Abstract
Background:
Seasonality in insulin sensitivity has been the focus of controversial literature in the past decades. The aim of this study was to analyze seasonality of insulin use in patients with diabetes who were followed in German general practices.
Methods:
This study included patients affected by type 1 (T1DM) or type 2 diabetes mellitus (T2DM) who received intensified conventional insulin therapy over a period of at least 12 months between 2013 and 2015. The main outcome was the median insulin dose per day (calculated daily insulin doses, CDDs) between June and August (summer) and between December and February (winter).
Results:
The present study included 1197 T1DM patients and 3836 T2DM patients from 492 general practitioner or diabetologist practices. The mean age was 45.4 years (SD = 16.2 years) in the T1DM group and 65.2 years (SD = 14.1 years) in the T2DM group. The most frequent basal insulin therapy was insulin glargine (T1DM: 45.7%; T2DM: 41.1%), and the most frequent bolus insulin therapy was insulin lispro in the T1DM group (38.7%) and human insulin in the T2DM group (45.2%). The consumption of basal and bolus insulins did not significantly differ between summer and winter in T1DM individuals (basal therapy: 30.8 international units (IU)/day versus 31.2 IU/day; bolus therapy: 39.4 IU/day versus 37.8 IU/day). This consumption was also similar between the two seasons in the T2DM group (basal therapy: 31.0 IU/day versus 30.6 IU/day; bolus therapy: 44.3 IU/day versus 44.1 IU/day).
Conclusions:
There was no significant difference in the use of basal and bolus insulin therapies between summer and winter in German patients with T1DM or T2DM.
Diabetes is a chronic disorder found in more than 8.5% of adults in the world, 90% of which are affected by type 2 diabetes mellitus (T2DM). 1 Each year, diabetes is involved in hundreds of thousands of deaths. In Germany, almost 8% of the population suffers from this chronic condition, which therefore has a major impact on the health and the economy of this country. 2 Recently, it has been found that more than one T2DM patient out of three receive insulin in this country. 3
Seasonality in insulin sensitivity has been the focus of controversial literature in the past decades. In 2000, Gravholt and colleagues discovered no seasonal variation of insulin sensitivity and glucose effectiveness in healthy young men over a period of 15 months. 4 By contrast, Bunout et al estimated in 2003 that insulin resistance and triacylglycerol levels in healthy elderly patients were higher in summer than in winter. 5 More recently, a Swedish analysis found a contradictory result, as insulin sensitivity was lower in winter than in summer. 6 Furthermore, the same study showed no significant association between fasting plasma glucose and seasonality. Interestingly, in line with the findings of Berglund and colleagues, 6 it has been suggested that 25-hydroxyvitamin D may decrease insulin resistance and may protect against the risk of developing T2DM. 7 However, even though these results are of great interest, little is known about the impact of seasons on the insulin needs of patients affected by diabetes.
Therefore, the goal of the present study was to analyze the seasonality of insulin use in patients with diabetes who were followed in German general practices.
Methods
Database
The Disease Analyzer database (QuintilesIMS) compiles drug prescriptions, diagnoses, and basic medical and demographic data obtained directly and in anonymous format from computer systems used in the practices of general practitioners. 8 Diagnoses (ICD-10), prescriptions (Anatomical Therapeutic Chemical [ATC] Classification System), and the quality of reported data are monitored by QuintilesIMS based on a number of criteria (eg, completeness of documentation, linkage between diagnoses and prescriptions).
In Germany, the sampling methods used for the selection of physicians’ practices were appropriate for obtaining a representative database of primary care practices. 8 Prescription statistics for several drugs were very similar to data available from pharmaceutical prescription reports. 8 The age groups for given diagnoses in the Disease Analyzer also agreed well with those in corresponding disease registries. 8
Finally, this database has already been used in several studies focusing on diabetes.3,9-11
Study Population
This study included patients affected by type 1 (T1DM) or type 2 diabetes mellitus who received intensified conventional insulin therapy (ICT) over a period of at least 12 months between January 2013 and December 2015 and had at least two prescriptions of basal insulin (ATC: A10C2, A10C5) and at least two prescriptions of short acting insulin (ATC: A10C1) within 12 months.
Study Outcome and Covariables
The main outcome of the study was the median insulin dose per day (calculated daily insulin doses or CDDs) between June and August (summer) and between December and February (winter). CDDs were estimated by dividing the number of insulin units in the prescribed package by the number of days between two subsequent prescriptions.
Demographic data included age, sex, health insurance (private/statutory), and type of diabetes care (diabetologist/general practitioner practices). Data on HbA1c levels and body mass index, which were documented in the practices, were also analyzed. Three macrovascular complications were determined based on primary care diagnoses (ICD-10 codes): coronary heart disease (I20, I24, I25), myocardial infarction (I21, I22, I23, I25.2), and peripheral vascular disease (E10.5, E11.5, E14.5, I73.9). Microvascular complications included retinopathy (E10.3, E11.3, E14.3), neuropathy (E10.4, E11.4, E14.4), and nephropathy (E10.2, E11.2, E14.2, N18, N19). Lipid disorders (E78) and hypertension (I10) were also assessed.
Statistical Analyses
Descriptive analyses were obtained for all demographic variables and mean ± SD was calculated for normally distributed variables. Differences between CDDs in summer versus winter were tested using the Wilcoxon test for paired data. P values < .05 were considered statistically significant. The analyses were carried out using SAS version 9.3.
Results
The present study included 1197 T1DM patients and 3836 T2DM patients from 492 general practitioner or diabetologist practices (Table 1, Figure 1). The mean age was 45.4 years (SD = 16.2 years) in the T1DM group and 65.2 years (SD = 14.1 years) in the T2DM group. There were 62.8% and 55.3% male patients in the two groups, respectively. Baseline HbA1c levels were 7.7% and 7.6% in people with T1DM and T2DM, respectively. The most frequent basal insulin therapy was insulin glargine (T1DM: 45.7%; T2DM: 41.1%), and the most frequent bolus insulin therapy was insulin lispro in the T1DM group (38.7%) and human insulin in the T2DM group (45.2%). Finally, hypertension was found in 39.7% of patients with T1DM and in 75.0% of those with T2MD.
Baseline Characteristics of Diabetes Patients Treated With Intensified Conventional Insulin Therapy (ICT) (Disease Analyzer).
Data are means (SD) or proportions (%).
Selection of study patients.
The estimations of the median insulin dose per day are displayed in Table 2. The consumption of basal and bolus insulins was not significantly different between summer and winter in individuals with T1DM (basal therapy: 30.8 IU/day versus 31.2 IU/day; bolus therapy: 39.4 IU/day versus 37.8 IU/day). This consumption was also similar between the two seasons in the T2DM group (basal therapy: 31.0 IU/day versus 30.6 IU/day; bolus therapy: 44.3 IU/day versus 44.1 IU/day).
Estimations of the Daily Consumption of Insulin in Patients With Diabetes Included in the Study.
Discussion
This German study, which included more than 5000 German outpatients with T1DM or T2DM who were followed in general practices, showed that there was no significant difference in the use of basal and bolus insulin therapies between summer and winter.
The association between seasonality and insulin sensitivity has been studied by several authors in the past decades. In 2000, a Danish study discovered no significant seasonal variation in insulin sensitivity and glucose effectiveness in healthy young men who had been followed over a period of 15 months. 4 By contrast, three years later, Bunout and colleagues showed that, in the 108 elderly individuals studied, insulin resistance and triacylglycerol levels were lower in winter than in summer. 5 The authors further found that nutritional supplementation and training led to a decrease in the levels of low-density lipoprotein cholesterol. These results were in line with a previous American study which found that the activity of an insulin-stimulated enzyme, the adipose tissue lipoprotein lipase, was higher in winter than in summer. 12 Despite the interesting design of the study performed by Bunout et al, 5 the findings have not been clearly corroborated and must thus be interpreted with great caution.
Later, Alemzadeh et al found that hypovitaminosis D (serum 25[OH]D concentration < 75 nmol/L) was present in 74% and vitamin D deficiency (serum 25[OH]D concentration < 50 nmol/L) in 32.3% of a sample of 127 obese children and adolescents. 13 Intake, season, ethnicity, and adiposity were found to have a significant impact on vitamin D status. Furthermore, vitamin D was positively correlated with insulin sensitivity (probably due to outdoor activities) and negatively correlated with HbA1c levels, suggesting that obese children and adolescents with hypovitaminosis D or vitamin D deficiency are at a particular risk of developing insulin resistance and, indirectly, T2DM. More recently, in 2011, Berglund and colleagues, in a Swedish study including more than 1100 elderly patients, examined seasonal variations of insulin sensitivity, insulin secretion, and fasting plasma glucose. 6 Insulin sensitivity was found to be 11% lower—and the incremental area under the insulin curve 16% higher—in winter than in summer, even if fasting plasma glucose did not significantly differ between the two seasons. Moreover, it was estimated in the same population-based cohort of older people that outdoor temperature was positively associated with insulin sensitivity, with such relation being independent of the season. Interestingly, these findings are in line with the 2009 study of Gupte and colleagues, 14 who found in rats fed a high-fat diet that heat treatment protects skeletal muscle from insulin resistance via the activation and overexpression of heat shock proteins.
Contrary to the study of Berglund et al, 6 the present retrospective work pertaining to patients in Germany found no significant association between seasonality and the use of insulin in outpatients with T1DM or T2DM. The major difference between these two studies is that the first one aimed to analyze insulin sensitivity and the second one insulin consumption. Therefore, although insulin sensitivity may be higher in summer than in winter, it remains possible that this difference has no impact on the use of insulin over the year. Another important difference that could account for the discrepancy in the findings is that these two studies were performed in two different populations, as Berglund and colleagues included healthy elderly men who had not received insulin treatments, whereas the present analysis included only T1DM and T2DM patients followed in general practices in Germany. 6
The present study has several limitations, which should be mentioned. First, no valid information was provided on diabetes duration. In addition, the assessment of complications and comorbidity relied solely on ICD codes entered by primary care physicians. Data on socioeconomic status (eg, education and income) and lifestyle-related risk factors (eg, smoking, alcohol, and physical activity) were also lacking. Unfortunately, the documentation of hypoglycemia was insufficient and could not be used, although hypoglycemia may exhibit a seasonal pattern and may be an indirect marker of insulin use. Finally, as adherence and compliance are known to be suboptimal in individuals with diabetes, the present estimations of the daily consumption of insulin may be higher than the real insulin consumption. One strength of the study is the large number of patients available for analysis. Another strength is the use of real-world data in primary care practices where diagnoses are continuously documented, allowing for unbiased exposure assessment (no recall bias).
Overall, there was no seasonality in the use of insulin in German outpatients with T1DM or T2DM. Further research is needed to gain a better understanding of the relation between insulin sensitivity, insulin consumption, and seasonality.
Footnotes
Abbreviations
ATC, Anatomical Therapeutic Chemical; CDD, calculated daily insulin dose; ICT, intensified conventional insulin therapy; IU, international unit; SD, standard deviation; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.