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Meta-Analysis
. 2004 Oct 18;2004(4):CD003418.
doi: 10.1002/14651858.CD003418.pub2.

Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus

A N Goudswaard  1 , N J Furlong, G E H M Rutten, R P Stolk, G D Valk
Affiliations
Meta-Analysis

Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus

A N Goudswaard et al. Cochrane Database Syst Rev. .

Abstract

Background: It is unclear whether patients with type 2 diabetes who have poor glycaemic control despite maximal oral hypoglycaemic agents (OHAs) should be commenced on insulin as monotherapy, or insulin combined with oral hypoglycaemic agents (insulin-OHA combination therapy).

Objectives: To assess the effects of insulin monotherapy versus insulin-OHA combinations therapy.

Search strategy: Eligible studies were identified by searching MEDLINE, EMBASE, and The Cochrane Library. Date of last search: May 2004.

Selection criteria: Randomised controlled trials (RCTs) with 2 months minimum follow-up duration comparing insulin monotherapy (all schemes) with insulin-OHA combination therapy.

Data collection and analysis: Data extraction and assessment of study quality were undertaken by three reviewers in pairs.

Main results: Twenty RCTs (mean trial duration 10 months) including 1,811 participants, with mean age 59.8 years and mean known duration of diabetes 9.6 years. Overall, study methodological quality was low. Twenty-eight comparisons in 20 RCTs were ordered according to clinical considerations. No studies assessed diabetes-related morbidity, mortality or total mortality. From 13 studies (21 comparisons), sufficient data were extracted to calculate pooled effects on glycaemic control. Insulin-OHA combination therapy had statistically significant benefits on glycaemic control over insulin monotherapy only when the latter was applied as a once-daily injection of NPH insulin. Conversely, twice-daily insulin monotherapy (NPH or mixed insulin) provided superior glycaemic control to insulin-OHA combination therapy regimens where insulin was administered as a single morning injection. In more conventional comparisons, regimens utilising OHAs with bedtime NPH insulin provided comparable glycaemic control to insulin monotherapy (administered as twice daily, or multiple daily injections). Overall, insulin-OHA combination therapy was associated with a 43% relative reduction in total daily insulin requirement compared to insulin monotherapy. Of the 14 studies (22 comparisons) reporting hypoglycaemia, 13 demonstrated no significant difference in the frequency of symptomatic or biochemical hypoglycaemia between insulin and combination therapy regimens. No significant differences in quality of life related issues were detected. Combination therapy with bedtime NPH insulin resulted in statistically significantly less weight gain compared to insulin monotherapy, provided metformin was used +/-sulphonylurea. In all other comparisons no significant differences with respect to weight gain were detected.

Reviewers' conclusions: Bedtime NPH insulin combined with oral hypoglycaemic agents provides comparable glycaemic control to insulin monotherapy and is associated with less weight gain if metformin is used.

PubMed Disclaimer

Conflict of interest statement

In 1999 ANG has received an unrestricted research grant from Novo Nordisk for conducting studies on monitoring and treatment of patients with type 2 diabetes in primary care. Research conducted by NJF during 1999‐2001 was supported by an unrestricted research grant from Novo Nordisk.

Figures

1
1
Funnel plot for the outcome HbA1c
1.1
1.1. Analysis
Comparison 1 Insulin once daily versus insulin once daily plus oral antihyperglycaemic agents (OHAs), Outcome 1 HbA1c (change from baseline [%]).
2.1
2.1. Analysis
Comparison 2 insulin twice daily versus insulin plus OHAs, Outcome 1 HbA1c (change from baseline [%]).
2.2
2.2. Analysis
Comparison 2 insulin twice daily versus insulin plus OHAs, Outcome 2 weight gain (change from baseline[kg]].
3.1
3.1. Analysis
Comparison 3 insulin basal/bolus versus insulin plus OHA, Outcome 1 HbA1c (change from baseline [%]).
3.2
3.2. Analysis
Comparison 3 insulin basal/bolus versus insulin plus OHA, Outcome 2 weight gain (change from baseline[kg]].
4.1
4.1. Analysis
Comparison 4 Insulin monotherapy versus insulin plus metformine +/‐ sulphonylurea (SU), Outcome 1 HbA1c (change from baseline [%]).
See this image and copyright information in PMC

Comment in

References

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Raskin 2001 {published data only}
    1. Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin‐treated type 2 diabetes. Diabetes Care 2001;24(7):1226‐32. - PubMed
Reich 1987 {published data only}
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Relimpio 1998 {published data only}
    1. Relimpio F, Pumar A, Losada F, Mangas MA, Acosta D, Astorga R. Adding metformin versus insulin dose increase in insulin‐treated but poorly controlled Type 2 diabetes mellitus: an open‐label randomized trial. Diabetic Medicine 1998;15(12):997‐1002. - PubMed
Rivellese 2000 {published data only}
    1. Rivellese AA, Patti L, Romano G, Innelli F, Marino L, Annuzzi G, et al. Effect of insulin and sulfonylurea therapy, at the same level of blood glucose control, on low density lipoprotein subfractions in type 2 diabetic patients. Journal of Clinical Endocrinology & Metabolism 2000;85(11):4188‐92. - PubMed
Robinson 1998 {published data only}
    1. Robinson AC, Burke J, Robinson S, Johnston DG, Elkeles RS. The effects of metformin on glycemic control and serum lipids in insulin‐treated NIDDM patients with suboptimal metabolic control. Diabetes Care 1998;21(5):701‐5. [MEDLINE: ] - PubMed
Rodier 1995 {published data only}
    1. Rodier M. Effects of insulin therapy upon plasma lipid fatty acids and platelet aggregation in NIDDM with secondary failure to oral antidiabetic agents. Diabetes Research and Clinical Practice 1995;28(1):19‐28. - PubMed
Romano 1997 {published data only}
    1. Romano G, Patti L, Innelli F, Marino L, Annuzzi G, Iavicoli M, et al. Insulin and sulfonylurea therapy in NIDDM patients. Are the effects on lipoprotein metabolism different even with similar blood glucose control?. Diabetes 1997;46:1601‐6. - PubMed
Rosak 1985 {published data only}
    1. Rosak C, Schwarz O, Althoff PH, Schoffling K, Schmidt FH. [Combined treatment of type‐2 diabetics with insulin and glibenclamide after secondary drug failure. Double‐blind, insulin‐placebo‐controlled crossover study]. [German]. Deutsche Medizinische Wochenschrift 1985;110(51‐52):1975‐80. - PubMed
Samanta 1987 {published data only}
    1. Samanta A, Burden AC, Kinghorn HA. A comparative study of sulphonylurea and insulin therapy in non insulin dependent diabetics who had failed on diet therapy alone. Diabetes Research 1987;4:183‐5. - PubMed
Sanchez 1999 {published data only}
    1. Sanchez‐Barba Izquierdo MI, Ibarra Rueda JM, Ruiz de Adana PR. [The combination of insulin and metformin in obese patients with type‐2 diabetes mellitus]. [Spanish]. Atencion Primaria 1999;24(8):462‐67. - PubMed
Sane 1992 {published data only}
    1. Sane T, Helve E, Yki‐Järvinen H, Taskinen MR. One‐year response to evening insulin therapy in non‐insulin‐ dependent diabetes. Journal of Internal Medicine 1992;231:253‐60. [MEDLINE: ] - PubMed
Sangiorgio 1996 {published data only}
    1. Sangiorgio L, Rabuazzo MA, Cordaro G, Grasso G, Condorelli L, Lunetta M. [Comparative study of the efficiency of ultralente insulin and NPH insulin combined with sulfonylurea in type 2 diabetes patients with secondary tolerance to sulfonylurea. Possible selection criteria]. Minerva Endocrinol 1996;21(2):47‐52. [MEDLINE: ] - PubMed
Schade 1987 {published data only}
    1. Schade DS, Mitchell WJ, Griego G. Addition of sulfonylurea to insulin treatment in poorly controlled type II diabetes. A double‐blind, randomized clinical trial. JAMA 1987;257(18):2441‐45. - PubMed
Schwartz 1997 {published data only}
    1. Schwartz SL, Fischer JS, Kipnes MS, Boyle M. Effects of short‐term insulin therapy upon therapeutic response to glipizide. American Journal of Medicine 1987;83(3A):22‐30. - PubMed
Schwartz 1998 {published data only}
    1. Schwartz S, Raskin P, Fonseca V, Graveline JF. Effect of troglitazone in insulin‐treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group. [see comments]. New England Journal of Medicine 1998;338(13):861‐66. - PubMed
Simonson 1987 {published data only}
    1. Simonson DC, Delprato S, Castellino P, Groop L, DeFronzo RA. Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin‐treated diabetic patients. Diabetes 1987;36(2):136‐46. - PubMed
Simpson 1990 {published data only}
    1. Simpson HC, Sturley R, Stirling CA, Reckless JP. Combination of insulin with glipizide increases peripheral glucose disposal in secondary failure type 2 diabetic patients. Diabetic Medicine 1990;7(2):143‐47. - PubMed
Sinagra 1998 {published data only}
    1. Sinagra D, Scarpitta AM, Amato M. Effects of insulin‐oral hypoglycemic agents combined therapy in outpatients with type 2 diabetes. European Review for Medical & Pharmacological Sciences 1998;2(5‐6):175‐79. - PubMed
Soneru 1993 {published data only}
    1. Soneru IL, Agrawal L, Murphy JC, Lawrence AM, Abraira C. Comparison of morning or bedtime insulin with and without glyburide in secondary sulfonylurea failure. Diabetes Care 1993;16(6):896‐901. - PubMed
Sotaniemi 1990 {published data only}
    1. Sotaniemi EA, Vierimaa E, Huupponen R, Karvonen I, Vuoti MJ, Rytomaa K. Insulin and sulphonylurea in the therapy of type 2 diabetes. Diabetes Research and Clinical practice 1990;8:243‐51. - PubMed
Standl 1999 {published data only}
    1. Standl E, Baumgartl HJ, Fuchtenbusch M, Stemplinger J. Effect of acarbose on additional insulin therapy in type 2 diabetic patients with late failure of sulphonylurea therapy. Diabetes Obesity & Metabolism 1999;1(4):215‐20. - PubMed
Stenman 1988 {published data only}
    1. Stenman S, Groop PH, Saloranta C, Totterman KJ, Fyhrqvist F, Groop L. Effects of the combination of insulin and glibenclamide in type 2 (non‐insulin‐dependent) diabetic patients with secondary failure to oral hypoglycaemic agents. Diabetologia 1988;31(4):206‐13. - PubMed
Stocks 1988 {published data only}
    1. Stocks AE MAH. Lack of effect of glibenclamide on insulin requirements and diabetic control in persons with insulin‐dependent diabetes. Medical Journal of Australia 1988;149(9):472‐73. - PubMed
Stradner 1990 {published data only}
    1. Stradner F, Pieber T, Toplak H, Schreiber U, Pfeiffer KP. [Insulin‐sulfonylurea combination therapy in secondary therapy failure with sulfonylurea compounds. Randomized study between evening and morning intermediary insulin administration using the Novo Pen semi‐ automatic insulin injector]. Schweizerische medizinische Wochenschrift 1990;120(27‐28):989‐94. [MEDLINE: ] - PubMed
Thompson 1998 {published data only}
    1. Thompson RG, Pearson L, Schoenfeld SL, Kolterman OG. Pramlintide, a synthetic analog of human amylin, improves the metabolic profile of patients with type 2 diabetes using insulin. The Pramlintide in Type 2 Diabetes Group. Diabetes Care 1998;21(6):987‐93. - PubMed
Tovi 1998 {published data only}
    1. Tovi J, Ingemansson SO, Engfeldt P. Insulin treatment of elderly type 2 diabetic patients: effects on retinopathy. Diabetes & Metabolism 1998;24(5):442‐47. - PubMed
Trischitta 1992 {published data only}
    1. Trischitta V, Italia S, Mazzarino S, Buscema M, Rabuazzo AM, Sangiorgio, L, et al. Comparison of combined therapies in treatment of secondary failure to glyburide. Diabetes Care 1992;15(4):539‐42. - PubMed
Trischitta 1998 {published data only}
    1. Trischitta V, Italia S, Raimondo M, Guardabasso V, Licciardello C, Runello F, et al. Efficacy of combined treatments in NIDDM patients with secondary failure to sulphonylureas. Is it predictable?. Journal of Endocrinological Investigation 1998;21(11):744‐47. - PubMed
Trznadel 1997 {published data only}
    1. Trznadel‐Morawska I, Malecki M, Sieradzki J. [Estimation of different models of insulin therapy in noninsulin‐dependent diabetes mellitus]. Przeglad lekarski 1997;54(5):308‐13. [MEDLINE: ] - PubMed
Turner 1999 (2) {published data only}
    1. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999;281(21):2005‐12. - PubMed
UKPDS 13 1995 {published data only}
    1. United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non‐insulin dependent diabetes followed for three years. [see comments]. BMJ 1995;310(6972):83‐88. - PMC - PubMed
UKPDS 24 1998 {published data only}
    1. United Kingdom Prospective Diabetes Study 24: a 6‐year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. United Kingdom Prospective Diabetes Study Group. [see comments]. Annals of Internal Medicine 1998;128(3):165‐75. - PubMed
UKPDS 33 1998 {published data only}
    1. Intensive blood‐glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. [see comments]. [erratum appears in Lancet 1999 Aug 14;354(9178):602]. Lancet 1998;352(9131):837‐53. - PubMed
Vigneri 1991 {published data only}
    1. Vigneri R, Trischitta V, Italia S, Mazzarino S, Rabuazzo MA, Squatrito, S. Treatment of NIDDM patients with secondary failure to glyburide: comparison of the addition of either metformin or bed‐time NPH insulin to glyburide. Diabete et Metabolisme 1991;17(1 Pt 2):232‐34. - PubMed
Wolffenbuttel 1989 {published data only}
    1. Wolffenbuttel BH, Weber RF, Koetsveld PM, Weeks L, Verschoor L. A randomized crossover study of sulphonylurea and insulin treatment in patients with type 2 diabetes poorly controlled on dietary therapy. Diabetic Medicine 1989;6:520‐25. - PubMed
Yki‐Jarvinen 2000 {published data only}
    1. Yki‐Jarvinen H, Dressler A, Ziemen M, HOE 901/300s Study, Group. Less nocturnal hypoglycemia and better post‐dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care 2000;23(8):1130‐36. - PubMed
Yu 1999 {published data only}
    1. Yu JG, Kruszynska YT, Mulford MI, Olefsky JM. A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin‐treated type 2 diabetic patients. Diabetes 1999;48(12):2414‐21. - PubMed
Yudkin 2000 {published data only}
    1. Yudkin JS, Panahloo A, Stehouwer C, Emeis JJ, Bulmer K, Mohamed‐Ali V, Denver AE. The influence of improved glycaemic control with insulin and sulphonylureas on acute phase and endothelial markers in Type II diabetic subjects. Diabetologia 2000;43(9):1099‐1106. - PubMed

References to studies awaiting assessment

Goudswaard 2004 {published data only}
    1. Goudswaard AN, Stolk RP, Zuithoff P, Valk HW, Rutten GE. Starting insulin in type 2 diabetes: Continue oral hypoglycemic agents? A randomized trial in primary care. Journal of Family Practice 2004;53(5):393‐399. - PubMed
Olsson 2002 {published data only}
    1. Olsson PO, Lindstrom T. Combination‐therapy with bedtime nph insulin and sulphonylureas gives similar glycaemic control but lower weight gain than insulin twice daily in patients with type 2 diabetes. Diabetes Metab 2002;28(4 Pt 1):272‐277. - PubMed
Stehouwer 2003 {published data only}
    1. Stehouwer MH, DeVries JH, Lumeij JA, Ader HJ, Engbers AM, Iperen AA, Snoek FJ, Heine RJ. Combined bedtime insulin‐daytime sulphonylurea regimen compared with two different daily insulin regimens in type 2 diabetes: effects on HbA1c and hypoglycaemia rate‐a randomised trial. Diabetes Metab Res Rev 2003;19(2):148‐152. - PubMed

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