Participants and clinical measurement at the baseline study

The METSIM study was performed in 2005–2010 at the Clinical Research Unit of the University of Kuopio and included 10,197 men, aged 45–73 years, randomly selected from the population register of Kuopio, Eastern Finland (population 95,000) [23]. An OGTT (75 g of glucose, glucose and insulin measurements at 0, 30 and 120 min) was performed, and glucose tolerance was classified according to the American Diabetes Association criteria [24]. Participants with previously diagnosed type 1 diabetes (n = 25), newly (n = 6 4 9) or previously diagnosed type 2 diabetes (n = 763) or those without an OGTT at baseline (n = 11) were excluded. A total of 8,749 men without diabetes at baseline were included in the statistical analyses (age 57 ± 7 years, BMI 26.8 ± 3.8 kg/m2, mean ± SD).

Participants and clinical measurements at the follow-up study

A follow-up started in 2010 and so far 5,419 individuals have participated. The study protocol and measurements are identical to those of the baseline study.

Diagnosis of new type 2 diabetes

Out of 8,749 non-diabetic participants at baseline, 625 developed type 2 diabetes during a 5.9 year follow-up study. Diagnosis of type 2 diabetes was based on the following criteria: (1) fasting plasma glucose (FPG) ≥7.0 mmol/l, 2 h plasma glucose (2hPG) ≥11.1 mmol/l in an OGTT or HbA 1c ≥6.5% (48 mmol/mol) among 4,806 non-diabetic individuals who participated in the ongoing METSIM follow-up study in 2010–2014 (327 cases of new diabetes); (2) glucose-lowering medication started between the baseline study and 31 December 2013 (n = 261 cases of new diabetes; information obtained from the National Drug Reimbursement registry for all 8,749 non-diabetic participants); (3) type 2 diabetes diagnosed by physician as per medical records and/or FPG ≥7.0 mmol/l, 2hPG ≥11.1 mmol/l or HbA 1c ≥6.5% (48 mmol/mol) in outpatient/primary care laboratory measurements (n = 37 cases of new diabetes) and the lack of symptoms and signs indicating type 1 diabetes. Of the diabetes diagnoses in the METSIM follow-up study, 22.6% were based on FPG alone, 24.9% on 2hPG alone, 31.6% on HbA 1c alone and 20.8% on different combinations of these criteria. The study was approved by the Ethics Committee of the University of Eastern Finland and Kuopio University Hospital and conducted in accordance with the Helsinki Declaration. All study participants gave written informed consent.

Statin treatment

A total of 2,142 (24.5%) of the 8,749 non-diabetic men were on statin medication at baseline (65.9% on simvastatin, 18.1% on atorvastatin, 8.6% on rosuvastatin, 3.8% on fluvastatin, 2.3% on lovastatin and 1.3% on pravastatin).

Measurements

Height and weight were measured to the nearest 0.5 cm and 0.1 kg, respectively. BMI was calculated as weight (kg) divided by height (m) squared. Waist circumference was measured at the midpoint between the lateral iliac crest and lowest rib. Smoking status was defined as current smoking (yes vs no). Family history of diabetes (yes vs no) was defined as a first-degree or second-degree relative having diabetes vs no family history of diabetes. Physical activity (physically active vs inactive) refers to leisure-time exercise (physically active, regular exercise [at least 30 min once or twice a week] vs physically inactive, occasional exercise or no exercise). Alcohol intake was defined as total alcohol intake in grams per week. The use of beta-blockers and diuretics at baseline was recorded (yes vs no). CVD at baseline was defined as a history of non-fatal myocardial infarction or stroke.

Laboratory measurements

Plasma glucose was measured by enzymatic hexokinase photometric assay (Konelab Systems reagents; Thermo Fisher Scientific, Vantaa, Finland). HbA 1c was analysed with a Tosoh G7 glycohaemoglobin analyser (Tosoh Bioscience, San Francisco, CA, USA). Plasma insulin concentrations were measured by a luminometric immunoassay measurement (ADVIA Centaur Insulin IRI, no. 02230141; Siemens Medical Solutions Diagnostics, Tarrytown, NY, USA). LDL-cholesterol, HDL-cholesterol and total triacylglycerols were measured by enzymatic colorimetric tests (Konelab Systems reagents).

Calculations

The trapezoidal method was used to calculate the glucose and insulin AUCs in an OGTT based on samples collected at 0, 30 and 120 min. The Matsuda index of insulin sensitivity (ISI) was calculated as 10,000 / √(fasting insulin × fasting glucose × mean insulin during OGTT × mean glucose in an OGTT), and by HOMA-IR [25]. Disposition index (DI) was calculated as a product of insulin sensitivity and insulin secretion (Matsuda ISI × insulin AUC 0–30 min /glucose AUC 0–30 min ) and insulin secretion by HOMA of beta cell function (HOMA-B) as previously reported [23].

Statistical analysis

Statistical analyses were conducted using the SPSS version 19 (SPSS, Chicago, IL, USA). BMI, waist circumference, total cholesterol, LDL-cholesterol, HDL-cholesterol, total triacylglycerols, glucose and HbA 1c levels, Matsuda ISI and DI were log-transformed to correct for their skewed distribution. Baseline characteristics of the groups were compared using t test or χ 2 test. The p value for per cent differences between statin and no statin groups was calculated using the general linear or logistic regression models, as appropriate (Table 1). HRs for the risk of diabetes were calculated with Cox regression (Table 2, electronic supplementary material [ESM] Table 1). Risk of diabetes according to the type of statin (simvastatin, atorvastatin, or other statins [including rosuvastatin, pravastatin, fluvastatin and lovastatin] vs no statin), the dose of statin, and changes in statin treatment during the study were calculated with Cox regression (Fig. 1, ESM Fig. 1). The association of statin treatment with FPG, 2hPG and glucose AUC at follow-up was evaluated with linear regression analysis (N = 4,679 non-diabetic participants at baseline had follow-up data available, excluding individuals diagnosed with diabetes between baseline and follow-up). Adjustments were made in models 2–14 (Table 2) for age, BMI, waist circumference, current smoking, physical activity, alcohol intake, family history of diabetes, use of beta-blockers and use of diuretics, as well as for the length of follow-up time (in months) in linear regression analysis. Additional adjustments were made for FPG, 2hPG, Matsuda ISI, DI, LDL-cholesterol, HDL-cholesterol, total triacylglycerols and CVD and the changes in LDL-cholesterol, HDL-cholesterol, total triacylglycerols and BMI. In Table 2, p < 0.004 was considered as statistically significant given the 12 different models tested (Bonferroni correction for multiple testing) and p < 0.05 was considered nominally significant. Differences in Matsuda ISI and DI (Table 3) and HOMA-IR (ESM Table 2) in non-diabetic individuals at baseline treated with simvastatin or atorvastatin vs no statin and in individuals receiving low-dose or high-dose atorvastatin or simvastatin vs no statin were compared with the ANOVA post hoc tests. Matsuda ISI and DI between the individuals with and without statin therapy in categories of FPG and 2hPG were compared using the t test (unadjusted model, Fig. 2), and linear regression (adjusted for age, BMI, waist circumference, current smoking, physical activity, alcohol intake and family history of diabetes) (ESM Table 3), and similarly for HOMA-IR and HOMA-B (ESM Table 4).

Table 1 Comparison of metabolic risk factors at baseline between individuals by statin treatment at baseline and by development of new type 2 diabetes during a 5.9 year follow-up of the METSIM cohort Full size table

Fig. 1 Risk of type 2 diabetes by statin treatment during the 5.9 year follow-up. (a) Total cohort (625 cases of new type 2 diabetes and 8,124 non-diabetic controls). Black line, statin treatment at baseline (n = 2,141); grey line, no statin treatment at baseline (n = 6,607). (b) Risk by different statins. Black continuous line, atorvastatin (n = 388); black dotted line, simvastatin (n = 1,409); grey dotted line, other statins (including rosuvastatin, pravastatin, fluvastatin and lovastatin, n = 342); grey continuous line, no statin treatment. (c) Risk by dose of simvastatin. Black line, high dose (40 or 80 mg/day, n = 385); dotted line, low dose (10 or 20 mg/day, n = 971); grey line, no statin treatment. (d) Risk by dose of atorvastatin. Black line, high dose (20 or 40 mg/day, n = 197); dotted line, low dose (10 mg/day, n = 175); grey line, no statin treatment. Unadjusted Cox regression analysis Full size image

Table 2 Association of statin treatment at baseline with the risk of new diabetes and worsening of hyperglycaemia during a 5.9 year follow-up of the METSIM cohort Full size table

Table 3 The association of simvastatin and atorvastatin treatment at baseline and their doses with insulin sensitivity (Matsuda ISI) and insulin secretion (DI) in non-diabetic participants in the cross-sectional METSIM study Full size table