ELECTRONIC SUPPLEMENTARY MATERIAL

Search strategy for electronic databases

Medline (via PubMed)

#1 “GLP-1”

#2 “glucagon-like peptide 1”

#3 “glucagon-like peptide-1 receptor” [nm]

#4 “rGLP-1 protein” [nm]

#5 “glucagon-like peptide 1” [mh]

#6 exenatide

#7 Byetta

#8 Bydureon

#9 AC2993

#10 AC3174

#11 exenatide [nm]

#12 AC3174 [nm]

#13 liraglutide

#14 Victoza

#15 NN2211

#16 liraglutide [nm]

#17 lixisenatide

#18 Lyxumia

#19 AVE0010

#20 “ZP10A peptide” [nm]

#21 dulaglutide

#22 Trulicity

#23 LY2189265

#24 dulaglutide [nm]

#25 albiglutide

#26 Tanzeum

#27 Eperzan

#28 GSK716155

#29 semaglutide

#30 NN9935

#31 semaglutide [nm]

#32 OR/#1-31

#33 “basal insulin”

#34 “insulin, long-acting” [mh]

#35 glargine

#36 Lantus

#37 HOE901

#38 glargine [nm]

#39 detemir

#40 Levemir

#41 NN304

#42 “insulin detemir” [nm]

#43 degludec

#44 Tresiba

#45 NN1250

#46 “insulin degludec” [nm]

#47 OR/#33-46

#48 #32 AND #47

#49 xultophy

#50 IDegLira

#51 NN9068

#52 LixiLan

#53 OR/#48-52

#54 randomized controlled trial [pt]

#55 controlled clinical trial [pt]

#56 randomized [tiab]

#57 placebo [tiab]

#58 drug therapy [sh]

#59 randomly [tiab]

#60 trial [tiab]

#61 groups [tiab]

#62 OR/#54-61

#63 animals [mh] NOT humans [mh]

#64 #62 NOT #63

#65 #53 AND #64

Embase (via Ovid)

#1 GLP-1.mp. or glucagon like peptide 1/

#2 glucagon-like peptide 1.mp.

#3 glucagon-like peptide-1 receptor.mp. or exp glucagon like peptide 1 receptor/

#4 rGLP-1 protein.mp.

#5 exenatide.mp. or exp exendin 4/

#6 Byetta.mp.

#7 Bydureon.mp.

#8 AC2993.mp.

#9 AC-2993.mp.

#10 AC3174.mp.

#11 AC-3174.mp.

#12 exp liraglutide/ or liraglutide.mp.

#13 Victoza.mp.

#14 NN2211.mp.

#15 NN-2211.mp.

#16 lixisenatide.mp. or exp lixisenatide/

#17 Lyxumia.mp.

#18 AVE0010.mp.

#19 AVE-0010.mp.

#20 ZP10A peptide.mp.

#21 dulaglutide.mp. or exp dulaglutide/

#22 Trulicity.mp.

#23 LY2189265.mp.

#24 LY-2189265.mp.

#25 albiglutide.mp. or exp albiglutide/

#26 Tanzeum.mp.

#27 Eperzan.mp.

#28 GSK716155.mp.

#29 GSK-716155.mp.

#30 semaglutide.mp. or exp semaglutide/

#31 NN9935.mp.

#32 NN-9935.mp.

#33 OR/#1-32

#34 basal insulin.mp.

#35 insulin long-acting.mp. or exp long acting insulin/

#36 insulin glargine/ or glargine.mp.

#37 Lantus.mp.

#38 HOE901.mp.

#39 HOE-901.mp.

#40 exp insulin detemir/ or detemir.mp.

#41 Levemir.mp.

#42 NN304.mp.

#43 NN-304.mp.

#44 exp insulin degludec/ or degludec.mp.

#45 Tresiba.mp.

#46 NN1250.mp.

#47 NN-1250.mp.

#48 OR/#34-47

#49 33 AND 48

#50 xultophy.mp. or exp insulin degludec plus liraglutide/

#51 ideglira.mp.

#52 NN9068.mp.

#53 NN-9068.mp.

#54 lixilan.mp.

#55 OR/#49-54

#56 Clinical trial/

#57 Randomized controlled trial/

#58 Randomization/

#59 Single blind procedure/

#60 Double blind procedure/

#61 Crossover procedure/

#62 Placebo/

#63 Randomi?ed controlled trial$.tw.

#64 Rct.tw.

#65 Random allocation.tw.

#66 Randomly allocated.tw.

#67 Allocated randomly.tw.

#68 (allocated adj2 random).tw.

#69 Single blind$.tw.

#70 Double blind$.tw.

#71 ((treble or triple) adj (blind$).tw.

#72 Placebo$.tw.

#73 Prospective study/

#74 OR/#56-73

#75 Case study/

#76 Case report.tw.

#77 Abstract report/ or letter/

#78 OR/#75-77

#79 #74 NOT #78

#80 #55 AND #79

Cochrane Library

#1 GLP-1

#2 glucagon-like peptide 1

#3 exenatide

#4 Byetta

#5 Bydureon

#6 AC2993

#7 AC3174

#8 liraglutide

#9 Victoza

#10 NN2211

#11 lixisenatide

#12 Lyxumia

#13 AVE0010

#14 dulaglutide

#15 Trulicity

#16 LY2189265

#17 albiglutide

#18 Tanzeum

#19 Eperzan

#20 GSK716155

#21 semaglutide

#22 NN9935

#23 OR/#1-22

References to excluded studies after full text review

1. National Horizon Scanning Centre. Liraglutide (Victoza) in combination with

basal insulin for type 2 diabetes. http://www.hsric.nihr.ac.uk/topics/liraglutide-

victoza-in-combination-with-basal-insulin-for-type-2-diabetes. Accessed 15

Mar 2017

2. National Horizon Scanning Centre. Exenatide (Byetta) for type 2 diabetes

mellitus – in combination with basal insulin.

http://www.hsric.nihr.ac.uk/topics/exenatide-byetta-for-type-2-diabetes-

mellitus-in-combination-with-basal-insulin. Accessed 15 Mar 2017

3. Abdul-Ghani MA, Williams K, Kanat M, Altuntas Y, DeFronzo RA. Insulin

vs GLP-1 analogues in poorly controlled type 2 diabetic subjects on oral

therapy: a meta-analysis. J. Endocrinol. Invest. 36(3), 168-173 (2013)

4. Aroda V, Jaeckel E, Jarlov H, Abrahamsen TJ, Vilsboll T, Similar incidence

of gastrointestinal side effects between IDegLira and non-glucagon-like

peptide-1 receptor agonist comparators. Diabetologia 58(Suppl 1), 401 (2015)

5. Aroda VR, Jaeckel E, Jarlov H, Abrahamsen TJ, Vilsboll T. Incidence of

gastrointestinal side effects similar between IDeg-Lira and non-GLP-1RA

comparators. Diabetes 64(Suppl 1), A257 (2015)

6. Bain SC, DeVries JH, Seufert J, D’ Alessio D, Rodbard HW, Thomsen AB,

Sondergaard RE, Rosenstock J. Adding insulin detemir (IDet) to liraglutide

and metformin improves glycaemic control with sustained weight reduction

and low hypoglycaemia rate: 52 week results. Diabetologia 54(Suppl 1), S37

(2011)

7. Brod M, Manghi FCP, Garcia-Hernandez PA, Norwood P, Jarlov H, Kongso

JH, Lingvay I. Adding insulin detemir (IDet) to liraglutide and metformin

improves glycaemic control with sustained weight reduction and low

hypoglycaemia rate: 52 week results. Diabetes 64(Suppl 1), A644 (2015)

8. Chaplin S, Patel V. Xultophy: Combination therapy for the treatment of type 2

diabetes. Prescriber 26(17), 32-34 (2015)

9. Charbonnel B, Bertolini M, Tinahones FJ, Puig Doming M, Davies M.

Lixisenatide plus basal insulin in patients with type 2 diabetes mellitus: a

meta-analysis. J. Diabetes Complications 28(6), 880-886 (2014) [Database of

Abstracts of Reviews of Effects]

10. Del Prato S. Fixed-ratio combination of basal insulin and GLP-1 receptor

agonist: is two better than one? Lancet Diabetes Endocrinol. 2(11), 856-858

(2014)

11. Distiller LA, Nortje H, Wellmann H, Amod A, Lombard L. A 24-week,

prospective, randomized, open-label, treat-to-target pilot study of obese type 2

diabetes patients with severe insulin resistance to assess the addition of

exenatide on the efficacy of U-500 regular insulin plus metformin. Endocr.

Pract. 20(11), 1143-1150 (2014)

12. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1

receptor agonist and basal insulin combination treatment for the management

of type 2 diabetes: a systematic review and meta-analysis. Lancet 384(9961),

2228-2234 (2014)

13. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1

receptor agonist and basal insulin combination treatment for the management

of type 2 diabetes: a systematic review and meta-analysis. Lancet 384(9961),

2228-2234 (2014) [Database of Abstracts of Reviews of Effects]

14. Freemantle N, Lingvay I, Kongso JH, Abrahamsen TJ, Bjorner JB. Ideglira

improves health utility compared with insulin glargine in patients with type 2

diabetes. Value Health 18(7), A614 (2015)

15. Goldenberg RM, Puig-Domingo M, Fonseca V, Wang EC, Lin J, Davies MJ,

Tinahines FJ, Charbonnel B. Meta-analysis of randomized controlled trials of

lixisenatide as add on to basal insulin and/or oral antihyperglycemic agents in

patients with type 2 diabetes mellitus. Can. J. Diabetes 37(Suppl 1), S36

(2013)

16. Gough SC, Bode BQ, Woo VC, Rodbard HW, Linjawi S, Zacho M, Reiter

PD, Buse JB. One-year efficacy and safety of a fixed combination of insulin

degludec and liraglutide in patients with type 2 diabetes: results of a 26-week

extension to a 26-week main trial. Diabetes Obes. Metab. 17(10), 965-973

(2015)

17. Gough SCL, Bode V, Woo V, Rodbard HW, Linjawi S, Poulsen P, Damgaard

LH, Buse JB, NN9068-3697 DUAL-I trial investigators. Efficacy and safety

of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira)

compared with its components given alone: results of a phase 3, open-label,

randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2

diabetes. Lancet Diabetes Endocrinol. 2(11), 885-893 (2014)

18. Kalra S. Insulin and glucagon-like peptide receptor agonist (GLP 1 RA)

combinations. J. Pak. Med. Assoc. 64(3), 359-361 (2014)

19. Kapitza C, Bode B, Ingwersen SH, Jacobsen LV, Poulsen P. Preserved

pharmacokinetic exposure and distinct glycemic effects of insulin degludec

and liraglutide in IDegLira, a fixed-ratio combination therapy. J. Clin.

Pharmacol. 55(12), 1369-1377 (2015)

20. Kapitza C, Bode BW, Ingwersen SH, Jacobsen LV, Poulsen P. Preserved

pharmacokinetic properties and distinct glycaemic effects of insulin degludec

and liraglutide in IDegLira, a fixed ratio combination product. Diabetologia

57(Suppl 1), S392-S393 (2014)

21. Kapitza C, Bode BW, Ingwersen SH, Jacobsen LV, Poulsen P. Preserved

pharmacokinetic properties and distinct glycaemic effects of insulin degludec

and liraglutide in IDegLira, a fixed ratio combination product. Diabetologia

57(Suppl 1), S392-S393 (2014)

22. Kumar A. Insulin degludec/liraglutide: Innovation-driven combination for

advancement in diabetes therapy. Expert Opin. Biol. Ther. 14(6), 869-878

(2014)

23. Mathieu C, Rodbard HW, Cariou B, Handelsman Y, Philis-Tsimikas A,

Ocampo Francisco AM, Rana A, Zinman B. Comparison of addition of

liraglutide to insulin degludec plus metformin vs. addition of a single dose of

rapid-acting insulin analog to largest meal in type 2 diabetes. Diabetes

62(Suppl 1), A231 (2013)

24. Mathieu C, Rodbard HW, Cariou B, Handelsman Y, Philis-Tsimikas A,

Ocampo Francisco AM, Rana A, Zinman B, Begin Victoza add-on study

group. A comparison of adding liraglutide versus a single daily dose of insulin

aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA

ADD-ON). Diabetes Obes. Metab. 16(7), 636-644 (2014)

25. O’ Neal D, Umpierrez G, DiGenio A, Goldenberg R, Hernandez-Triana E, Lin

J, Park CY, Renard E, Kovatchev B. Lixisenatide added to basal insulin

reduces glycaemic variability in patients with type 2 diabetes mellitus.

Diabetologia 57(Suppl 1), S342 (2014)

26. Piatti P, Lahtela J, Ahmann A, Rodbard H, Rosenstock J, De Loredo L,

Tornoe K, Boopalan A, Mancuso M, Nauck M. Efficacy and safety of

liraglutide vs placebo when added to basal insulin analogues in subjects with

type 2 diabetes: A randomised, placebo-controlled trial. Ital. J. Med. 9(Suppl

2), 80 (2015)

27. Piatti P, Lahtela J, Ahmann A, Rodbard H, Rosenstock J, De Loredo L,

Tornoe K, Boopalan A, Mancuso M, Nauck M. Efficacy and safety of

liraglutide vs placebo when added to basal insulin analogues in subjects with

type 2 diabetes: A randomised, placebo-controlled trial. Ital. J. Med. 9(Suppl

2), 80 (2015)

28. Probstfield JL, Hirsch I, O’ Brien K, Davis B, Bergenstal R, Kingry C,

Khakpour D, Pressel S, Branch KR, Riddle M. Design of FLAT-SUGAR:

Randomized trial of prandial insulin versus prandial GLP-1 receptor agonist

together with basal insulin and metformin for high-risk type 2 diabetes.

Diabetes Care 38(8), 1558-1566 (2015)

29. Rausch R. Basal insulin and liraglutide combined in a pen. Med. Monatsschr.

Pharm. 38(4), 154-156 (2015)

30. Rizos EC, Ntzani EE, Papanas N, Tsimihodimos V, Mitrogianni Z, Maltezos

E, Elisaf MS. Combination therapies of DPP4 inhibitors and GLP1 analogues

with insulin in type 2 diabetic patients: a systematic review. Curr. Vasc.

Pharmacol. 11(6), 992-1000 (2013)

31. Rodbard HW, Bode BW, Harris SB, Rose L, Lehmann L, Jarlov H, Thurman

J. Ideglira in insulin-naive patients with type 2 diabetes (T2D) inadequately

controlled on sulfonylureas (SU) alone or in combination with metformin: the

dual IV study. Diabetes 64(Suppl 1), A255-A256 (2015)

32. Rodbard HW, Buse JB, Woo VC, Vilsboll T, Langbakke I, Korsholm L,

Gough S. Novel combination of insulin degludec and liraglutide (IDegLira) is

efficacious across the range of disease progression in type 2 diabetes.

Diabetologia 57(Suppl 1), S338-S339 (2014)

33. Rodbard HW, Buse JB, Woo V, Vilsboll T, Lankbakke IH, Kvist K, Gough

SC. Benefits of combination of insulin degludec and liraglutide are

independent of baseline glycated haemoglobin level and duration of type 2

diabetes. Diabetes Obes. Metab. 18(1), 40-48 (2016)

34. Rosenstock J, Ahren B, Chow F, Fonseca V, Gross J, Ratner R, Johnson S,

Stewart M, Yang F, Leiter L. Once-weekly GLP-1 receptor agonist albiglutide

vs. titrated prandial lispro added on to titrated basal insulin glargine in type 2

diabetes (T2D) uncontrolled on glargine plus oral agents: similar glycemic

control with weight loss and less hypoglycemia. Diabetes 61(Suppl 1), A15-

A16 (2012)

35. Rosenstock J, Rodbard HW, Bain SC, D’ Alessio D, Seufert J, Thomsen AB,

Svendsen CB, DeVries JH. One-year sustained glycemic control and weight

reduction in type 2 diabetes after addition of liraglutide to metformin followed

by insulin detemir according to HbA1c target. J. Diabetes Complications

27(5), 492-500 (2013)

36. Rosenstock J, Shenouda SK, Bergenstal RM, Buse JB, Glass LC, Heilmann

CR, Kwan AY, MacConell LA, Hoogwerf BJ. Baseline factors associated with

glycemic control and weight loss when exenatide twice daily is added to

optimized insulin glargine in patients with type 2 diabetes. Diabetes Care

35(5), 955-958 (2012)

37. Rosenstock J, Shenouda SK, Bergenstal RM, Buse JB, Glass LC, Heilmann

CR, Kwan AY, MacConell LA, Hoogwerf BJ. Baseline factors associated with

glycemic control and weight loss when exenatide twice daily is added to

optimized insulin glargine in patients with type 2 diabetes. Diabetes Care

35(5), 955-958 (2012)

38. Rosenstock J, Shenouda SK, Bergenstal RM, Buse JB, Glass LC, Heilmann

CR, Kwan AY, MacConell LA, Hoogwerf BJ. Baseline factors associated with

glycemic control and weight loss when exenatide twice daily is added to

optimized insulin glargine in patients with type 2 diabetes. Diabetes Care

35(5), 955-958 (2012)

39. Salari P, Nikfar S, Abdollahi M. No superiority of exenatide over insulin in

diabetic patients in terms of weight reduction or incidence of adverse effects: a

meta-analysis. Int. J. Pharmacol. 7(7), 749-756 (2011)

40. Scheen AJ, Paquot N. Potential of a GLP-1 receptor agonist combined with

basal insulin in the treatment of type 2 diabetes. Rev. Med. Suisse 10(439),

1549-1554 (2014)

41. Seino Y, Kaneko S, Fukuda S, Osonoi T, Shiraiwa T, Nishijima K, Kaku K.

Combination therapy with liraglutide and insulin in Japanese subjects with

type 2 diabetes: The Lira-add2insulin Japan trial. Diabetes 63(Suppl 1), A253

(2014)

42. Simpson R, King A. Can a fixed-ratio combination of insulin degludec and

liraglutide help type 2 diabetes patients to optimize glycemic control across

the day? Expert Rev. Clin. Pharmacol. 8(2), 179-188 (2015)

43. Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, Zhang Y, Ji L, Zhan S. Effect of

GLP-1 receptor agonists on waist circumference among type 2 diabetes

patients: a systematic review and network meta-analysis. Endocrine 48(3),

794-803 (2015) [Database of Abstracts of Reviews of Effects]

44. Umpierrez G, Atkin S, Bain S, Rossing P, Scott D, Shamkhalova M, Bosch-

Traberg H, Syren A, Davies M. Efficacy and safety of liraglutide versus

placebo in subjects with type 2 diabetes and moderate renal impairment

(LIRA-RENAL): a randomised trial. Diabetologia 57(Suppl 1), S84 (2014)

45. Van Der Klauw MM, Wolffenbuttel BHR. The combination of insulin and

GLP-1 analogues in the treatment of type 2 diabetes. Neth. J. Med. 70(10),

436-443 (2012)

46. Wintle M, Pencek R, Han J, Miller S, Buse J. The combination of insulin and

GLP-1 analogues in the treatment of type 2 diabetes. Diabetologia 55(Suppl

1), S331 (2012)

47. Vedtofte L, Knop FK, Vilsboll T. Fixed combination of insulin and a

glucagon-like peptide-1 analog for the treatment of type 2 diabetes,

exemplified by insulin degludec and liraglutide. Expert Rev. Clin. Pharmacol.

8(3), 273-282 (2015)

48. Vilsboll T, Thurman J, Blevins T, Langbakke IH, Damgaard LH, Rodbard

HW. Liraglutide makes a significant contribution to the improvement in

glycaemic control achieved with IDegLira: a double-blind phase 3 trial in type

2 diabetes. Diabet. Med. 31(Suppl 1), 49 (2014)

49. Wintle M, Pencek R, Han J, Miller S, Buse J. Addition of fixed-dose exenatide

to insulin glargine therapy improved glycaemic control without increasing

hypoglycaemia or weight gain across a range of insulin titration. Diabetologia

55(Suppl 1), S331 (2012)

50. Wintle M, Pencek R, Han J, Miller S, Buse J. Addition of fixed-dose exenatide

to insulin glargine therapy improved glycaemic control without increasing

hypoglycaemia or weight gain across a range of insulin titration. Diabetologia

55(Suppl 1), S331 (2012)

51. Zhang L, Zhang M, Zhang Y, Tong N. Efficacy and safety of dulaglutide in

patients with type 2 diabetes: a meta-analysis and systematic review. Sci. Rep.

8, 18904 (2016)

Supplementary Fig. 1 Review authors’ judgments about each risk of bias item for

each included study (green colour indicates low and red colour indicates high risk of

bias)

Supplementary Fig. 2 Forest plot for patients achieving haemoglobin A1c < 7%.

Results are from Mantel-Haenszel (M-H) fixed effects meta-analysis. CI confidence

interval, GLP-1 RA glucagon like peptide 1 receptor agonist.

Supplementary Fig. 3 Forest plot for incidence of hypoglycaemia. Results are from

Mantel-Haenszel (M-H) fixed effects meta-analysis. CI confidence interval, GLP-1

RA glucagon like peptide 1 receptor agonist.

Supplementary Fig. 4 Forest plot for incidence of nausea. Results are from Mantel-

Haenszel (M-H) fixed effects meta-analysis. CI confidence interval, GLP-1 RA

glucagon like peptide 1 receptor agonist.

Supplementary Fig. 5 Forest plot for incidence of vomiting. Results are from

Mantel-Haenszel (M-H) fixed effects meta-analysis. CI confidence interval, GLP-1

RA glucagon like peptide 1 receptor agonist.