Introduction
Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia due to changes in insulin secretion or altered action of insulin, or both. Type 1 DM (T1DM) results from the destruction of pancreatic beta cells mediated by cellular autoimmune responses [
1].
The treatment of patients with T1DM consists of repositioning of insulin that is not produced endogenously. This involves administering either rapid-acting insulin, more intermediate or long-acting insulin. Recombinant DNA (rDNA) insulin and neutral protamine Hagedorn (NPH), which has an intermediate-acting time, are typically first-line choices among the insulins used for basal glycemic control [
2,
3]. Glargine, a long-acting insulin analog, is used as an alternative to rDNA insulin. It is a molecule structurally similar to human insulin and is developed by modification of the amino acid sequence, with the aim of prolonging the duration of the effect and decreasing intra-individual variability [
4].
Metabolic control through active management of patients with T1DM is based on three fundamental principles: adequate food, weight, and glycemic control. These provide benefits to patients and decrease the risk of complications [
5,
6]. The glycated hemoglobin (HbA1c) level is the average glycemic level of an individual over a period of 2–3 months prior to the test day. Consequently, it can be used to evaluate glycemic control and the effectiveness of current treatments. Glycemia tests indicate blood glucose levels during testing. Both these methods are important, since the information they provide is complementary and helps to obtain a more global evaluation of glycemic control. When used together, they provide safer and more accurate results, thereby minimizing possible interferences due to the different technical methodologies used [
7].
T1DM may cause acute and chronic complications, with hypoglycemia one of the most important acute complications that can occur. Microvascular (causing retinopathy, nephropathy, and neuropathy) and macrovascular (causing peripheral arterial disease, carotid disease, and coronary artery diseases) are the most prevalent chronic complications [
1].
The studies and systematic reviews performed to date to compare rDNA insulin with long-acting analogs, including the authors’ own systematic review of randomized controlled trials (RCTs), did not show any significant differences in the clinical benefits obtained between the different formulations of insulin although there can be considerable differences in costs [
3,
8‐
10]. Published studies though, including observational studies, have reported better effectiveness of insulin analogs compared with human insulin [
11‐
13]. However, the published studies that have evaluated the performance of different insulins in non-controlled situations do appear inconclusive when combined. It is important to address this confusion given, as mentioned, the considerable differences in costs that can occur between the different formulations, for example, in Brazil, the cost of treating a patient with insulin glargine is 536% that of treatment with NPH insulin [
3].
Consequently, the aim of this study was to evaluate the clinical effectiveness of insulin glargine through a systematic review of observational studies, which was not addressed in the authors’ original systematic review [
3], and as a result, help to determine the performance of long-acting insulins versus NPH and other insulins in the real-world in non-controlled situations to provide future guidance. It is not about assessing the effectiveness of different interventions to encourage the prescribing of particular insulin formulations.
Methods
This review was conducted in accordance with the recommendations of the Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE) guidelines [
14]. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.
Study Search
Electronic searches of relevant articles published until June 2015 in MEDLINE (PubMed), Latin American and Caribbean Health Sciences (LILACS), and Cochrane Library were performed. Various combinations of terms were used, including terms related to the disease and type of intervention study (Table
1).
Table 1
Search strategies
LILACS | ((mh:”Diabetes Mellitus Tipo 1” AND “CetoacidoseDiabética”) OR (tw:dmid OR dmt1 OR (diabet$ tip$I) OR (diabet$ tip$1) OR (diabet$ tip$ I) OR (diabet$ tip$ 1) OR (Diabetes Auto-Imune) OR (C18.452.394.750.124) OR (C19.246.267) OR (C20.111.327) OR (Diabetes Mellitus Instável) OR (Diabetes Mellitus Insulino-Dependente) OR (Diabetes Mellitus Dependente de Insulina) OR (Diabetes Mellitus de InícionaJuventude) OR (Diabetes Mellitus com Tendência à Cetose) OR (Diabetes Mellitus de InícioSúbito))) AND NOT (mh:”Diabetes Insípido” OR tw:(diabet$ insipid$)) AND ((“Insulina” OR “Insulina NPH” OR D06.472.699.587.200.500.625 OR D12.644.548.586.200.500.625 OR D06.472.699.587.200.300.200) OR (tw: glargin$ OR insulin$ OR isofan$ OR nph OR isophane) OR (ti: glargin$ OR insulin$ OR isofan$ OR nph OR isophane) OR (ab: glargin$ OR insulin$ OR isofan$ OR nph OR isophane)) AND ((mh:Cohort Studies) OR tw: Seguimento$ OR tw:coort$ OR (tw:Análise de Coortes) OR tw:incidenc$ OR (tw:Observational study OR EstudioObservacional OR Estudoobservacional OR V03.200.650)) AND NOT ((tw: cat$ OR dog$ OR anima$ OR mice OR rat OR rabbits) OR ab:Prevalence OR ti:Guideline$ OR (ab:Cross-Sectional Study) OR (tw:case report)) | 381 |
Medline (via PubMed) | (((((((((((((((((((Diabetic Ketoacidosis[MeSH Terms]) OR Diabetes Mellitus, Type 1[MeSH Terms]) OR Diabetes Mellitus, Insulin*Dependent[Text Word]) OR Insulin-Dependent Diabetes Mellitus[Text Word]) OR Juvenile-Onset Diabetes Mellitus[Text Word]) OR Type 1 Diabetes Mellitus[Text Word]) OR Sudden-Onset Diabetes Mellitus[Text Word]) OR Diabetes Mellitus, Type I[Text Word]) OR IDDM[Text Word]) OR Insulin*Dependent Diabetes Mellitus 1[Text Word]) OR Juvenile*Onset Diabetes[Text Word]) OR Brittle Diabetes Mellitus[Text Word]) OR Ketosis-Prone Diabetes Mellitus[Text Word]) OR Diabetes, Autoimmune[All Fields] OR Autoimmune Diabetes[Text Word]) NOT diabetes insipidus[MeSH Terms])))) AND ((((((Insulin, Isophane[MeSH Terms]) OR Isophane Insulin[Text Word]) OR NPH Insulin[Text Word]) OR NPH[Text Word]) OR Protamine Hagedorn Insulin[Text Word]) OR Neutral Protamine Hagedorn Insulin[Text Word]))) AND (((((((glargine[Supplementary Concept]) OR glargine[Text Word]) OR lantus[Text Word]) OR insulin glargine[Text Word]) OR HOE*901[Text Word])) OR “Insulin, Long-Acting”[Mesh]))) AND (((“Cohort Studies”[Mesh]) OR (((cohort$[Text Word]) OR controlled clinical trial[Publication Type]) OR epidemiologic methods)))) | 231 |
Cochrane | #1MeSH descriptor: [Diabetic Ketoacidosis] explode all trees #2MeSH descriptor: [Diabetes Mellitus, Type 1] explode all trees#3 Diabetes Mellitus, Insulin$Dependent (Word variations have been searched) #4Insulin-Dependent Diabetes Mellitus (Word variations have been searched)#5 Juvenile-Onset Diabetes Mellitus (Word variations have been searched)#6 Type 1 Diabetes Mellitus (Word variations have been searched)#7 Sudden-Onset Diabetes Mellitus (Word variations have been searched)#8 Diabetes Mellitus, Type I (Word variations have been searched)#9 Insulin$Dependent Diabetes Mellitus 1 (Word variations have been searched)#10 Brittle Diabetes Mellitus (Word variations have been searched)#11 Ketosis-Prone Diabetes Mellitus (Word variations have been searched)#12 Diabetes, Autoimmune (Word variations have been searched) #13Autoimmune Diabetes (Word variations have been searched)#14 insulin$* depend$ (Word variations have been searched)#15Type 1 diabetes (Word variations have been searched)#16 {or #1-#15} #17 MeSH descriptor: [Insulin, Long-Acting] explode all trees#18glargine (Word variations have been searched)#19 lantus (Word variations have been searched)#20 insulin glargine (Word variations have been searched)#21HOE$901 (Word variations have been searched) #22{or #17-#21} #23 MeSH descriptor: [Insulin, Isophane] explode all trees#24 Isophane Insulin (Word variations have been searched)#25 NPH (Word variations have been searched)#26 Protamine Hagedorn Insulin (Word variations have been searched)#27 Neutral rotamineHagedorn Insulin (Word variations have been searched)#28 {or #23-#27} #34 #28 or #33 #35 #22 and #34 #36#16 and #35 #37 MeSH descriptor: [Cohort Studies] explode all trees #38cohort$ (Word variations have been searched)#39 epidemiologic methods #40controlled clinical trial:pt (Word variations have been searched)#41 {or #37-#40} #42#36 and #41 | 184 |
Hand searching was conducted in the references of all included studies and the electronic journal Diabetes Care from 2003 until March 2015. Diabetes Care was chosen as this is a reputable publication for studies involving patients with diabetes. The search for studies in the grey literature was also made among the theses and dissertations database of the Coordination for the Improvement of Higher Education Personnel (CAPES), the Digital Library of Theses and Dissertations of the Universidade Federal de Minas Gerais (UFMG), and ProQuest Dissertations and database thesis to ensure that the authors did not miss out important observational studies. These included lectures, publications and academic theses, government, congress, books, and reports.
Eligibility Criteria
Prospective and retrospective cohort studies and database records of patients with T1DM were selected. Studies that evaluated the insulin glargine preparations in comparison with rDNA insulin to assess the effectiveness and safety outcomes were included.
Studies that assessed the dosage, intervention methods, pregnant patients, clinical protocols, reviews, case reports, animal studies, in vitro studies, pharmacodynamics and/or pharmacokinetics studies, studies that included patients with T2DM, studies that evaluated concomitant oral therapies with insulin therapy for patients with T1DM, studies that evaluated less than or equal to 30 participants as deemed as too small for meaningful comparisons, or studies that had a follow-up time of less than 4 weeks were excluded.
Data Collection and Assessment of Methodological Quality
The studies found in the electronic databases were brought together in a single database for deleting duplicates. The selection was carried out in three stages by two independent reviewers and included the analysis of titles, abstracts, and full texts. Disagreements were resolved by a third reviewer. Data including methodological quality, information of participants, duration of treatment, efficacy, and safety data were extracted and collected in duplicate in an Excel form developed for this purpose and previously tested.
For the assessment of methodological quality, the authors used the Newcastle-Ottawa scale for observational studies [
15]. On this scale, each study was measured in three dimensions: selection of study groups, comparability of groups, and determination of the results of interest. The total score is nine, with studies considered of high methodological quality if above six. In addition, funding sources were identified to verify potential sources of bias. The possibility of publication bias was assessed by analysis of the funnel plot [
16]. It was felt there was conflict of interest in the study when somewhere in the text there was commentary on conflict of interest, it referred to sources of industry funding, or when there was some link of the study authors with the pharmaceutical industry.
Summary of the Findings and Statistical Analysis
Assessed outcomes included the concentration of HbA1c, or capillary blood glucose plasma fasting and episodes of severe hypoglycemia. Secondary outcomes included the impact on body mass index (BMI), weight gain, and the occurrence of adverse reactions.
Data from the studies were combined using random effects model the Review Manager (RevMan) software version 5.3. The authors chose RevMan as this is a typical software program used for preparing and maintaining Cochrane Reviews. It was developed through a continuous process of consultation with its users and Cochrane methodologists, to support standards and guidelines for Cochrane Reviews, and provide analytic methods, access to ‘online’ help, and validation mechanisms. RevMan is free to use for authors preparing a Cochrane Review or for purely academic use. The results are presented as mean difference (MD) for continuous variables with a 95% confidence interval (CI). Analysis with an I
2 > 40% and a P value of Chi square test <0.10 were considered significant heterogeneity. Sensitivity analyses were conducted to investigate the causes of any heterogeneity, excluding a study each time and recorded the changes in I
2 and P values.
Discussion
The introduction of analogs as therapeutic options to treat T1DM presented hope to millions of patients to obtain greater glycemic control and prevent both microvascular and macrovascular complications associated with hyperglycemia as well as potential injury caused by hypoglycemic episodes. In this systematic review with meta-analysis, the authors aimed to assess evidence of the improved effectiveness and safety of analog glargine compared to rDNA insulin for the treatment of patients with T1DM obtained through observational studies, that is, the real word [
26], thus building on their previous systematic review of RCTs [
3]. It is important to emphasize that, despite the fact that they provide robust evidence regarding the efficacy of interventions, RCTs can have low external validity, that is, extrapolation of the results to the community at large including patients with greater co-morbidities can be limited [
27,
28].
The HbA1c evaluation was performed on 1422 participants, comparing insulin glargine with rDNA insulin, and the result of the meta-analysis favored insulin glargine; however, this was without HbA1c control. Furthermore, for the pediatric subgroup of patients, the results of the difference in means did not show any significance. It should be emphasized that the discrete value of this result, which involved not achieving ideal control of HbA1c by the patients, established by the Brazilian Diabetes Society guidelines, was lower than 7.5% [
29].
In the study by Warren et al. [
30], a systematic review of the efficacy of analog glargine showed it to be more effective than rDNA insulin in decreasing fasting blood glucose, but not for reducing the HbA1c level. Another outcome assessed in the study involving 10,967 participants was the reduction of severe hypoglycemic episodes, with the findings favoring rDNA insulin [
30]. The study by Siebenhofer et al. [
31] showed similar results.
The follow-up period in the reported studies were divided into short duration (up to 3 months), intermediate (more than 3 months and up to 6 months), and long (more than 6 months) duration. Short-duration studies were not included since this parameter reflects the average glycemic control obtained in the period from three to 4 months, based on the red blood cell life cycle [
32]. Very short studies of one-month duration, for example, detected only 50% of the estimated variation in the glycemic control [
33], a fact that could introduce bias in the results. The intermediate duration studies [
19,
20] did not demonstrate significant statistical differences. Most studies included in this systematic review were of long duration [
12,
13,
17,
18,
21‐
24] and showed significant results favoring insulin glargine.
In this systematic review, it was observed that insulin glargine showed better effectiveness results compared with rDNA insulin. Vardi et al. [
34] showed similar results in their systematic review, but the analysis suggested only a modest clinical benefit using long-acting analogs instead of intermediate acting insulin preparations for patients with T1DM. Its effect was more prominent for the control of night hypoglycemia [
34].
Only one study reported the reason why insulin glargine treatment was discontinued [
22], which was observed in 9% of the patients who discontinued treatment before completing 1 year of follow-up. The reasons for interrupting therapy were night hypoglycemia (
n = 2), failure to reach good glycemic control (
n = 3), patients considered the multiple injection therapy too laborious (
n = 2), and pain associated with the application (
n = 1). After interruption, two of the patients continued their treatment with an insulin pump and five with rDNA insulin.
The authors believe it is worth highlighting the conflict of interest associated with research, especially in regards to its ethical and bioethical aspects. According to Thompson [
35], conflict of interest is a group of conditions in which professional judgment could be improperly influenced by interests such as financial gain. Conflicts of interest include, for instance, omission of sponsorship or financial involvement when publishing a scientific paper or presenting results at congresses, avoiding disclosing negative results or delaying this disclosure with the aim of protecting a potential market [
36]. Publications confirm that financial relations between the industry, scientific researchers, and academic institutions can be persuasive affecting studies and utilization patterns [
37,
38] and may influence important aspects of biomedical research [
39]. In this systematic review when assessing the results of HbA1c, the subgroup of studies in which there was no conflict of interest did not demonstrate significant statistical difference between the findings from either insulin glargine or rDNA insulin. On the other hand, in the subgroup that reported conflicts of interest, the findings were favorable for insulin glargine (Fig.
6).
The studies selected in this systematic review and meta-analysis may have been influenced by publication bias, which is the tendency of the results published being systematically different from reality. For example, examination of clinical trials with a registered protocol in the registry database ClinicalTrials.gov revealed that <70% of the studies are eventually published [
40], which may be due to a variety of reasons [
41]. For instance, in a review of published studies comparing different atypical antipsychotics, in 90% of the studies supported by pharmaceutical companies the reported overall outcome was in favor of the sponsor’s drug [
42]. However, in this systematic review, the analysis of the funnel chart did not show asymmetry, suggesting the absence of publication bias. Having said this, there were differences in results between the reviewed studies with and without conflicts of interest (Fig.
6). In addition, the majority of studies that showed little precision were generally performed with small samples and distributed symmetrically in the largest part of the funnel. Only the study by Johansen et al. [
13] showed greater precision and was situated in the narrowest part of the funnel.
This systematic review included only cohort and patient record studies, which is one of the limitations of systematic reviews of observational studies, that is, referring to selection bias inherent to this type of study design and to non-controlled confounding factors. Some studies did not present complete and accurate information to be included in the quantitative analysis, thereby affecting the explanation of the high heterogeneity found in some comparisons. Differences in the number of participants between the groups were also observed as well as during the follow-up period. Despite this fact, observational studies have the advantage of potentially large patient groups and represent real-world conditions since they are performed in non-controlled conditions without the strict confines of RCTs [
27].
Another limitation in the interpretation of the results was the statistical heterogeneity among the studies found in the meta-analysis. The small number of studies included in the comparisons, in addition to the lack of complete and accurate information in these studies, hindered the explanation of the sources of heterogeneity. In the sensitivity analysis, the inclusion and exclusion of studies in each comparison did not change the direction of a majority of the outcomes, with alterations in heterogeneity. It should be highlighted that the studies that significantly changed heterogeneity [
17‐
20,
24,
36] were all sponsored by the pharmaceutical industry, with the exception of Yamamoto-Honda et al. [
18].
The absence of other published systematic reviews on the effectiveness and safety of the different insulins in ‘real-world’ conditions hinders any comparison with the results from this review. Typically, systematic reviews evaluate efficacy studies, that is, patients enrolled into RCTs, as seen by ours and other published reviews [
3,
8,
31,
34,
43], rather than including real-world studies. Overall, any recommendation of the insulin analogs as first-line therapy should still be considered with caution, considering the small difference between the outcomes in the meta-analyses that have been performed including this study, potential conflict of interests, and the appreciable differences in treatment costs in comparison with therapeutic alternatives that are available.