Persistent lipid abnormalities in statin-treated patients with diabetes mellitus in Europe and Canada: results of the Dyslipidaemia International Study

Authors


Dr Lawrence A. Leiter, St Michael’s Hospital, 61 Queen Street East, Room 6121Q, Toronto, ON M5C 2T2, Canada. E-mail: leiterl@smh.ca

Abstract

Diabet. Med. 28, 1343–1351 (2011)

Abstract

Aim  To assess the prevalence of persistent lipid abnormalities in statin-treated patients with diabetes with and without the metabolic syndrome.

Methods  This was a cross-sectional study of 22 063 statin-treated outpatients consecutively recruited by clinicians in Canada and 11 European countries. Patient cardiovascular risk factors, risk level, lipid measurements and lipid-modifying medication regimens were recorded.

Results  Of the 20 129 subjects who had documented diabetes and/or metabolic syndrome status, 41% had diabetes (of whom 86.8% also had the metabolic syndrome). Of those with diabetes, 48.1% were not at total cholesterol target compared with 58% of those without diabetes. Amongst those with diabetes, 41.6 and 41.3% of those with and without the metabolic syndrome, respectively, were not at their LDL cholesterol goal relative to 54.2% of those with metabolic syndrome and without diabetes, and 52% of those with neither condition. Twenty per cent of people with diabetes but without the metabolic syndrome were not at the optimal HDL cholesterol level compared with 9% of those with neither condition. Of people with diabetes and the metabolic syndrome, 49.9% were not at optimal triglyceride level relative to 13.5% of people with neither diabetes nor the metabolic syndrome. Simvastatin was the most commonly prescribed statin (> 45%) and the most common statin potency was 20–40 mg/day (simvastatin equivalent). Approximately 14% of patients were taking ezetimibe alone or in combination with a statin.

Conclusions  Despite evidence supporting the benefits of lipid modification and international guideline recommendations, statin-treated patients with diabetes had a high prevalence of persistent lipid abnormalities. There is frequently room to optimize therapy through statin dose up-titration and/or addition of other lipid-modifying therapies.

Abbreviations
AIM-HIGH

Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes

DM

diabetes mellitus

DYSIS

Dyslipidaemia International Study

HPS2-THRIVE

Treatment of HDL to Reduce the Incidence of Vascular Events

IMPROVE-IT

IMProved Reduction of Outcomes: Vytorin Efficacy International Trial

MetS

metabolic syndrome

REVEAL

Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification

Introduction

A causal relationship has been suggested between elevated levels of plasma cholesterol, particularly LDL cholesterol, and increased risk of cardiovascular disease. The benefit of statin therapy in the prevention of vascular disease was demonstrated in patients with Type 2 diabetes [1] and confirmed in a meta-analysis of 14 trials comprising 90 056 statin-treated subjects. This meta-analysis demonstrated that, for every 1.0 mmol/l reduction in LDL cholesterol, there was an approximately 20% reduction in cardiovascular disease events, irrespective of baseline LDL cholesterol levels, with similar risk reductions in those with diabetes (n = 18 686) as those without [2]. Statins are therefore recommended as first-line therapy in patients at risk of cardiovascular disease [3–5]. Despite the clinical trial evidence, guidelines and recommendations, there is evidence of suboptimal use of lipid-modifying therapies [4–6].

Amongst people with diabetes, there is heterogeneity of vascular risk, with the presence of co-morbid features of the metabolic syndrome increasing risk of premature coronary artery disease events [7]. The objective of the present analysis was to assess the prevalence of persistent lipid abnormalities in statin-treated patients with diabetes with and without the metabolic syndrome.

Patients and methods

The Dyslipidaemia International Study (DYSIS) was an epidemiologic multi-centre, cross-sectional study of the lipid profiles of 22 063 statin-treated outpatients in both primary and secondary care settings from 2954 sites across 11 European countries (Austria, Denmark, France, Germany, Ireland, the Netherlands, Norway, Portugal, Spain, Sweden, the UK) and Canada. The results of the global study have been reported recently [8]. This paper describes the pre-specified secondary analysis performed in the subset of patients with diabetes and/or the metabolic syndrome.

Study population

Outpatients were eligible for inclusion if they had been on statin therapy for ≥ 3 months, were ≥ 45 years old and had at least one lipid measurement available while receiving statin therapy. Exclusion criteria included active participation in another clinical study. Patients were enrolled from consecutive visits over a 2-month recruitment period at each site.

Data collection

Data were collected from clinical examination and medical charts aligned with single outpatient visits occurring between April 2008 and February 2009. Data were submitted via web-based or faxed forms to a central database managed at the Institut für Herzinfarktforschung Ludwigshafen an der Universität, Heidelberg, Germany.

Lipid measurements from the last available lipid test within the previous 6–12 months for total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides were recorded, as were specific patient-related lipid targets (i.e. whether patients were at goal/optimal levels) and the relevance of the different lipid parameters for the physicians. Risk classification and definitions of optimal LDL cholesterol, HDL cholesterol and triglycerides levels were based on the European Society of Cardiology recommendations [5].

Information on the treating physicians (specialty, medical practice and location) was documented. Patient demographic and the following clinical variables were recorded: patient and/or family history of diabetes (previous diagnosis of diabetes or serum glucose ≥ 7.0 mmol/l or patient currently on diabetes therapy); fasting plasma glucose and HbA1c; height; weight; waist circumference (measured in the standing position at the midpoint between the iliac crest and the costal margin in the mid-axillary line. Cut-offs for waist circumference were ≥ 94 cm for men and ≥ 80 cm for women); blood pressure; metabolic syndrome [International Diabetes Federation criteria: presence of central obesity (defined as ≥ 94 cm for men and ≥ 80 cm for women) plus two or more of the following: fasting plasma glucose ≥ 5.6 mmol/l or previously diagnosed diabetes; blood pressure ≥ 130/85 mmHg or receiving treatment for previously diagnosed hypertension; HDL cholesterol < 1.0 mmol/l for men or < 1.3 mmol/l for women; triglycerides ≥ 1.7 mmol/l) [9]]; smoking history; first-degree family history of premature cardiovascular disease; sedentary lifestyle (patient does not walk 20–30 min 3–4 days/week or equivalent); alcohol consumption (usual frequency of consumption of beer, wine or liquor reported as the average number of drinks in a week. A drink was considered as a can of beer, a glass of wine or 45 ml of spirits), hypertension (treatment of previously diagnosed hypertension or blood values > 140/90 mmHg); ischaemic heart disease; cerebrovascular disease; heart failure; peripheral arterial disease; daily dose of current statin; daily dose of statin in use at last blood test; and use of other lipid-modifying therapies at visit and before the previous blood test were recorded. Statin dose was normalized using a potency calculation described elsewhere [10]. In brief, the potency of different statins was benchmarked against six different simvastatin doses.

Ethics review

The study protocol was approved by local ethics review committees and written informed consent was obtained from all participating patients. No patient identifiers were used.

Statistical analysis

Categorical variables are presented as absolute numbers and percentages and continuous variables are reported as means with standard deviations (sd) or medians with 25th and 75th percentiles (interquartile range) as appropriate. Group comparisons for continuous variables were made using the non-parametric Kruskal–Wallis test. Chi-square test was used to compare categorical values. All statistical comparisons were two-tailed, with P-values < 0.05 considered statistically significant. Data were analysed with the Statistical Analyzing System, version 9.1 (SAS Institute Inc., Cary, NC, USA).

Results

Patients

Table 1 outlines the patient characteristics. Of the 20 129/22 063 statin-treated outpatients who had documented diabetes and/or metabolic syndrome status, 41% had diabetes and, of these, 86.8% also had the metabolic syndrome. Approximately half (50.7%) of the subjects who did not have diabetes met the International Diabetes Federation definition for the metabolic syndrome. Full lipid profiles (LDL cholesterol, HDL cholesterol, triglycerides and total cholesterol) were available for 18 182 patients.

Table 1.   Patient characteristics
 DM+MetS
N = 7213 (35.8%)
DM only
N = 1099 (5.5%)
MetS only
N = 5993 (29.8%)
No DM/No MetS
N = 5824 (28.9%)
P-value*
  1. *< 0.05 based on the Kruskal–Wallis test.

  2. †Based on data from 20 036 patients.

  3. ‡First-degree family history of premature CVD; defined as parent, brother or sister with myocardial infarction or sudden death before 55 years (male) or 65 years (female).

  4. §International Diabetes Federation cut-points for Caucasians/Europids.

  5. ¶Defined as current treatment or previously diagnosed or blood pressure values ≥ 140/90 mmHg.

  6. **Based on data from 20 102 patients.

  7. ††Based on data from 20 099 patients.

  8. ‡‡ESC/ESH goals [5]. Goals were individualized according to risk status.

  9. §§Defined as established CVD or diabetes or ESC-Score ≥ 5.0%, based on data from 20 002 patients.

  10. CAD, coronary artery disease; CVD, cardiovascular disease; DM, diabetes mellitus; DBP, diastolic blood pressure; ESC, European Society of Cardiology; ESH, European Society of Hypertension; M, men; MetS, metabolic syndrome; N/A, not available; PAD, peripheral arterial disease; SBP, systolic blood pressure; W, women.

Age, years, mean ± sd66.3 ± 9.366.2 ± 10.165.2 ± 9.965.5 ± 10.3< 0.0001
Female, % (n/N)43.7 (3155/7213)22.0 (242/1099)42.9 (2571/5993)39.2 (2282/5818)< 0.0001
Caucasian, % (n/N)95.0 (5501/5788)88.1 (730/829)97.1 (4394/4526)96.7 (4058/4195)< 0.0001
First-degree family history of premature CVD, % (n/N)‡30.1 (2160/7179)24.9 (272/1093)31.3 (1863/5957)28.5 (1649/5783)< 0.0001
Current smoker, % (n/N)14.4 (1039/7205)15.9 (175/1099)16.2 (971/5977)14.9 (865/5810)< 0.05
Sedentary lifestyle, % (n/N)56.2 (4036/7178)45.3 (495/1092)51.0 (3045/5968)42.0 (2433/5788)< 0.0001
BMI, kg/m², mean ± sd31.1 ± 5.525.8 ± 4.029.3 ± 4.626.0 ± 4.2< 0.0001
BMI < 25 kg/m² (normal weight), % (n/N)8.2 (594/7208)43.9 (482/1098)13.1 (784/5988)42.9 (2492/5808)<0.0001
BMI 25 to < 30 kg/m² (overweight), % (n/N)39.7 (2864/7208)45.7 (502/1098)50.2 (3007/5988)44.2 (2567/5808)< 0.0001
BMI ≥ 30 kg/m² (obese), % (n/N)52.0 (3750/7208)10.4 (114/1098)36.7 (2197/5988)12.9 (749/5808)< 0.0001
Waist circumference§≥ 94 cm (M), ≥ 80 cm (W), % (n/N) 100.0 (7213/7213)21.0 (229/1090)100.0 (5993/5993)51.2 (2928/5723)< 0.0001
CAD, cerebrovascular disease and/or PAD, % (n/N)45.1 (3254/7209)45.4 (499/1099)47.5 (2844/5991)47.2 (2747/5821)< 0.05
Hypertension,¶% (n/N)88.6 (6388/7212)62.1 (682/1099)78.6 (4712/5993)57.1 (3326/5822)< 0.0001
SBP, mmHg, mean ± sd**136.3 ± 15.6128.9 ± 14.4136.1 ± 14.5130.7 ± 14.7< 0.0001
DBP, mmHg, mean ± sd††78.4 ± 9.475.1 ± 9.279.8 ± 8.977.0 ± 8.6< 0.0001
Blood pressure < 140/90 mmHg, % (n/N)55.2 (3977/7208)74.5 (816/1096)54.4 (3257/5988)69.3 (4025/5807)< 0.0001
Blood pressure < 130/80 mmHg, % (n/N) 18.1 (1305/7209)38.8 (425/1096)14.6 (872/5988)29.1 (1689/5807)< 0.0001
Blood pressure: goal of treatment achieved, % (n/N)‡‡18.1 (1305/7209)38.8 (425/1096)37.3 (2236/5987)52.5 (3051/5806)< 0.0001
HbA1c in patients with diabetes, mmol/mol (mean ± sd); % (mean ± sd)51 (44–58)
6.8 (6.2–7.5)
49 (43–57)
6.6 (6.1–7.4)
N/AN/A0.79
High risk, % (n/N)§§10010068.8 (4087/5940)66.6 (3831/5750)< 0.0001

Subjects were subdivided into four groups for subsequent analyses—diabetes and the metabolic syndrome (DM+MetS), diabetes without the metabolic syndrome (DM only), the metabolic syndrome without diabetes (MetS only) and neither diabetes nor metabolic syndrome (No DM/No MetS). Across the four groups, subjects in the DM+MetS group had the highest mean BMI, highest prevalence of obesity (≥ 30 kg/m2), highest rate of sedentary lifestyle, highest incidence of hypertension and lowest percentage of patients at treatment-targeted blood pressure (Table 1). At least one quarter of each of the former three groups had a family history of premature cardiovascular disease and this was true for 28.5% of the subjects in the No DM/No MetS group. The prevalence of ischaemic heart disease, cerebrovascular disease and/or peripheral arterial disease was comparable across the groups (45.1–47.5%). The majority of the DYSIS cohort was at high risk of cardiovascular disease and almost half already had known cardiovascular disease.

When patients in the DM+MetS group were compared with the DM-only group, the former were more likely to be female (43.7 vs. 22.0%), Caucasian (95 vs. 88.1%), have a family history of premature cardiovascular disease in a first-degree relative (30.1 vs. 24.9%), a sedentary lifestyle (56.2 vs. 45.3%), a higher BMI (31.1 vs. 25.8 kg/m2), a waist circumference above recommended targets (100 vs. 21%), hypertension (88.6 vs. 62.1%) and to have not achieved blood pressure target at time of visit (18.1 vs. 38.8%).

Fewer differences were revealed when the patients in the DM+MetS group were contrasted against the MetS-only group, with the former having a higher BMI (31.1 vs. 29.3 kg/m2), increased prevalence of hypertension (88.6 vs. 78.6%) and a lesser likelihood of achieving blood pressure target at the time of visit (18.1 vs. 37.3%).

Lipid measurements and usage of statin therapy

Mean lipid levels and the proportions of patients achieving optimal values are described in Table 2 and shown in Fig. 1. Regardless of the absence or presence of the metabolic syndrome, nearly half of the subjects with diabetes were not at their total cholesterol target (48.1% for DM+MetS and 48.1% DM only) compared with 58.8 and 57.8% of the patients in the MetS-only and No DM/No MetS groups, respectively. Similarly, patients with diabetes were more successful at achieving LDL cholesterol targets (58.4% for DM+MetS and 58.7% for DM only) relative to those without diabetes (45.8% for MetS only and 48.0% for No DM/No MetS). In people with diabetes without the metabolic syndrome, 20% were not at their desirable gender-specific HDL cholesterol level, compared with 9% of individuals with neither condition. Approximately half (49.9%) of those with diabetes did not have a desirable triglyceride level compared with 13.5% of those without diabetes or the metabolic syndrome.

Table 2.   Lipid parameters in patients with at least one lipid parameter measured
 DM+MetSDM onlyMetS onlyNo DM/No MetSP-value*
  1. *P < 0.05 based on the Kruskal–Wallis test.

  2. †Based on data from 19 872 patients.

  3. ‡Based on data from 19 050 patients.

  4. §Based on data from 19 231 patients.

  5. ¶Based on data from 19 825 patients.

  6. **Total cholesterol ≥ 4.5 mmol/l/5.0 mmol/l [5]. Goals were individualized according to risk status.

  7. ††Greater than or equal to 2.5 mmol/l/3.0 mmol/l [5]. Goals were individualized according to risk status.

  8. ‡‡Less than 1.0 mmol/l for men/< 1.2 mmol/l for women [5].

  9. §§Greater than 1.7 mmol/l [5].

  10. DM, diabetes mellitus; IQR, interquartile range; MetS, metabolic syndrome.

Total cholesterol, mmol/l, mean ± sd†4.6 ± 1.14.5 ± 1.15.0 ± 1.24.9 ± 1.1< 0.0001
LDL cholesterol, mmol/l, mean ± sd‡2.5 ± 0.92.5 ± 0.92.9 ± 1.02.9 ± 0.9< 0.0001
HDL cholesterol, mmol/l, mean ± sd§1.2 ± 0.41.4 ± 0.41.2 ± 0.41.5 ± 0.4< 0.0001
Triglycerides, mmol/l, median (IQR)¶1.7 (1.2–2.3)1.2 (0.9–1.7)1.8 (1.3–2.3)1.2 (0.9–1.5)< 0.0001
Total cholesterol not at goal, % (n/N)**48.1 (3413/7097)48.1 (520/1080)58.8 (3473/5910)57.8 (3304/5718)< 0.0001
LDL cholesterol not at goal, % (n/N)††41.6 (2818/6767)41.3 (432/1047)54.2 (3041/5611)52.0 (2870/5519)< 0.0001
Low HDL cholesterol, % (n/N)‡‡36.2 (2460/6801)19.9 (209/1051)36.5 (2090/5733)8.9 (501/5640)< 0.0001
Elevated triglycerides, % (n/N)§§49.9 (3399/6805)25.9 (274/1059)56.9 (3307/5809)13.5 (759/5612)< 0.0001
LDL cholesterol, HDL cholesterol‡‡ and triglycerides§§ (< 150) ‘optimal’, % (n/N)23.5 (1501/6384)39.0 (389/998)13.3 (721/5403)39.0 (2085/5348)< 0.0001
Figure 1.

 Venn diagrams showing the distribution of single and multiple combined lipid abnormalities in patients with full lipid status information in the following groups: (a) DM+MetS; (b) DM only; (c) MetS only; and (d) No DM/No MetS. Elements in the grey, red, blue and green ellipses represent patients who have no persistent lipid abnormality, LDL cholesterol (LDL-C) not at target (≥ 2.5 mmol/l), elevated triglycerides (TG) (> 1.7 mmol/l) and low HDL cholesterol (HDL-C) (< 1.0 mmol/l for men and < 1.2 mmol/l for women), respectively.

Subjects in the No DM/No MetS group were most likely (52.6%) to have optimal levels of the three lipid measurements (LDL cholesterol, HDL cholesterol and triglycerides) compared with patients in the DM/MetS (20.1%), DM-only (36.9%) and MetS-only (14.5%) groups. As low HDL cholesterol and elevated triglycerides are criteria for the diagnosis of the metabolic syndrome, it is not surprising that not only was the proportion of patients in the DM+MetS group with optimal levels of all three lipid measurements lower than that of the DM-only group (Table 2; Fig. 1a and b) but that patients in the MetS-only group exhibited the highest incidence of persistent lipid abnormality amongst the four groups of patients investigated. As shown in Fig. 1b and d, the DM-only and the No DM/No MetS groups had the same proportion of patients with no persistent lipid abnormalities (39%).

The presence of cardiovascular disease did not appear to exert clinically meaningful effects on the lipid target achievement of patients with diabetes. Relative to patients with diabetes and no cardiovascular disease, those with diabetes and cardiovascular disease were more likely to be at their LDL cholesterol goal, less likely to have desirable HDL cholesterol and triglycerides levels and no more likely to have optimal levels of all three lipids measurements (Table 3). Patients with diabetes and cardiovascular disease were also on a higher mean statin dose (39.5 vs. 31.8 mg/day, simvastatin equivalent unit) and were more likely to be on some form of combination therapy (Table 4).

Table 3.   Lipid parameters by cardiovascular status in patients with and without diabetes
 Diabetes
N = 8308
No DM/No MetS
N = 5821
With CVD
N = 3753 (45.2%)
Without CVD
N = 4555 (54.8%)
P-valueWith CVD
N = 2747 (47.2%)
Without CVD
N = 3074 (52.8%)
P-value
  1. *Based on data from 13 389 patients.

  2. †Based on data from 13 492 patients.

  3. ‡Based on data from 13 469 patients.

  4. CVD, cardiovascular disease (coronary artery disease, peripheral arterial disease or cerebrovascular disease); DM, diabetes mellitus; IQR, interquartile range; MetS, metabolic syndrome.

LDL cholesterol, mmol/l, mean ± sd*2.4 ± 0.92.6 ± 0.9< 0.00012.5 ± 0.83.2 ± 1.0< 0.0001
HDL cholesterol, mmol/l, mean mean ± sd†1.2 ± 0.41.3 ± 0.4< 0.00011.4 ± 0.41.6 ± 0.4< 0.0001
Triglycerides, mmol/l, median (IQR)‡1.7 (1.2–2.3)1.6 (1.1–2.2)< 0.00011.1 (0–1.4)1.2 (0.9–1.5)< 0.0001
Patients not at LDL cholesterol goal, % (n/N)37.5 (1331/3548)45.0 (1919/4263)<0.000142.1 (1116/2649)61.1 (1751/2867)< 0.0001
Patients not at HDL cholesterol goal, % (n/N)38.3 (1357/3541)30.4 (1311/4308)< 0.000111.7 (311/2666)6.4 (190/2971)< 0.0001
Patients not at triglycerides goal, % (n/N)49.1 (1729/3524)44.8 (1943/4336)< 0.00111.9 (314/2643)15.0 (445/2966)< 0.001
Patients achieving all three (LDL cholesterol, HDL cholesterol and triglyceride) goals, % (n/N)25.2 (843/3342)25.8 (1055/4088)0.5746.4 (1187/2560)32.3 (904/2797)< 0.0001
Table 4.   Statin monotherapy and combination therapy by cardiovascular status in patients with and without diabetes
 Diabetes
N = 8308
No DM/No MetS
N = 5821
With CVD
N = 3753 (45.2%)
Without CVD
N = 4555 (54.8%)
P-valueWith CVD
N = 2747 (47.2%)
Without CVD
N = 3074 (52.8%)
P-value
  1. *Based on data from 13 952 patients.

  2. CVD, cardiovascular disease (coronary artery disease, peripheral arterial disease or cerebrovascular disease); DM, diabetes mellitus; MetS, metabolic syndrome.

Statin dose, mg/day simvastatin equivalent unit, mean ± sd*39.5 ± 31.131.8 ± 22.2< 0.000139.1 ± 31.727.5 ± 21.4< 0.0001
Patients using ezetimibe in addition to statin, % (n/N)12.0 (450/3742)8.2 (374/4540)< 0.000111.7 (319/2737)7.4 (225/3048)< 0.0001
Patients using combined formulation of ezetimibe plus statin, % (n/N)5.2 (195/3742)3.3 (152/4540)< 0.015.0 (136/2737)3.0 (92/3048)< 0.001
Patients using nicotinic acid in addition to statin, % (n/N)0.9 (32/3742)0.4 (16/4541)0.520.7 (20/2737)0.3 (9/3048)< 0.05
Patients using fibrate in addition to statin, % (n/N)2.5 (92/3743)2.3 (104/4542)0.620.9 (26/2737)1.1 (34/3048)0.53
Patients using bile acid sequestrants in addition to statin, % (n/N)0.5 (17/3742)0.2 (8/4539)< 0.050.5 (15/2737)0.3 (10/3048)0.2

As shown in Table 3, amongst the subjects in the No DM/No MetS group, those with cardiovascular disease had markedly lower mean LDL cholesterol levels than those without cardiovascular disease. However, there were no clinically meaningful differences in HDL cholesterol and triglycerides between these two patient populations. Accordingly, patients in the No DM/No MetS group with cardiovascular disease were much more likely to be at their LDL cholesterol goal and more likely to have optimal levels for all three lipid types (Table 3). These patients were also on higher statin doses (39.1 vs. 27.5 mg/day simvastatin equivalent unit) and more likely to be on some form of combination therapy when compared with the subjects in the No DM/No MetS group who did not present with cardiovascular disease (Table 4).

Discussion

Despite the cumulative evidence supporting the benefits of lowering total cholesterol and LDL cholesterol, and the wide dissemination of guideline-recommended target lipoprotein levels and treatment strategies, clinical inertia was apparent in this cohort of patients who were already at high risk and on statin therapy. Achievement of optimal lipid levels with treatment was only modestly better amongst those with a history of cardiovascular disease.

Subjects in the DYSIS with diabetes were more likely than those without diabetes to be at target total cholesterol and LDL cholesterol levels, perhaps reflecting better lipid-focused treatment once a patient is diagnosed with diabetes. However, despite the fact that nearly half of the subjects with diabetes also had cardiovascular disease, 40% of this subgroup did not have optimal LDL cholesterol levels and only a quarter achieved all three lipid—LDL cholesterol, HDL cholesterol and triglycerides—goals. Not surprisingly, low HDL cholesterol and elevated triglycerides were more prevalent in the DM+MetS group than the DM group, likely indicative of the fact that these two conditions are criteria for diagnosing the metabolic syndrome. That the presence of diabetes in patients with the metabolic syndrome was not associated with less desirable HDL cholesterol or triglycerides values suggests that glycaemic control in these subjects was remarkably good.

Despite what appears to be considerable residual risk, as measured by LDL cholesterol values, very few patients were on high-dose statins or receiving treatment for other lipid parameters. Even in patients with diabetes, the proportions of patients receiving any other lipid treatment were very low. Notably, although over one third (37.5%) of the patients with diabetes and existing cardiovascular disease were not at their LDL cholesterol goal, only moderate doses of statins were utilized and only approximately 14% were receiving any combination therapy.

Other recent studies have also reported ongoing suboptimal management of dyslipidaemia [6,11–17]. In the EUROASPIRE III survey of modifiable cardiovascular risk factors in patients with coronary artery disease in eight European countries, almost half of patients had lipid levels above recommended values [6]. Foley and colleagues [15] reported that, of high-risk subjects who did not achieve their therapeutic target with a starting dose of statin, only 45% had dose up-titration. Similarly, Yan and colleagues found that only 10% of high-risk patients who failed to meet their LDL cholesterol targets were taking high-dose statins [13]. In a German cohort of approximately 60 000 patients with Type 2 diabetes, only 16% were at the LDL cholesterol goal of 2.6 mmol/l, yet only 33% were receiving lipid-modifying medications (25% on statins) [16]. In a Canadian survey of 3002 patients with diabetes, 74% were taking statins but 36% had LDL cholesterol levels above the goal of 2.5 mmol/l and, of those above target, 43% were not on a statin [17].

In contrast to other studies that focused only on LDL cholesterol, DYSIS also examined other lipid fractions and found LDL cholesterol was frequently raised, in combination with low HDL cholesterol and elevated triglycerides. Despite this, few patients were receiving therapy in addition to statins. In a study aimed at identifying which lipid factors drive vascular risk in statin-treated patients with coronary artery disease, it was found that a pattern of low HDL cholesterol, low apolipoprotein A1, small LDL cholesterol particles and high triglycerides propels this risk, particularly in those with Type 2 diabetes [18]. In a pan-European survey that included 3866 patients with Type 2 diabetes, half of the women and 25% of men with diabetes had very low HDL cholesterol (defined as < 1.03 mmol/l for men and < 1.29 mmol/l for women) [19], while in an American study of patients with Type 2 diabetes in primary care, almost 50% of patients had low HDL cholesterol levels (< 1.43 mmol/l for men and < 1.78 mmol/l for women). In the latter study, 63% were on a statin, but only 8% were prescribed medication to raise HDL cholesterol [20].

The reasons underlying this care gap are likely multifactorial, with both physician- and patient-associated factors playing contributory roles. The increasing complexity of many guidelines, coupled with recommendations based on varying strengths of evidence, may limit the motivation of some physicians to initiate and continue more aggressive therapeutic strategies [21]. Suboptimal patient compliance towards typical and increasing dosages of statins, as well as the perceived complexity of combinational therapy, may also in part factor into poor lipid goal achievements. Furthermore, patients’ access to public vs. private insurance that may or may not cover the cost of lipid-lowering drugs may define both the physicians’ prescription practices as well as the patients’ willingness to pursue a new or more intense regimen.

Despite LDL cholesterol reduction with high-dose statins, there is a significant residual risk for patients at high risk for cardiovascular disease. Beyond LDL cholesterol reduction, reducing the total cholesterol/HDL cholesterol ratio, increasing HDL cholesterol and reducing triglycerides may help to reduce this residual risk. Robinson and colleagues [22] recently sought through a meta-analysis to determine the relationship between non-HDL cholesterol lowering and coronary artery disease risk reduction for various lipid-modifying therapies. They concluded that non-HDL cholesterol is an important target of therapy for coronary artery disease prevention and found that most lipid-modifying drugs used had an approximately 1:1 relationship between per cent of non-HDL cholesterol lowering and coronary artery disease reduction. In a separate study, Robinson and colleagues [23] concluded that the pleiotropic effects of statins did not reduce cardiovascular risk beyond that expected from the degree of LDL cholesterol lowering, suggesting that lowering LDL cholesterol may be more important than the method of LDL cholesterol lowering.

A recent meta-analysis of 20 large-scale statin trials demonstrated an independent and significant inverse association between HDL cholesterol levels and cardiovascular outcomes that was not impacted by statin therapy. Statin-treated patients had the same degree of risk associated with lower levels of HDL cholesterol than control subjects (even after adjustment for on-treatment LDL cholesterol levels, age, hypertension, diabetes and tobacco use) [24]. The findings highlight the risk associated with low levels of HDL cholesterol, even in statin-treated patients.

Currently, we lack conclusive evidence that adding a second lipid-modifying agent to statins will improve outcomes. In fact, the results of Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid did not show any benefit of routinely adding fenofibrate to ongoing statin therapy in 5518 patients with Type 2 diabetes, but instead suggested a possible benefit in the subgroup with high triglycerides/low HDL cholesterol [25]. Ongoing clinical trials may clarify whether adding other lipid-modifying agents to a statin (niacin plus simvastatin vs. simvastatin in AIM-HIGH and HPS2-THRIVE, dalcetrapib vs. placebo in statin-treated patients in dal-OUTCOMES, anacetrapib vs. placebo in statin-treated patients in REVEAL and simvastatin/ezetimibe combination vs. simvastatin in IMPROVE-IT) will be associated with additional cardiovascular risk reduction.

Study limitations

The DYSIS collected cross-sectional data but did not evaluate long-term outcomes. Lipid parameters were taken from patient medical records without blood sample collection or central, core laboratory evaluation. The fact that current statin use was a patient eligibility criterion may have introduced a treatment centre self-selection bias, although this suggests that the data perhaps overestimate the use and impact of statins. In addition, statins are the mainstay of therapy, with rates up to 95% in some of the countries included in DYSIS. Finally, data on patient full lifestyle, genetic predisposition to cardiovascular disease (although family history was recorded) or adherence to treatment regimen were not collected. Despite these limitations, this study reflects ‘real-world’ clinical practice in a variety of settings and countries.

Conclusions

Statin-treated patients with diabetes (with or without the metabolic syndrome and with or without known cardiovascular disease) had a high prevalence of persistent lipid abnormalities. There is room to optimize therapy through statin dose up-titration and/or addition of other lipid-modifying therapies to manage HDL cholesterol and triglycerides. The results of ongoing clinical trials to assess the impact of adding a second lipid-modifying agent are awaited.

Competing interests

The authors received reimbursement for travel and accommodation expenses related to their roles as DYSIS Scientific Committee members. The authors declare the following: LAL has received research funding from, provided continuing medical education on behalf of, and/or has acted as a consultant to Abbott, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, GSK, Merck, Novartis, NovoNordisk, Pfizer, Roche, Sanofi-Aventis and Servier; PMdaS has received fees for speaking at medical meetings supported by the pharmaceutical industry (Pfizer, Servier, MSD, Bayer, Novartis and Abbott) and is a member of the DYSIS steering committee; AKG has received honoraria and travel cost reimbursement by Merck to attend steering committee meetings. PL, HD and CJ have nothing to declare.

Acknowledgments

The Scientific Committee thanks the individual investigators for their participation; the study sponsor, Merck & Co. Inc., for their support through an unrestricted research grant; Sandra Joshua-Gotlib, the study coordinator; Dr Steffen Schneider who provided statistical support in the analysis of the study results; and Cynthia N. Lank and Hwee Teoh for writing and editorial support to authors in the preparation of this manuscript. Cynthia N. Lank and Hwee Teoh were funded by Merck & Co. to provide writing and editorial support to the authors in the preparation of this manuscript.

Previous publication in abstract form

Leiter L, Feely J, Ferrieres J, Gitt A, Gonzalez-Juanatey JR, Korsgaard Thomsen K et al. Characteristics of statin-treated patients with diabetes mellitus in Europe and Canada: Results of the Dyslipidemia International Study. IDF World Congress. Montreal, Quebec, Canada, 18–22 October 2009. Abstract no. D-0812, page 275. Available at http://www.worlddiabetescongress.org/montreal2009/pages/final-programme Last accessed 26 March 2011.

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