9/1 (57/39/4) Caucasian/ African/ Hispanic/ other =263/ 2/22/9 (88.9/0.7/7.4 /3.0) Caucasian/ African/ Hispanic/oth er=268/3/ 18/12 (89.0/ 1.0/6.0/4.0) Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 11.80±1.59 b 28.76±0.88 b (78.89±2.61 b ) 8.0±5.8 a 9.17±1.50 a 29.8±4.4 a (83.0± 15.2 a ) 7.4±5.4 a 9.27±1.55 a 29.6±4.5 a (81.7± 15.7 a ) 13.5± ± ±5.0 32/17 (65/35) 19/7 (73/27) 13/10 (57/43) Caucasian/ Asian/other =41/3/5 (83.7/6.1/ 10.2) Caucasian/ Asian/other =22/1/3 (84.6/3.8/ 11.5) Caucasian/ Asian/other =19/2/2 (82.6/8.7/ 8.7) 10.6±5.8 a 10.1±1.3 a 27.7±3.7 a 10.9±5.2 a 9.9±1.3 a 27.7±3.6 a 10.3±6.5 a 10.3±1.3 a 27.6±4.0 a Rate of (patient/ 30 days) 0.08±0.59 a 0.07±0.57 a A-32

33 Study Number of Patients Age, Years Male/ female (%) Roach 72 all ± 61/ a (35/65) ILis (Humalog Mix25) ± 8.9 a 30/55 (35/65) Race or ethnicity (%) 100% Caucasian 100% Caucasian Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 10.2±6.6 a 27.2±3.2 a (75.0± 11.9) 10.3±7.1 a 9.85±1.2 a 26.8±3.4 a (74.1± 12.4) 31/56 Glib ± 100% 10.2±6.2 a 10.07±1.4 a 27.6±3.0 a (75.8± 7.5 a (36/64) Caucasian 11.4) Roach 73 ILis+NPL / (52/48) HI+NPH / (42/58) Ross 74 ILis+NPH 70 59±1 b 26/ ±0.9 b 10.7±0.2 b 28±1 b (37/63) HI+NPH 78 58±1 b 30/ ±0.8 b 10.6±0.2 b 27±1 b (38/62) Sargin 75 ILis+NPH ± 11.8±4.3 a 9.6±1.5 a 30.7±3.3 a 9.6 a HI+NPH ± 10.8±3.7 a 9.2±1.3 a 31.2±3.0 a 6.6 a Schernthaner 76 ILis+NPL ± 3/ ±8.4 a 8.3±0.8 a 29.5±4.8 a 8.5 a (17/83) HI+NPH ± 8.4 a 5/12 (29/71) 14.2±7.3 a 8.5±1.2 a 28.8±3.7 a a =mean±sd (standard deviation) ; b =mean±se. Rate of (patient/ 30 days) A-33

34 APPENDIX 5C: Characteristics of Patients in RCTs Involving Type 1 and 2 DM Patients Study Number of Patients Age, Years Male/ female (%) 82/80 85/89 74/71 79/71 35/20 34/15 46/39 46/56 16/14 Anderson 77 ILis+basal 162 type ± 0.9 b (51/49) HI+basal 174 type ± 09 b (49/51) ILis+basal 145 type ± 0.7 b (51/49) HI+basal 150 type ± 0.7 b (53/47) Boehm 78 BIAsp30 55 type ± 13.4 a (64/36) BHI type ± 12.8 a (69/31) BIAsp30 85 type ± 8.8 a (54/46) BHI type ± 8.4 a (45/55) Chan 79 all (ILis and 30 ( (20 HI) type 1; 18 to 67) d (53/47) type 2) Howorka 80 Kotsanos 81 all (ILis and HI) all (ILis and HI) all (ILis and HI) 55 (49 type 1) 41.8± 16.0 a 26/26 (50/50) 468 type ± 207/ a (44.2/ 55.8) 474 type ± 202/ a (43/57) Race or ethnicity Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 12.7±0.7 b 8.2±0.1 b 24.1±0.2 b 6.2±0.5 b 12.1±0.7 b 8.2±0.1 b 24.4±0.2 b 7.3±0.6 b 12.4±0.6 b 8.7±0.1 b 28.3±0.3 b 2.1±0.3 b 12.0±0.7 b 8.9±0.1 b 28.6±0.3 b 2.5±0.4 b 14.9±11.0 a 8.37±1.24 a 26.1±3.7 a (76.1± 14.2 a ) 17.0±13.0 a 8.38±1.14 a 26.4±3.1 a (79.7± 14.5 a ) 15.0±9.1 a 8.09±1.20 a 28.1±3.5 a (80.9± 13.9 a ) 14.4±7.4 a 8.18±1.32 a 28.0±3.9 a (78.0± 12.1 a kg) (probably 7.8±2.7 a 7.8±1.7 a 25.0±4.3 a (66.1± Asian) after 8-week 16.3 a ) run-in (9.0± 2.2 a when recruited) 16.0±9.6 a 7.6±0.9 a 25.6±3.1 a Caucasian/ African/ Hispanic/other =(96.6/1.7/1.3/ 0.4) Caucasian/ African/ Hispanic/other 12.6±9.0 a 8.4±1.7 a 24.5± ±7.5 a 8.8±1.6 a 28.3±4.0 Rate of (patient/ 30 days) A-34

35 Study Number of Patients Age, Years Male/ female (%) Race or ethnicity =(87.1/7.8/3.6/ 1.5) Duration of Diabetes, Years HbA1c, % BMI, kg/m 2 (weight, kg) 7.8± ± ± ±4.3 Laube 82 all (ILis and 7 type (25 HI) to 64) d all (ILis and 7 type (53 HI) to 74) d Roach 83 ILis+NPL 86 type 1 and /27 (69/31) African/ Caucasian/east or southeast Asian/other= 1/81/3/1 (1.2/94.2/3.5/ 1.2) HI+NPH 80 type 1 and /27 (66/34) Roach 84 ILis or HI 19 type /7 (63/37) HI or ILis 18 type /5 (72/28) ILis 34 type /16 followed by (53/47) HI HI followed 29 type /17 by ILis (41/59) Skrha 85 all (ILis and 55 type 1; 35.7± 36/26 HI 7 type a (58/42) Vignati 86 all (ILis and 379 type (18 HI) all (ILis and HI) a =mean±sd (standard deviation); b =mean±se; d =mean (range). Caucasian 79 (98.8); east or southeast Asian 1 (1.3) ±7.7 a 7.5±1.4 a 24.6±3.5 a 213/ (0.2 to 8.0±1.5 a to 70) d 48.2) d 328 type (30 174/ (0.4 to 8.1±1.3 a to 71) d 41.4) d 24.8 (17.7 to 6.1±6.0 a 50.5) d 28.5 (15.8 to 2.5±4.7 a 44.4) d Rate of (patient/ 30 days) A-35

36 APPENDIX 5D: Characteristics of Patients in RCTs with GDM Patients Study Ilic 87 (abstract) Jovanovic 88 Mecacci 89 b =mean±se; g =median (range). Number of Patients Age, Years Race/ ethnicity Weeks of Gestation at Giagnosis HbA1c, % BMI, kg/m 2 (weight, kg) all (ILis and 19 ILis/22 HI) HI ILis ±1.3 b Caucasian 2; Hispanic ±0.09 b 31.5±1.1 b (76.3±2.9 b) HI ±1.0 b Hispanic ±0.09 b 33.3±1.2 b (78.5±2.5 b) ILis (24 to 28 (25 to 32) g 5.5± (19.2 to 25.1) g 40) g HI (28 to 28 (26 to 32) g 5.4± (19.8 to 25.3) g 41) g Rate of (patient/ 30 days) A-36

37 APPENDIX 6: Inclusion and Exclusion Criteria for Selecting Patients in RCTs Author Inclusion Criteria Exclusion Criteria DM Type Abrahamia 50 insulin naivety or inadequate treatment with combination of oral 2 agents and insulin or insulin monotherapy; HbA1c 7%; BMI 40 kg/m² Altuntas 51 type 2 DM (ADA criteria); secondary OAD drug failure using 2 maximal doses of Sfu Anderson 52 NIDDM (WHO criteria); age 35 to 85 years; HI therapy 2 before study other severe disease; β-adrenergic receptor blocking therapy; glucocorticoid therapy; insulin infusion therapy; history of severe hypoglycemia unawareness; insulin 2 Anderson 1 Anderson 77 Annuzzi 2 IDDM (WHO criteria); age 12 to 70 years; HI therapy 2 before study IDDM (WHO criteria) and age 12 to 70 years; NIDDM (WHO criteria) and age 35 to 70 years; HI therapy 2 before study type 1 DM (WHO criteria); age 18 to 50 years; diagnosis of diabetes before age 35 years; interval between diagnosis and insulin therapy <1 year; diabetes duration >2 years; 3 daily insulin injections for >2 ; insulin dose >0.3 U/kg; HbA1c 7.5% to 10.0% dosage >2.0 U/kg; BMI >35 kg/m² other severe disease; BMI >35 kg/m²; insulin dosage >2.0 U/kg; history of clinically significant hypoglycemia unawareness; pregnancy other severe disease; current use of OAD drugs; insulin infusion therapy history of cancer; cerebrovascular or symptomatic peripheral vascular disease; heart failure; liver or renal disease; visual impairment; pregnancy or lactation; clinically significant hypoglycemia unawareness Arslanian 3 type 1 DM for 12 ; age 6 to 18 years; HbA1c 12.0% 1 Bastyr 54 type 2 DM (WHO criteria); secondary oral-agent failure; HbA1c <8.5%; >20% of FBG >8.9 mmol/l and/or pre-meal BG >10 mmol/l after maximal doses of Sfu during 1-week period before initial visit 2 Bastyr 53 Bode 5 Bode 4 type 2 DM (WHO criteria); secondary oral-agent failure; FBG >7.8 mmol/l (140 mg/dl) or postprandial BG >10 mmol/l (180 mg/dl) 3 times in preceding 3 or HbA1c >150% upper limit of non-diabetic range type 1 DM for 12 ; fasting C-peptide <0.5 ng/ml; adult; CSII therapy continuously 3 ; BMI 35.0 kg/m²; HbA1c 5.7% to 9.7% Type 1 DM for 2 to 25 yrs prior to study; adult; C-peptide negative; CSII therapy with IAsp or buffered regular HI 7 weeks 2 impaired hepatic function (liver enzymes 2 times upper limit of normal); impaired renal function (serum creatinine >2.0 mg/dl); impaired cardiac function; recurrent major hypoglycemia; pregnancy; lactation; women not using contraception hypoglycemia unawareness; recurrent severe hypoglycemia; deficiency of hypoglycemic counter 1 1, A-37

38 Author Inclusion Criteria Exclusion Criteria DM Type regulation; significant cardiovascular, renal or retinal disease Boehm 78 type 1 or 2 DM; adult; BMI 35.0 kg/m²; HbA1c 11.0%; 2 times 1, 2 daily insulin regimen Boehm 55 type 2 DM >24 previous to study; age 18 years; BMI use of oral glucose-lowering drugs in previous month kg/m²; HbA1c 11.0%; using biphasic insulin or mix of short- and intermediate-acting insulin in 2 times daily regimen (total daily doses <1.4 U/kg) Bott 6 type 1 DM (WHO criteria) 2 years before study; adult; BMI 35.0 kg/m²; HbA1c 11.0%; HI therapy 1 year previous to 1 Bretzel 56 study type 2 DM (WHO criteria) >1 year before study; age 35 years; anti-diabetic agents >1 year; HbA1c 10.0%; BMI 23 kg/m² to 37 kg/m² unstable and/or untreated proliferative retinopathy; clinical significant nephropathy, neuropathy or hepatic disease; heart failure; uncontrolled hypertension; systemic treatment with corticosteroids; insulin dosage >1.4 U/kg Caixàs 7 type 1 DM; previously treated with MII diabetic complications or other diseases known to affect lipid metabolism Chan 79 type 1 or 2 DM; age 18 to 70 years; 2 times daily insulin regimen weakened liver function (liver enzymes 2 upper limit of normal); impaired renal function (serum creatinine >300 µmol/l; cardiovascular events in previous 6 ; history of symptomatic peripheral vascular disease; pregnancy or planned pregnancy during study; lactation; inability to give self-injections; history of insulin allergies Ciofetta 8 type 1 DM; C-peptide negative (plasma C-peptide <0.15 nmol/l, 6 minutes after 1 mg intravenous glucagon); adult; undergoing intensive insulin therapy microangiopathic complications 1 Colombel 9 type 1 DM with inadequate metabolic control severe complications of diabetes 1 Dailey 57 type 2 DM; age 18 years; insulin therapy 6 previous to 2 study; HbA1c 6.0% to 11.0% Danne 10 pre-school children with type 1 DM 1 Deeb 11 type 1 DM 12 previous to study; pre-pubertal children; 1 insulin therapy 2 previous to randomization Del Sindaco 12 type 1 DM; HbA1c 6.0% to 7.5%; undergoing intensive insulin microangiopathic complications; autonomic neuropathy 1 therapy; C-peptide negative (plasma C-peptide <0.15 nmol/l) DeVries 13 type 1 DM; HbA1c 7.0% to 10.0%; BMI 35 kg/m 2 ; age >18 years 1 active proliferative retinopathy or nephropathy (serum creatinine >150 µmol/l); recurrent severe hypoglycemia (>2 events requiring 3rd - party help in last 6 ) or 2 1 1, 2 A-38

39 Author Inclusion Criteria Exclusion Criteria DM Type hypoglycemia unawareness; high insulin requirement (use of >1.4 U/kg body weight); substance abuse and other major disease; lactation, pregnancy, or women using inadequate contraception Ferguson 14 type 1 DM for >5 years; adult; reduction in warning symptoms of hypoglycemia 2 years; 2 episodes of severe hypoglycemia in systemic renal or hepatic disease; pregnancy 1 Ford-Adams 15 Forst 58 Gale 16 previous 2 years; HbA1c <13.0% type 1 DM for >1 year; pre-pubertal children; 3 times daily insulin regimen (isophane insulin and soluble insulin) type 2 DM; OAD therapy; age 35 to 70 years; HbA1c <1.7 upper limit of normal; C-peptide response 0.4 nmol/l after 1.0 mg intravenous glucagon type 1 DM for >1 year, developed before age 40 years; adult; HbA1c <1.5 upper limit of non-diabetic range; insulin dose 4 times daily, injected within 15 minutes of meals on >50% of occasions previous use of ILis; diabetic complications; obesity 1 (BMI >35); other chronic diseases; HbA1c >12%; repeated severe hypoglycemia insulin therapy 2 major complications due to diabetes 1 Gallagher 59 type 2 DM currently treated with insulin 2 Garg 18 type 1 DM (WHO criteria) currently treated with NPH or UL 1 Garg 17 type 1 DM; age 18 years; insulin therapy 1 year; HbA1c 6.0% to 10.0%; BMI <35 kg/m 2 1 active proliferative retinopathy; history of seizure disorders, hypersensitivity to insulin and its analogues, or impaired renal or hepatic function; previous pancreatectomy or pancreas islet cell transplantation; alcohol or drug abuse; clinically relevant physical or psychological medical condition Hedman 19 type 1 DM; adult; currently using CSII therapy 1 Heller 21 type 1 DM 2 years; adult; BMI 35 kg/m²; HbA1c <9.0% impaired renal or hepatic function; uncontrolled hypertension; cardiac problems; progressed late-diabetic complications; drug or alcohol abuse; concurrent use of systemic corticosteroids 1 Heller 20 type 1 DM 2 years; adult; basal-bolus regimen 3 ; HbA1c <8.0%; desire for tight glucose control proliferative retinopathy; symptomatic peripheral neuropathy; serum creatinine >250 µmol/l; admittance to hospital >3 times with severe hypoglycemia in previous 12 Herz 60 type 2 DM; adult; HbA1c <10% BMI >35 kg/m²; use of OAD therapy; use of systemic 2 glucocorticoids; insulin dosage >2.0 U/kg Herz 22 type 1 DM >2 years; good health; HbA1c 1.75 upper limit of history of 2 episodes of severe hypoglycemia (requiring 1 non-diabetic range external assistance) within preceding 3 Herz 62 type 2 DM >1 year; treated with oral anti-hyperglycemic agent >6 treatment with insulin in last 6 ; treatment with 2 1 A-39