Current Medical Research & Opinion Vol. 26, No. 7, 2010, 1621–1628 0300-7995 Article 5166/485087 doi:10.1185/03007995.2010.485087 All rights reserved: reproduction in whole or part not permitted Original article Starting insulin therapy with basal insulin analog or premix insulin analog in T2DM: a pooled analysis of treat-to-target trials Vivian Fonseca Abstract Tulane University Health Sciences Center, New Orleans, LA, USA Objective: Although the choice of starting insulin for people with type 2 diabetes mellitus (T2DM) is often a basal or Jaime Davidson premix insulin analog, there is little evidence to base this decision on. This analysis aimed to determine if UT Southwestern Medical School & Medical Center, measurable clinical characteristics prior to starting insulin could predict differences in improved glycemic Dallas, TX, USA control between these options. Philip Home Newcastle University, Newcastle upon Tyne, UK Research design and methods: James Snyder A thorough literature search was performed for treat-to-target studies in insulin-naı¨veindividuals with T2DM Las Vegas, NV, USA treated with biphasic insulin aspart (BIAsp 30), a basal insulin analog (insulin glargine or insulin detemir) or NPH insulin regimens once or twice daily plus oral glucose-lowering drugs (OGLDs). Patient data were Paul Jellinger thorised users can download, pooled and mean baseline age, diabetesle duration, copy gender, for personal body mass index use (BMI), HbA1c, fasting plasma Center For Diabetes & Endocrine Care, Hollywood, glucose (FPG), average postprandial plasma glucose over three meals (PPG) and bedtime PG were For personal use only. CA, USA investigated for prediction of improved HbA1c, FPG or PPG. Statistical analyses employed a linear mixed Anders Dyhr Toft model with insulin type, OGLD, time and time-squared as fixed effects and patient and trial as random Novo Nordisk A/S, Virum, Denmark effects. Anthony Barnett Results: University of Birmingham and Heart of England NHS Foundation Trust, Birmingham, UK Baseline age (p ¼ 0.022) and bedtime PG (p ¼ 0.036) were inter-related predictors of HbA1c. In older individuals with higher bedtime PG, BIAsp 30 appeared to be more beneficial. In contrast, basal insulin Copyright ©appeared 2010 to be a Informa better choice in younger UK individuals Limited with lower bedtime PG. For FPG, BMI (p ¼ 0.011) and Address for correspondence: post-breakfast PG (p ¼ 0.042) were identified as predictors. Basal insulin appeared to achieve better FPG in Prof. Vivian Fonseca, Tulane University Health patients with lower BMI and higher post-breakfast PG, while BIAsp 30 appeared to be better in patients with Sciences Center, 1430 Tulane Avenue, New Orleans, Not for Salehigher or BMI and Commercial lower post-breakfast PG. Age Distribution (p ¼ 0.0347) was the only baseline characteristic associated LA 70112, USA. display, view and print a sing Curr Med Res Opin Downloaded from informahealthcare.com by University of Washington on 12/22/14 Tel.: þ 1 504 988 4023; Fax: þ1 504Unauthorized 988 6271; with use differences prohibited. in average PPG: Au mean PPG was similar between regimens in younger people, but BIAsp 30 [email protected] achieved better PPG results in older persons. Minor hypoglycemia was reported by 56% of BIAsp 30- and 45% of basal-treated individuals. The major limitation of the study was that only Novo Nordisk trials were included in the analysis as access to individual patient data was required. As the trials were fairly Key words: heterogeneous a strict methodology was used to minimize potential confounding factors. Blood glucose – Insulin aspart – Insulin detemir – Insulin glargine – Pooled analysis – Type 2 diabetes Conclusions: Accepted: 9 April 2010; published online: 29 April 2010 Premix analog rather than basal insulin may be an appropriate choice to target HbA1c values in older Citation: Curr Med Res Opin 2010; 26:1621–28 individuals and those with higher bedtime PG, while basal insulin may be more appropriate to target FPG in patients with lower BMI and higher post-breakfast PG. Introduction For individuals with T2DM who are unable to control their blood glucose with maximal dosing of oral glucose-lowering drugs (OGLDs), the choice for starting ! 2010 Informa UK Ltd www.cmrojournal.com Pooled analysis of basal versus premix insulin analog Fonseca et al. 1621 Current Medical Research & Opinion Volume 26, Number 7 July 2010 insulin is commonly between a basal or premix insulin most benefit from one or the other of the insulin types regimen1,2, although a mealtime þ basal approach can using characteristics derived from an evidence-based anal- also be used3. Given that this is an important choice for ysis of the published studies. Therefore, the current pooled patients and their physicians to make, there is a relative analysis was performed to identify whether differences in lack of evidence-based information available about which patients’ baseline criteria, including HbA1c, fasting plasma regimen is more effective when starting insulin in terms of glucose (FPG), post-prandial glucose (PPG), age, gender baseline clinical characteristics. Accordingly, lifestyle fac- or duration of diabetes, could be used to predict differences tors, convenience and physician preferences often play a in the clinical efficacy of the basal or premix insulin analog large part in determining the chosen regimen. For exam- regimens. ple, physicians may prefer premix insulin for elderly patients, those with vision problems or those with arthritis because they offer the ability to address both basal and prandial glucose control with fewer daily injections Patients and methods versus a multiple injection approach. A thorough literature search of PubMed was carried out A number of studies have compared basal and premix using the search terms ‘insulin apart’, ‘insulin lispro’, ‘insu- insulin analog regimens in combination with one or more lin detemir’, ‘insulin glargine’ and ‘insulin naı¨ve’. OGLDs using a treat-to-target approach3–11. Overall, Abstracts were reviewed to identify treat-to-target studies these studies demonstrated that while both basal-only comparing insulin initiation with premix or basal insulin. and premix insulin regimens significantly improve The study then included all Novo Nordisk clinical trials in HbA1c levels, premix insulin may offer benefits in terms insulin-naı¨ve patients with T2DM who started treatment of the magnitude of HbA1c reduction. However, the more with once- or twice-daily BIAsp 30 according to a treat- intensive premix insulin regimens also tended to be asso- to-target protocol (biphasic insulin aspart, NovoMix 30, ciated with increased rates of minor hypoglycemic episodes Novo Nordisk A/S, Bagsværd, Denmark or NovoLog Mix and greater weight gain compared with basal regimens. 70/30 in the US, Novo Nordisk Inc., Princeton, New Furthermore, the OGLDs used together with the insulin Jersey, USA). In addition, trials of the basal insulin analogs may also have affected the rates of hypoglycemia and (insulin glargine [Lantus, Sanofi Aventis, Bridgewater, weight effects observed in the studies, particularly in New Jersey, USA] or insulin detemir [Levemir, Novo those studies in which insulins were combined with Nordisk A/S, Bagsværd, Denmark]) or NPH insulin once For personal use only. sulfonylureas. or twice daily using a treat-to-target protocol were Given the differences between these two treatment included (Table 1)4–9. In all trials, insulin treatment was options in terms of the balance between clinical efficacy combined with one or more OGLDs. The literature search and the potential for unwelcome side effects, it would be also identified a number of non-Novo Nordisk studies in helpful to be able to identify those patients who would insulin-naı¨ve patients that examined the initiation of basal Table 1. Key characteristics of the included trials. Study Insulin treatment OGLD treatment Randomized Trial duration patients (n) (weeks) Rosenstock et al., 2008 Detemir once or twice daily vs. Metformin, insulin secretagogue and 582 52 5 Curr Med Res Opin Downloaded from informahealthcare.com by University of Washington on 12/22/14 80 sites (Europe and the USA) once-daily glargine (partici- alpha-glucosidase inhibitors in pants on once-daily detemir mono- or combination therapy may switch to twice daily) Hermansen et al., 2006 Twice-daily detemir vs. twice- Metformin, insulin secretagogue or 476 24 58 sites in 10 European countries6 daily NPH alpha-glucosidase inhibitors in mono- or combination therapy Philis-Tsimikas et al., 2006 Two arms once-daily detemir Continue current OGLD therapy. 504 20 91 sites (Europe and the USA)8 (morning and evening) vs. Alpha-glucosidase inhibitor mono- once-daily NPH therapy not allowed. TZDs may be taken if approved Raskin et al., 2005 Twice-daily BIAsp 30 vs. once- Metformin with and without TZDs 233 30 25 sites in the USA9 daily glargine Garber et al., 2006 Intensifying treatment starting on Continue prior OGLD regimen 100 16 (only first phase 7 13 sites in the USA once-daily BIAsp 30, if HbA1c is (enrolled) included) above 6.5 a second injection was added Raskin et al., 2009 Twice-daily BIAsp 30 and OGLDs Metformin and pioglitazone 200 24 73 centers in the USA4 vs. OGLDs only NPH ¼ neutral protamine Hagedorn; OGLD ¼ oral glucose-lowering drug; TZD ¼ thiazolidinedione. 1622 Pooled analysis of basal versus premix insulin analog Fonseca et al. www.cmrojournal.com ! 2010 Informa UK Ltd Current Medical Research & Opinion Volume 26, Number 7 July 2010 insulin analogs or premix insulin using a treat-to-target Statistical modeling approach10–16. Due to the need for patient-level data the published reports did not include enough detail to be A two-round screening procedure was applied to assess included in the analysis. Requests were made for patient- which baseline characteristics had a significant effect on level data from the manufacturers of insulin lispro and glycemic endpoints and to compare any variation in effec- insulin glargine, but these data were not available.