The online version of this article (doi:10.1186/s12902-015-0052-z) contains supplementary material, which is available to authorized users.
The project was supported by an unrestricted scientific grant from Novo Nordisk. The author(s) declare that they have no competing interests. There is no specific organization that may in any way gain or lose financially from the publication of this manuscript.
MJ, JP, MN, ER, and MC are the authors of the general approach. MJ, JP, ER, OAS, and MN participated in the systematic review. MJ designed the statistical approach. All authors participated in preparing, reading, and approving the final manuscript.
Diabetes mellitus (DM) leads to multiple complications, including severe hypoglycaemia events (SHEs). SHEs can impact a patient’s quality of life and compliance and may directly result in additional costs to the health care system. The aim of this review was to evaluate the risk of severe hypoglycaemia in patients with type 1 (T1) and 2 (T2) DM as observed in everyday clinical practice for various drug regimens.
We conducted a systematic review of observational (retrospective or prospective) studies in the MEDLINE, Embase, and Cochrane Library databases that covered at least 100 children or adults with T1/T2 DM. In T1 DM, basal-bolus/pre-mix insulin (human or analogue) and insulin pump were reviewed, and in T2 DM, basal-bolus/pre-mix insulin (human or analogue), oral antidiabetic drugs supported with basal insulin (human or analogue), sulfonylureas in monotherapy, and combined oral treatment were reviewed. In order to estimate SHE rates, we extracted data on the time horizon of the study, number of patients, number of SHEs, and number of patients experiencing at least one SHE. We used a random effects model to estimate the annual SHE rate. We considered the risk for other antidiabetic medications in T2 DM to be negligible and the results of our main review yielded no observational data for premixes in T1 DM so they were assessed based on relative rates taken from additional systematic reviews. The study, being a desk research, did not involve any human subjects (including human material or human data) and no ethical committee approval was asked for. For the same reason there was no need to collect informed consent for participation in the study.
We identified 76 observational studies encompassing 707,722.30 patient-years. The estimated annual SHE rate varied from 0.168 (95 % CI 0.123–0.237) for insulin pump up to 1.628 for biphasic human insulin in T1 DM patients, and from 0.0035 for oral antidiabetic drugs up to 0.554 (95 % CI 0.157–7.534) for basal-bolus with human insulin in T2 DM patients.
Our review indicates that SHE rates differ between patients depending on treatment regimen. However, SHEs are also driven by other factors. Proper modelling techniques are needed to use various types of information in published studies.
Additional file 1: Search strategies. (PDF 220 kb)12902_2015_52_MOESM1_ESM.pdf
Additional file 2: Model specification and JAGS codes. (PDF 343 kb)12902_2015_52_MOESM2_ESM.pdf
Additional file 3: Study selection process. (PDF 318 kb)12902_2015_52_MOESM3_ESM.pdf
Additional file 4: Studies characteristics. (PDF 332 kb)12902_2015_52_MOESM4_ESM.pdf
Additional file 5: Individual studies data. (PDF 466 kb)12902_2015_52_MOESM5_ESM.pdf
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;16:1047–53. CrossRef
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53. CrossRef
Diabetes Control and Complications Trial Research (DCCT) Group. The effect of intensive treatment in diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus. N Engl J Med. 1993;329:977–86. CrossRef
Whipple AO. The surgical therapy of hyperinsulinism. J Int Chir. 1938;3:237–76.
Workgroup on Hypoglycemia, Workgroup on Hypoglycemia, American Diabetes Association. Defending and reporting hypoglycaemia in diabetes. Diabets Care. 2005;28:1245–9. CrossRef
UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes; effects of treatment modalities and their duration. Diabetologia. 2007;50:1140–7. CrossRef
Jakubczyk M, Pawęska J, Niewada M, Rdzanek E, Czech M. Risk of severe hypoglycaemia for various treatment regimens – a systematic review and meta-analysis of observational studies. JHPOR. 2014; doi: 10.7365/JHPOR.2014.2.9
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 10 Mar 2015.
Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al. Evaluating non-randomised intervention studies. Health Technol Assess. 2003;7:1–173. iii-x. CrossRef
Higgins JPT, Green S. Tools for assessing methodological quality or risk of bias in non-randomized studies. In: Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. http://handbook.cochrane.org/chapter_13/13_5_2_3_tools_for_assessing_methodological_quality_or_risk_of.htm. Accessed 10 Mar 2015.
Viechtbauer W. Package ‘metafor’. In: The Comprehensive R Archive Network. Package ‘metafor’. http://cran.r-project.org/web/packages/metafor/metafor.pdf; Accessed 10 Mar 2015.
Andayani TM, Ibrahim MIM, Asdie AH. The safety of triple therapy with oral antidiabetics versus insulin in type 2 diabetes. Asian J Pharm Clin Res. 2010;3:201–3.
Biesenbach G, Bodlaj G, Pieringer H. Weight gain and metabolic control in newly insulin-treated patients with type 2 diabetes with different insulin regimens. Can J Diabetes. 2006;30:384–9. CrossRef
Dornhorst A, Lüddeke HJ, Koenen C, Meriläinen M, King A, Robinson A, et al. Transferring to insulin detemir from NPH insulin or insulin glargine in type 2 diabetes patients on basal-only therapy with oral antidiabetic drugs improves glycaemic control and reduces weight gain and risk of hypoglycaemia: 14-week follow-up data from PREDICTIVE®. Diabetes Obes Metab. 2008;10:75–81. PubMed
Esteghamati A, Rajabian R, Amini M, Bahrami A, Khamseh ME, Afkhami-Ardekani M, et al. The safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) in Iranians with type 2 diabetes: An open-label, non-randomised, multi-centre observational study - The Iran subgroup of the IMPROVE® study. Endokrynol Pol. 2010;61:364–70. PubMed
Furlong NJ, McNulty SJ, O’Brien SV, Hardy KJ. Comparison of metformin versus sulphonylurea in combination with daily NPH insulin in patients with type 2 diabetes inadequately controlled on oral hypoglycaemic agents; median follow-up 29 months. Practical Diabetes Int. 2002;19:245–9. CrossRef
Gao Y, Guo XH. Switching from human insulin to biphasic insulin aspart 30 treatment gets more patients with type 2 diabetes to reach target glycosylated hemoglobin <7%: The results from the China cohort of the PRESENT study. Chin Med J (Engl). 2010;123:1107–11.
Garg SK, Gottlieb PA, Hisatomi ME, D’Souza A, Walker AJ, Izuora KE, et al. Improved glycemic control without an increase in severe hypoglycemic episodes in intensively treated patients with type 1 diabetes receiving morning, evening, or split dose insulin glargine. Diabetes Res Clin Pract. 2004;66:49–56. PubMedCrossRef
Giorda C, Boemi M, Borzì V, Chiaramonte F, Mattei P, Tribulato A. The IMPROVE study a multinational, multicentre, observational study in type 2 diabetes: results from the Italian cohort. Acta Biomed. 2010;81:115–24. PubMed
Gumprecht J, Benroubi M, Borzi V, Kawamori R, Shaban J, Shah S, et al. Intensification to biphasic insulin aspart 30/70 (BIAsp 30, NovoMix® 30) can improve glycaemic control in patients treated with basal insulins: A subgroup analysis of the IMPROVE observational study. Int J Clin Pract. 2009;63:966–72. PubMedCentralPubMedCrossRef
Gumprecht J, Zurawska G, Wolnik B, Dzida G. The IMPROVE study - A multinational, observational study in type 2 diabetes: Data from the Polish cohort. Endokrynol Pol. 2008;59:460–6. PubMed
Hanefeld M, Fleischmann H, Landgraf W, Pistrosch F. EARLY study: Early basal insulin therapy under real-life conditions in type 2 diabetics. Diabetes Stoffwech H. 2012;21:91–7.
Hassan MI, Aamir AH, Miyan Z, Siddiqui LA, Qureshi MS, Shaikh MZ. Safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) in people with type 2 diabetes mellitus in the Pakistani population: Results from the A1chieve study. J Pak Med Assoc. 2012;62:929–36. PubMed
Hermansen K, Lund P, Clemmensen K, Breum L, Kleis Moller M, Mette Rosenfalck A, et al. 3-Month results from Denmark within the globally prospective and observational study to evaluate insulin detemir treatment in type 1 and type 2 diabetes: The PREDICTIVE study. Rev Diabet Stud. 2007;4:89–97. PubMedCentralPubMedCrossRef
Jakisch BI, Wagner VM, Heidtmann B, Lepler R, Holterhus PM, Kapellen TM, et al. Comparison of continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) in paediatric Type 1 diabetes: a multicentre matched-pair cohort analysis over 3 years. Diabet Med. 2008;25:80–5. PubMedCrossRef
Kapellen TM, Wolf J, Rosenbauer J, Stachow R, Ziegler R, Szczepanski R, et al. Changes in the use of analogue insulins in 37 206 children and adolescents with type 1 diabetes in 275 German and Austrian centres during the last twelve years. Exp Clin Endocrinol Diabetes. 2009;117:329–35. PubMedCrossRef
Kawamori R, Valensi P. IMPROVE observational study of biphasic insulin aspart 30/70 in patients with Type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2010;5:507–16. CrossRef
Khader S, Abdelfattah W, Almansari A, Elnnagar NK. Safety and efficacy of switching to biphasic insulin aspart 30/70 (BIAsp 30) under the routine diabetic care in patients with type 2 diabetes: The IMPROVE observational study in the Gulf region. Int J Diabetes Mellit. 2010;2:110–3. CrossRef
Lüddeke HJ, Sreenan S, Aczel S, Maxeiner S, Yenigun M, Kozlovski P, et al. PREDICTIVE- a global, prospective observational study to evaluate insulin detemir treatment in types 1 and 2 diabetes: baseline characteristics and predictors of hypoglycaemia from the European cohort. Diabetes Obes Metab. 2007;9:428–34. PubMedCrossRef
Marre M, Pinget M, Gin H, Thivolet C, Hanaire H, Robert JJ, et al. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain: 52-week data from the PREDICTIVE study in a cohort of French patients with type 1 or type 2 diabetes. Diabetes Metab. 2009;35:469–75. PubMedCrossRef
Meneghini LF, Rosenberg KH, Koenen C, Merilainen MJ, Lüddeke HJ. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. Diabetes Obes Metab. 2007;9:418–27. PubMedCrossRef
Oishi M, Abe N, Yokoyama H, Kuribayashi N, Tomonaga O, Matoba K, et al. Observational 6-month open-label study of Japanese type 2 diabetes patients switching from NPH insulin to insulin detemir in basal-bolus regimen: 23rd article of the Japan diabetes clinical data management study group (JDDM23). J Int Med Res. 2012;40:787–97. PubMedCrossRef
Peczyńska J, Urban M, Głowińska B, Florys B. Decreased consciousness of hypoglycaemia and the incidence of severe hypoglycaemia in children and adolescents with diabetes type 1. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 2002;8:77–82. PubMed
Perriello G, Caputo S, De Pergola G, Di Carlo A, Grassi G, Lapolla A, et al. Improved glycemic control with weight loss and a low risk of hypoglycaemia with insulin detemir: insights from the Italian cohort of the PREDICTIVE study after 6-month observation in type 2 diabetic subjects. Expert Opin Pharmacother. 2011;12:2449–55. PubMedCrossRef
Reda E, Von Reitzenstein A, Dunn P. Metabolic control with insulin pump therapy: the Waikato experience. N Z Med J. 2007;120:U2401. PubMed
Scheidegger U, Allemann S, Scheidegger K, Diem P. Continuous subcutaneous insulin infusion therapy: effects on quality of life. Swiss Med Wkly. 2007;137:476–82. PubMed
Shah S, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, et al. Safety and effectiveness of biphasic insulin aspart 30/70 (NovoMix® 30) when switching from human premix insulin in patients with type 2 diabetes: Subgroup analysis from the 6-month IMPROVE observational study. Int J Clin Pract. 2009;63:574–82. PubMedCentralPubMedCrossRef
Sharma SK, Joshi SR, Kumar A, Unnikrishnan AG, Hoskote SS, Moharana AK, et al. Efficacy, safety and acceptability of biphasic insulin aspart 30 in Indian patients with type 2 diabetes: results from the PRESENT study. J Assoc Physicians India. 2008;56:859–63. PubMed
Strojek K, Tarasiuk A, Bijos P, Czech A. Gensulin M30 in patients with type 2 diabetes and secondary failure to oral antidiabetic drugs. the Progens-first-step study: A multicentre observational study in the outpatient setting. Diabet Dośw i Klin. 2008;8:179–84.
Suzuki D, Toyoda M, Kondo M, Miyatake H, Tanaka E, Sato H, et al. Efficacy of long-acting insulin analog insulin glargine at high dosage for basal-bolus insulin therapy in patients with type 2 diabetes. Tokai J Exp Clin Med. 2012;37:35–40. PubMed
Valensi P, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, et al. Initiating insulin therapy with, or switching existing insulin therapy to, biphasic insulin aspart 30/70 (NovoMix 30) in routine care: Safety and effectiveness in patients with type 2 diabetes in the IMPROVE observational study. Int J Clin Pract. 2009;63:522–31. PubMedCrossRef
Zjačic-Rotkvić V, Cigrovski-Berković M, Grulović N, Baršić B. Efficacy and safety of a basal-bolus regimen with insulin glargine in patients with type 2 diabetes after failing premix insulin therapy: A multicenter postmarketing study. Diabetol Croat. 2012;41:41–8.
El Naggar NK, Soewondo P, Khamseh ME, Chen JW, Haddad J. Switching from biphasic human insulin 30 to biphasic insulin aspart 30 in type 2 diabetes is associated with improved glycaemic control and a positive safety profile: results from the A 1chieve study. Diabetes Res Clin Pract. 2012;98:408–13. PubMedCrossRef
El-Naggar N, Almansari A, Khudada K, Salman S, Mariswamy N, Abdelfattah W, et al. The A1 chieve study - an observational non-interventional study of patients with type 2 diabetes mellitus initiating or switched to insulin analogue therapy: subgroup analysis of the Gulf population. Int J Clin Pract. 2013;67:128–38. PubMedCrossRef
Pīrāgs V, El Damassy H, Dąbrowski M, Gönen MS, Račická E, Martinka E, et al. Low risk of severe hypoglycaemia in patients with type 2 diabetes mellitus starting insulin therapy with premixed insulin analogues BID in outpatient settings. Int J Clin Pract. 2012;66:1033–41. CrossRef
Laubner K, Molz K, Kerner W, Karges W, Lang W, Dapp A, et al. Daily insulin doses and injection frequencies of neutral protamine hagedorn (NPH) insulin, insulin detemir and insulin glargine in type 1 and type 2 diabetes: a multicenter analysis of 51 964 patients from the German/Austrian DPV-wiss database. Diabetes Metab Res Rev. 2014;30:395–404. PubMedCrossRef
Maltoni G, Zucchini S, Scipione M, Rollo A, Balsamo C, Bertolini C, et al. Severe hypoglycemic episodes: a persistent threat for children with Type 1 diabetes mellitus and their families. J Endocrinol Invest. 2013;36:617–21. PubMed
Panelo AA, Dorado ED, Lelis M, Javelona JQ. A post-marketing surveillance study report to evaluate the safety and efficacy of a fixed-dose combination of glimepiride and metformin in the treatment of type 2 diabetes mellitus. Philipp J Intern Med. 2013;51:3.
Lieverse AG, Rodriguez M, Czupryniak L, Landgraf W, Loizeau V, Pilorget V, et al. Glycaemic control of type 2 diabetics with insulin glargine in everyday practice. Diabetes Stoffwech H. 2013;22:141–7.
Damci T, Emral R, Svendsen AL, Balkir T, Vora J. Lower risk of hypoglycaemia and greater odds for weight loss with initiation of insulin detemir compared with insulin glargine in Turkish patients with type 2 diabetes mellitus: local results of a multinational observational study. BMC Endocr Disord. 2014;14:61. PubMedCentralPubMedCrossRef
Tentolouris N, Kyriazopoulou V, Makrigiannis D, Baroutsou B. Intensification of insulin therapy in patients with type 2 diabetes: a retrospective, non- interventional cohort study of patients treated with insulin glargine or biphasic human insulin in daily clinical practice. Diabetol Metab Syndr. 2013;5:4. CrossRef
Banerjee S, Maji D, Baruah M. Addition of insulin aspart with basal insulin is associated with improved glycemic control in Indian patients with uncontrolled type 2 diabetes mellitus: the A1chieve observational study. J Assoc Physicians India. 2013;61 Suppl 1:24–7. PubMed
Chen L, Xing X, Lei M, Liu J, Shi Y, Li P, et al. Biphasic insulin aspart 30 improved glycemic control in Chinese patients with type 2 diabetes poorly controlled on oral glucose-lowering drugs: a subgroup analysis of the A 1chieve study. Chin Med J (Engl). 2014;127:208–12.
Hassan MI, Aamir AH, Miyan Z, Siddiqui LA, Mahmood S, Vohra EA. Switch from biphasic human insulin 30 to biphasic insulin aspart 30 in Pakistani subjects. J Pak Med Assoc. 2013;63:1290–4. PubMed
Home PD, Latif ZA, González-Gálvez G, Prusty V, Hussein Z. The effectiveness and safety of beginning insulin aspart together with basal insulin in people with type 2 diabetes in non-Western nations: results from the A 1chieve observational study. Diabetes Res Clin Pract. 2013;101:326–32. PubMedCrossRef
Kumar A, Sharma SK, Rajput R, Unnikrishnan AG. Initiating therapy or switching to biphasic insulin aspart improves glycaemic control in type 2 diabetes: an Indian experience from the A1chieve study. J Assoc Physicians India. 2013;61 Suppl 1:16–20. PubMed
Latif ZA, Pathan MF, Siddiqui MN, Sobhan MJ, Rahman MM, Ashrafuzzaman SM. Safety and effectiveness of biphasic insulin aspart 30 in a Bangladeshi subgroup of type 2 diabetic patients switched from biphasic human insulin 30: a sub-analysis of the A 1chieve study. Diabetes Res Clin Pract. 2013;100 Suppl 1:S30–4. PubMedCrossRef
Lim-Abrahan MA, Yu-Gan S, Jain AB, Sobrepena LM, Racho VA. Safety and effectiveness of biphasic insulin aspart 30 in type 2 diabetes patients switched from biphasic human insulin 30: results from the Filipino cohort of the A 1chieve study. Diabetes Res Clin Pract. 2013;100 Suppl 1:S35–40. PubMedCrossRef
Malek R, Arbouche Z, Bachaoui M, Zinai S, Dahaoui A, Senoussaoui S, et al. Criteria influencing the choice of starting insulin regimen in patients with type 2 diabetes in routine clinical practice: baseline data from the Algerian cohort of the A 1chieve study. Diabetes Res Clin Pract. 2013;101 Suppl 1:S45–9. PubMedCrossRef
Rao PV, Bhattacharyya A, Sahay RK. Initiation of insulin aspart to Indian subjects on OADs show significant improvement in glycaemic outcomes: the A1chieve observational study. J Assoc Physicians India. 2013;61 Suppl 1:21–3. PubMed
Soewondo P, Lindarto D, Wibisono S, Renaldi O, Dalem-Pemayun TG. Clinical safety and effectiveness of biphasic insulin aspart 30 in type 2 diabetes patients switched from biphasic human insulin 30: results from the Indonesian cohort of the A 1chieve study. Diabetes Res Clin Pract. 2013;100 Suppl 1:S41–6. PubMedCrossRef
Gönen MS, Yürümez A, Hersek Ö, Altunoğlu E, Rakıcı H, Scism-Bacon J, et al. The risk of severe hypoglycaemia in patients with type 2 diabetes mellitus starting insulin therapy with premixed insulin analogues taken twice daily: an observational study in Turkish patients. Turk Jem. 2013;17:83–8.
Walz L, Pettersson B, Rosenqvist U, Deleskog A, Journath G, Wändell P. Impact of symptomatic hypoglycemia on medication adherence, patient satisfaction with treatment, and glycemic control in patients with type 2 diabetes. Patient Prefer Adherence. 2014;30(8):593–601. CrossRef
Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Thomas S. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;2:CD004654. PubMed
Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2008;2:CD006739. PubMed
Clements MR, Tits J, Kinsley BT, Råstam J, Friberg HH, Ligthelm RJ. Improved glycaemic control of thrice-daily biphasic insulin aspart compared with twice-daily biphasic human insulin; a randomized, open-label trial in patients with type 1 or type 2 diabetes. Diabetes Obes Metab. 2008;10:229–37. PubMedCrossRef
Lemoine P. Biphasic Insulin Aspart 30 Treatment Option in Children and Adolescents. US Endocrinology,2006;2:DOI: 10.17925/USE.2006.00.02.1e
- Drug-related risk of severe hypoglycaemia in observational studies: a systematic review and meta-analysis
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II