Lipids seasonal variability in type 2 diabetes

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Metabolism www.metabolismjournal.com

Brief Reports

Lipids seasonal variability in type 2 diabetes Gianluca Bardini, Ilaria Dicembrini, Carlo Maria Rotella, Stefano Giannini⁎ Section of Endocrinology, Department of Clinical Pathophysiology, University of Florence, I-50134, Florence, Italy

A R T I C LE I N FO Article history: Received 13 February 2012 Accepted 9 May 2012

AB S T R A C T Objective. The objective was to evaluate the seasonal lipid variations in type 2 diabetic (DM2) outpatients. Materials/Methods. 302 (183 women and 119 men) DM2 subjects with or without statins therapy were screened. Body weight, HbA1c, total cholesterol (TC), high density lipoprotein (HDL-C), triglycerides (Trg) and low density lipoprotein cholesterol (LDL-C) were measured

Keywords:

and patients’ data of diet and physical activity were recorded during fall/winter (F/W) and

Type 2 diabetes

spring/summer (S/S) seasons. Results. HbA1c levels showed seasonal variability without statistical significance. During

Lipids

the colder seasons we observed an increase (P<.05) of weight associated with higher calorie

Seasons

intake and reduced physical activity. We showed a peak of TC, LDL-C and Trg levels during F/W while HDL-C levels were reduced. Median TC levels in F/W with respect to S/S were 197 vs 185 mg/dL (P<.001) without statins therapy and 172 vs 161 mg/dL (P<.001) in patients under statins therapy. Median LDL-C levels, without or with statin therapy, were 122 vs 114 mg/dL (P<.001) and 97.5 vs 88.5 mg/dL (P<.001), respectively. This seasonal lipids changes from F/W to S/S, modulated the percent of patients at LDL-C target <100 mg/dL, both without or under statins treatment: from 22% to 29.5% (P<.05) with odds ratio 0.73 (95% CI 0.62–0.87) and from 47% to 55% (P<.001) with odds ratio 0.68 (95% CI 0.58–0.76), respectively. Conclusions. DM2 patients showed a peak of TC and LDL-C during colder months associated with changes of diet and lifestyle habits. This seasonal lipid trend modified the percentage of patients at LDL-C therapeutical target. © 2012 Elsevier Inc. All rights reserved.

1.

Introduction

Plasma Low Density Lipoprotein-Cholesterol (LDL-C) is strongly associated to cardiovascular disease (CVD) risk in type 2 diabetes (DM2) and statins have proved to be the most effective lipid drugs to reduce LDL-C levels [1,2]. Interesting is the presence of a seasonal rhythm of lipid levels and how this variability is synchronous to CVD events during the

colder months [3]. In fact, some studies in dyslipidemic subjects showed a characteristic peak of total cholesterol (TC) and LDL-C in fall/winter and a nadir during spring/ summer [4]. This fact interferes in the attainment of therapeutical lipids target. To our knowledge, no data have been reported on the seasonal lipid trend in diabetes, thus we explored whether a variation in lipid levels exists in DM2 patients.

Abbreviations: LDL-C, Low Density Lipoprotein-Cholesterol; CVD, Cardiovascular Disease; DM2, Type 2 Diabetes; TC, Total Cholesterol; OHA, Oral Hypoglycaemic Agents; F/W, Fall/Winter; S/S, Spring/Summer; BMI, Body Mass Index; HDL-C, High Density Lipoprotein; Trg, Triglycerides; ADA, American Diabetes Association. ⁎ Corresponding author. Tel.: +39 55 7949960; fax: +39 55 4271474. E-mail address: [email protected] (S. Giannini). 0026-0495/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2012.05.009

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83

Patients and methods

**

**

170 150 130

**

mg/dl

Spring/Summer

110

**

90 70

Statins -

Statins +

Total cholesterol

Statins -

Statins +

LDL cholesterol

Fig. 1 – Seasonal variations of total and LDL cholesterol (mg/dL) median levels from Fall/Winter to Spring/Summer; *: P<.001 vs Fall/Winter.

Body weight (kg)

80

*

Fall/Winter

81

79

*

190

With statins

*

We consecutively investigated 302 (183 women and 119 men) DM2 clinical outpatients without CVD, from October 2005 through December 2006. All patients were treated with unmodified oral hypoglycaemic agents (OHA), with or without statins, in two years of observation. The insulin doses were unchanged by >10% throughout the study. Patients affected by liver, thyroid or chronic kidney diseases were excluded. Seasonal visits were grouped in fall/winter (F/W) and spring/ summer (S/S). We recorded body mass index (BMI), HbA1c, fasting glucose and lipid profile: TC, high density lipoprotein (HDL-C), and triglycerides (Trg). HbA1c was measured with high-pressure liquid chromatography (Menarini Diagnostics, Italy; upper limit of normal range 5.6%). Plasma glucose and lipids were automatically measured (Beckman Instruments, Brea, USA). LDL-C was calculated by the Friedewald formula [5]. All patients received by a nutritionist an appropriate diet according to the American Diabetes Association recommendations [6] and instructed to record quality and quantity of foods eaten supported by a reference book that contained nutrition advices and how to determine the calorie and fat gram content of their foods. All subjects were encouraged to participate in at least 150 min of moderate physical activity weekly. These advices were reinforced in each visit and monitored in a self recorded diary. The therapeutical LDL-C target < 100 mg/dL was considered [7]. All patients gave informed consent to the study which was approved by the University of Florence Medical Ethical Committee. The data distribution was checked by Kolmogorov–Smirnov test. Categorical variables were compared by Chi square test. Seasonal differences of continuous lipid values were reported as medians and analyzed by Wilcoxon test. Odds ratio estimates (95% confidence intervals, CIs) by logistic regression (age, sex, BMI adjusted) quantified the seasonal attainment of LDL-C target. Significance was considered for P<.05. All analyses were performed using SPSS 17.0 (SPSS, Chicago, IL).

210

Without statins

82

*

2.

78 77 76 Fall/Winter 1

Spring/Summer 1 Fall/Winter 2

Spring/Summer 2

Fig. 2 – Seasonal variations of body weight (kg) median levels; *: P<.05 vs Fall/Winter.

3.

Results

The cohort showed a mean age of 64.5±9.0 years, BMI of 28.6 ±2.7 kg/m2, HbA1c 7.0%±0.8% with 6.6±5.5 years duration of diabetes. OHA were used by 87.2% patients. In particular, 51.5% assumed metformin (Metf) alone, 32.7% Metf plus other OHA (25% thiazolidinediones (TZDs), 70% secretagogues, 5% acarbose), 3.0% OHA without Metf and 12.8% insulin plus Metf. Statins were used by 51.0% of patients and 1.0% other hypolipidemic drugs (fibrates, ezetimibe, niacin, fish oils, red rice yeast). 8.0% were currently smokers. Statistically significant higher TC, LDL-C and Trg concentrations were observed during F/W while HDL-C levels were reduced. Median TC levels in F/W with respect to S/S were 197 vs 185 mg/dL (P<.001) without statins therapy and 172 vs 161 mg/dL (P<.001) in patients under statins therapy. Median LDL-C levels, without or with statin therapy, showed a statistical seasonal difference (122 vs 114 mg/dL, P<.001; 97.5 vs 88.5 mg/dL, P<.001, respectively; Fig. 1). An opposite trend was observed between the HDL-C and Trg, with lower levels in F/W and higher values in S/S for the former, independent of the use of statins. Median HDL-C concentrations without statins were 43 vs 46 mg/dL and 46 vs 49 mg/dL in statins group (P<.05, for all). Median Trg levels without statins were 135 vs 129 mg/dL and in statins treated 127 vs 119 mg/dL (P<.05, for all). This seasonal lipids variability modulated the percent of patients at goal of LDL-C <100 mg/dL in both subjects without or with statins treatment: from 22% to 29.5% (P<.05) with odds ratio 0.73 (95% CI 0.62–0.87) and from 47% to 55% (P<.001) with odds ratio 0.68 (95% CI 0.58–0.76), respectively. When we looked at the effect of OHA on lipids seasonal variability, Metf alone showed a major LDL-C seasonal reduction from a median of 118.5 mg/dL in F/W to 114 mg/dL in S/S (P<.05). HbA1c levels were not associated to a significant seasonal variability. Data analysis obtained by self recorded diaries, showed a 40% increase of time spent for weekly physical activity during the warmer months and associated a 15% reduction of carbohydrates (bread and pasta) and lipids intake. These data were concordant to the sinusoidal-like trend of body weight, with a statistical significant peak in F/W and a nadir S/S, with or without lipid drugs (Fig. 2).

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In particular, we recorded a median weight of 80.5 vs 78.5 kg and 81.5 vs 80 kg without and with statins, respectively, in the first year of observation, while in the second year patients showed a median weight of 79.5 vs 78 kg without statins and 80.5 vs 79 kg under lipid drugs (P<.05, for all).

4.

Discussion

Accumulating evidences demonstrated a seasonal lipids variability both in hypercholesterolemic [4,8] and in patients with CVD [3,9]. We believe that the DM2 seasonal lipid profile, compared to familiar hypercholesterolemia, is an interesting model depending on the complexity of factors involved (e.g. physical activity, food intake, body weight, variations of light exposure and temperature). [10,11]. To our knowledge, this is the first report that shows a seasonal variation in lipid profile in DM2 outpatients taking or not statins. A hypothesized presence of a seasonal lipids change has been firstly demonstrated by Gordon et al [12], but the etiologies and mechanisms for this seasonal pattern were not clarified. Moreover, they analyzed only hypercholesterolemic male subjects and, in their model, diet and body weight modifications explained less than one-third of the seasonal variation of TC. These data have not been confirmed in a subsequent observation [13]. Ockene et al [4] suggested a possible link among seasons, environmental temperature and hematocrit variation. However, the role of blood volume has been recently questioned [8]. These apparent discordant results could be, in part, explained, because in these papers were studied many patients with familiar hyperlipidemia which, in part, could justify a mild response to diet and environmental factors. Moreover, Asian high prevalence of lean subjects could justify low seasonal oscillations of body weight and then minimal variations on lipid levels. Instead, mild, but significant seasonal variations in diet, physical activity and body weight have been demonstrated in overweight–obesity [10]. It is well known that body weight variations are accompanied by changes in lipid profile [11]. We confirmed this observation in our patients, where the oscillations of body weight were synchronous to different seasonal caloric intake and physical activity data recorded. This fact could explain the seasonal curve of TC and LDL-C levels. All together, these data could suggest the role of adiposity as one of the regulatory factor of cholesterol levels. We previously observed [14] that visceral adiposity and cholesterol levels are tightly associated in overweight subjects. Furthermore, a recent retrospective analysis of 4S trial [15] showed an increased cholesterol synthesis in subjects with enlarged waist circumference. This effect could be modulated by different adiponectin levels in insulin resistant subjects [16]. Recently, Luppattelli et al [17] underlined the role of visceral obesity to modulate HDL-C, Trg, but also TC and LDL-cholesterol. In our cohort, those patients treated with metformin, with well known positive effects on insulin sensitivity, showed a higher seasonal lipids variability with respect to other OHA or insulin regimens. Since most patients treated in combination with metformin received TZDs, secretagogues and glinides, with well demonstrated effects on weight gain and lipids, this pharmacological property

could explain the blunted effect on lipid profile variability recorded in patients treated with OHA combinations. Lowering LDL-C is the primary target in the management of dyslipidemia in patients at high CVD risk and the seasonal lipid variations modify the percent of patients at LDL therapeutical target during the warmer seasons. However, when we considered the statins group, those subjects showed mild seasonal body weight variation, suggesting that, in contrast with our hypothesis, the modification of lipid profile could be independent of body weight. This apparent discrepancy, could be explained by the fact that statins, while retaining their direct effect on lipids, seem to have adverse effects on insulin resistance, as very recently demonstrated [18]. This could counteract the seasonal effect of body weight as observed in non-statins treated group. Although a potential limitation of our study is the lack of additional data on physiological mechanisms of lipids seasonal variability, however, taking together these data confirmed a seasonal lipids variability in DM2 patients. This seasonal trend on TC and LDL-C levels should be accurately considered by the physicians with more frequent lipid control and optimizing statin therapy in the colder seasons to the attainment of the therapeutical LDL-C goals.

Author contributions G. Bardini collected patients’ data and provided statistical analysis, I. Dicembrini collected data, CM. Rotella revised manuscript and participated in the manuscript discussion, S. Giannini proposed the study and supervised the manuscript.

Funding This study was supported in part by an unconditioned grant from Pfizer Italy and Abiogen Pharma, Pisa, Italy.

Conflict of interests None.

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