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  • Original investigation
  • Open Access

Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy

†Contributed equally
Cardiovascular Diabetology201716:4

https://doi.org/10.1186/s12933-016-0486-2

©  The Author(s) 2017

  • Received: 5 September 2016
  • Accepted: 25 December 2016
  • Published:

Abstract

Background

To investigate the effects of dyslipidemia and statin therapy on progression of diabetic retinopathy and diabetic macular edema in patients with type 2 diabetes.

Methods

The medical records of 110 patients with type 2 diabetes (70 statin users and 40 non-users) were retrospectively reviewed. The two outcome measures were progression of diabetic retinopathy by two or more steps on the early treatment diabetic retinopathy study scale and diabetic macular edema based on optical coherence tomography. Serum lipid profiles were analyzed from 6 months prior to diagnosis of diabetic macular edema.

Results

Diabetic retinopathy progressed in 23% of statin users and 18% of non-users (p = 0.506), but diabetic macular edema was present in 23% of statin users and 48% of non-users (p = 0.008). Statins reduced low-density lipoprotein cholesterol levels in patients with and without diabetic macular edema (p = 0.043 and p = 0.031, respectively). Among statin users, patients with diabetic macular edema had higher levels of triglycerides (p = 0.004) and lower levels of high-density lipoprotein cholesterol (p = 0.033) than those without diabetic macular edema. Logistic regression analysis showed that statin use significantly lowered the risk of diabetic macular edema [odds ratio (OR): 0.33, 95% confidence interval (CI) 0.12–0.91, p = 0.032]. Hypertriglyceridemia at 6 months prior to development of macular edema was significantly associated with central retinal thickness (OR: 1.52; 95% CI 1.14–2.02, p = 0.005).

Conclusions

Lipid lowering therapy with statins protected against the development of diabetic macular edema and progression of diabetic retinopathy in patients with type 2 diabetes. Hypertriglyceridemia could be used as a surrogate marker for diabetic macular edema.

Keywords

  • Diabetic macular edema
  • Diabetic retinopathy
  • Statin
  • Triglyceride

Background

Lipid-lowering therapy with hydroxymethylglutaryl-CoA reductase inhibitors (statins) prevents major cardiovascular events and reduces mortality in patients with diabetes mellitus [1, 2]. However, recent studies found that statin use is associated with a small but significant increased risk for development of diabetes [3–5]. In contrast to these findings, the effect of statins on development of diabetic microvascular complications is unknown. A nationwide study in Denmark reported that statin users had a lower cumulative incidence of diabetic retinopathy (DR) and neuropathy before the diagnosis of diabetes [6]. On the other hand, Mansi et al. [5] reported that statin use was associated with an increased risk of diabetic complications in their study of propensity score-matched healthy statin users and non-users. Although these individual studies showed different results, the American College of Cardiology (ACC) and the American Heart Association (AHA) recently recommended statins for all people with diabetes between the ages of 40 and 75 years-old who have low-density lipoprotein (LDL) cholesterol of 70 mg/dL and above. If these guidelines are followed, it would make statins the second-most widely prescribed medication in the world, after hypoglycemic agents for treatment of diabetes [7]. However, the effect of statin use on the development of diabetic macular edema and progression of DR in patients with pre-existing type 2 diabetes is unknown.

DR is a microvascular complication of diabetes resulting from hyperglycemia and glucose-related hyperosmolarity, and diabetic macular edema is a leading cause of severe vision loss in patients with DR [8–10]. While the key factors for progression of DR and diabetic macular edema is known to be associated with the duration of diabetes and hypertension, dyslipidemia is considered a risk factor for DR and diabetic macular edema too [11–13]. Previous cohort studies suggested that increased levels of total cholesterol, triglycerides, and LDL cholesterol had positive associations with diabetic macular edema in patients with type 1 diabetes [14, 15]. The fenofibrate intervention and event lowering in diabetes (FIELD) study found that fenofibrate reduced the progression of DR in patients with type 2 diabetes [16, 17]. The action to control cardiovascular risk in diabetes (ACCORD) eye study examined the effects of fenofibrate on DR and showed that fenofibrate + simvastatin therapy slowed the progression of DR in patients with type 2 diabetes at 4 years [17, 18], although a follow-up study reported that fenofibrate provided no benefit at 8 years [17, 19]. A recent meta-analysis of the relationship of dyslipidemia with diabetic macular edema reported that most studies focused on the prevention of progression of DR, not on diabetic macular edema, because diabetic macular edema is not currently an indication for lipid lowering therapy [20].

The present study investigated the effect of statin administration and dyslipidemia on the development of diabetic macular edema in patients with type 2 diabetes. We also investigated the use of serum lipid profile as a surrogate maker for development of diabetic macular edema.

Methods

The medical records of 1127 patients diagnosed with type 2 diabetes and followed-up by the Ophthalmology Department of Ajou University Hospital (Suwon, Korea) from January 2010 to October 2015 were retrospectively reviewed. This study was approved by the Institutional Review Board of Ajou University Hospital and complied with the Declaration of Helsinki. The following demographic and clinical factors were obtained from medical records: age, sex, duration of diabetes, follow-up period, presence of hypertension, treatment with hypoglycemic agents and/or statins, ocular treatment with intravitreal anti-vascular endothelial growth factor (VEGF) injections, HbA1c level, and serum lipid profile.

The severity of DR was graded using the early treatment DR study (ETDRS) scale, with seven-field stereo photographs and fluorescein angiography performed simultaneously [21]. Diabetic macular edema was defined as retinal thickening in the macular area of either eye, according to the ETDRS scale, and identified by optical coherence tomography (OCT) [22]. Patients with diabetic macular edema were defined as those who developed macular edema during the follow-up period. Central retinal thickness in cases with diabetic macular edema was measured as the distance from the hyperreflective line of the internal limiting membrane to the hyperreflective line of the retinal pigment epithelium/Bruch’s membrane complex using OCT [23]. Patients were excluded if they had follow-ups for less than 1 year, fewer than 2 fundus photographs, other retinal diseases, no DR, vitrectomy, use of lipid-lowering agents other than statins (such as fenofibrate, niacin, and/or fish oil), and no records on use of systemic medications.

The primary outcome measures were progression of DR by two or more steps on the ETDRS scale [16] and diabetic macular edema involving the fovea with central retinal thickness of 300 μm or more based on OCT findings. Serum lipid profiles and other laboratory data were analyzed from 6 months before to 12 months after diagnosis of diabetic macular edema to assess the effect of serum lipid profile. The condition of patients without diabetic macular edema was confirmed during entire study period, and laboratory data were analyzed at the time of the final fundus angiography.

Pearson correlation analysis and a generalized estimating equation model were used to analyze the correlation of variables with central retinal thickness in patients with diabetic macular edema at 1, 3 and 6 months prior to diagnosis. Logistic regression analysis was performed to evaluate the association between statin use and diabetic macular edema after controlling for age, duration of diabetes, HbA1c, and lipid profiles. Categorical variables were compared using the Chi square test, and continuous variables using the independent t test. Statistical analysis was performed using SPSS software (version 23.0, SPSS, Chicago, IL). Statistical significance was defined as a p value less than 0.05.

Results

We initially examined the records 1127 patients with type 2 diabetes, and ultimately enrolled 110 patients (58 males and 52 females) who had DR. Table 1 summarizes demographic and clinical characteristics of patients who used statins (n = 70) and did not use statins (n = 40). Statin users were older (p = 0.016) and had a longer duration of diabetes (p = 0.019). DR progressed in 23% of statin users and 18% of non-users (p = 0.506). Notably, 16 of 70 statin users (23%) and 19 of 40 non-users (48%) showed diabetic macular edema based on OCT findings during the follow-up period (p = 0.008). Analysis of laboratory profiles indicated the statin users and non-users had no differences in the levels of HbA1c, triglycerides, and total and high-density lipoprotein (HDL) cholesterol. However, statin users had significantly lower levels of LDL cholesterol (p = 0.007).
Table 1

Baseline characteristics of patients with diabetic retinopathy (DR) who used or did not use statins

Variable

Statin group (n = 70)

No statin group (n = 40)

p value

Age

58.1 ± 11.6

52.3 ± 12.2

0.016a

Sex (male:female)

41:29

17:23

0.104

Duration of diabetes mellitus (years)

12.4 ± 8.0

8.6 ± 8.2

0.019a

Follow-up period (months)

26.8 ± 16.9

22.9 ± 15.4

0.251

Presence of hypertension

56/70 (80%)

26/40 (65%)

0.082

Initial DR severity scale

  

0.445

 Mild NPDR (20–35)

17

5

 

 Mod-severe NPDR (43–53)

50

30

 

 PDR (more than 61)

3

5

 

DR progression (≥2 steps of DRSS)

16/70 (23%)

7/40 (18%)

0.506

Presence of diabetic macular edema

16/70 (23%)

19/40 (48%)

0.008a

No. of IVT

1.2 ± 2.4

1.8 ± 3.0

0.317

HbA1c (%)

8.1 ± 1.7

8.0 ± 1.5

0.758

Total cholesterol (mmol/L)

4.4 ± 2.6

4.4 ± 1.5

0.904

Triglycerides (mmol/L)

1.9 ± 1.4

2.1 ± 1.5

0.569

HDL cholesterol (mmol/L)

1.1 ± 0.3

1.1 ± 0.3

0.990

LDL cholesterol (mmol/L)

2.1 ± 0.8

3.0 ± 1.3

0.007a

DR diabetic retinopathy, DRSS diabetic retinopathy severity scale, HDL high-density lipoprotein, IVT intravitreal injection of anti-VEGF agents, LDL low-density lipoprotein, NPDR non-proliferative diabetic retinopathy, PDR proliferative diabetic retinopathy

a p value <0.05 (independent t-test or Chi square test)

Subgroup analysis of patients with and without diabetic macular edema indicated that LDL cholesterol was significantly lower in statin users with and without diabetic macular edema (p = 0.043 and p = 0.031, respectively, Table 2). These results suggest that lipid lowering therapy with statins protected against the development of diabetic macular edema without increasing the risk of DR progression.
Table 2

Serum lipid profiles of patients with diabetic retinopathy who had or did not have diabetic macular edema (DME) and who used or did not use statins

Variable

Statin

No statin

p value

DME group (no. of patients)

16

19

 

 HbA1c (%)

7.7 ± 1.2

7.9 ± 1.6

0.642

 Total cholesterol (mmol/l)

4.7 ± 1.5

5.0 ± 1.2

0.501

 Triglycerides (mmol/l)

3.0 ± 2.7

2.3 ± 1.4

0.388

 HDL cholesterol (mmol/l)

0.9 ± 0.3

1.0 ± 0.4

0.410

 LDL cholesterol (mmol/l)

2.2 ± 0.8

3.2 ± 1.1

0.043a

No DME group (no. of patients)

54

21

 

 HbA1c (%)

8.2 ± 1.7

8.2 ± 1.7

0.932

 Total cholesterol (mmol/L)

4.3 ± 2.8

4.2 ± 1.6

0.866

 Triglycerides (mmol/L)

1.7 ± 0.9

1.9 ± 0.8

0.246

 HDL cholesterol (mmol/L)

1.1 ± 0.4

1.2 ± 0.3

0.916

 LDL cholesterol (mmol/L)

2.1 ± 0.8

2.8 ± 1.3

0.031a

DME diabetic macular edema, HDL high-density lipoprotein, LDL low-density lipoprotein

a p value <0.05 (independent t-test)

Despite this beneficial effect of statins, analysis of statin users indicated that those with diabetic macular edema had a significantly higher level of triglycerides (p = 0.004) and a lower level of HDL cholesterol (p = 0.033) (Table 3). This result suggests that hypertriglyceridemia, rather than dyslipidemia, may lead to the development of diabetic macular edema in statin users. There were similar trends in non-users of statins, but the differences were not statistically significant (data not shown). Logistic regression analysis was performed to evaluate factors associated with diabetic macular edema (Table 4). Statin use was associated with a significantly lower risk of diabetic macular edema (odd ratio (OR): 0.40; 95% confidence interval (CI) 0.17–0.90; p = 0.028). Triglycerides level was associated with diabetic macular edema, while HDL cholesterol level lowered the risk. When adjusted with age, duration of diabetes, HbA1c, triglycerides and HDL cholesterol in multivariate analysis, statin use had a significant protective effect on diabetic macular edema (OR: 0.33; 95% CI 0.12–0.91; p = 0.032).
Table 3

Serum lipid profiles of patients with diabetic retinopathy who used or did not use statins and who had or did not have diabetic macular edema (DME)

Variable

DME

No DME

p value

Statin group (no. of patients)

16

54

 

 HbA1c (%)

7.7 ± 1.2

8.2 ± 1.7

0.282

 Total cholesterol (mmol/L)

4.7 ± 1.5

4.3 ± 2.8

0.603

 Triglycerides (mmol/L)

3.0 ± 2.7

1.7 ± 0.9

0.004a

 HDL cholesterol (mmol/L)

0.9 ± 0.3

1.1 ± 0.4

0.033a

 LDL cholesterol (mmol/L)

2.2 ± 0.8

2.1 ± 0.8

0.761

No-statin group (no. of patients)

19

21

 

 HbA1c (%)

7.9 ± 1.6

8.2 ± 1.7

0.649

 Total cholesterol (mmol/L)

5.0 ± 1.2

4.2 ± 1.6

0.092

 Triglycerides (mmol/L)

2.3 ± 1.4

1.9 ± 0.8

0.349

 HDL cholesterol (mmol/L)

1.0 ± 0.4

1.2 ± 0.3

0.219

 LDL cholesterol (mmol/L)

3.2 ± 1.1

2.8 ± 1.3

0.443

DME diabetic macular edema, HDL high-density lipoprotein, LDL low-density lipoprotein

a p value <0.05 (independent t-test)

Table 4

Logistic regression analysis between patients with and without diabetic macular edema for variables associated with diabetic macular edema

Variable

OR (95% CI)

p value

Age

1.00 (0.97–1.04)

0.892

Duration of diabetes

1.00 (0.95–1.05)

0.843

Statin use

0.40 (0.17–0.90)

0.028a

HbA1c

0.98 (0.95–1.00)

0.091

Total cholesterol

1.11 (0.92–1.35)

0.289

Triglycerides

1.51 (1.06–2.14)

0.023a

HDL cholesterol

0.18 (0.04–0.80)

0.024a

LDL cholesterol

1.48 (0.89–2.44)

0.132

HDL high-density lipoprotein, LDL low-density lipoprotein

a p value <0.05 (logistic regression analysis)

We also examined serum lipid profiles and HbA1c levels from 6 months prior to 12 months after diagnosis of diabetic macular edema in all patients to investigate the effect of these variables on disease progression (Table 5). The results indicate that the levels of HbA1c, triglycerides, total cholesterol, and HDL cholesterol correlated with central retinal thickness. Specifically, the levels of triglycerides at 6 months prior to diabetic macular edema, HbA1c at the onset and 3 months prior to diabetic macular edema, and total cholesterol at the onset and 1 month prior to diabetic macular correlated positively with central retinal thickness; the HDL cholesterol level at 3 months prior to diabetic macular edema had a negative correlation with central retinal thickness. Furthermore, analysis using a generalized estimating equation indicated that only hypertriglyceridemia at 6 months prior to development of macular edema was associated with central retinal thickness (OR 1.52; 95% CI 1.14–2.02, p = 0.005). Taken together, these results indicate that hypertriglyceridemia is associated with the incidence and severity of diabetic macular edema in patients with type 2 diabetes who are taking statins.
Table 5

Correlation of serum variables with central retinal thickness in patients with diabetic macular edema

Variable

Months

R

p value

HbA1c

−3 M, 0 M

0.709

0.022a

Total cholesterol

−1 M, 0 M

0.516

0.028a

Triglycerides

−6 M

0.559

0.010a

HDL cholesterol

−3 M

−0.715

0.009a

LDL cholesterol

 

0.150

0.700

HDL high-density lipoprotein, LDL low-density lipoprotein. The time of diagnosis with diabetic macular edema is ‘0 M’, 1, 3, and 6 months prior to diabetic macular edema are presented as ‘−1 M’, ‘−3 M’, and ‘−6 M’

a p value <0.05 (Pearson correlation analysis)

Discussion

Dyslipidemia is common in patients with type 2 diabetes and is a well-known risk factor for atherosclerosis and cardiovascular diseases [24, 25]. Treatments that lower cholesterol, especially LDL cholesterol, reduce the risk of cardiovascular morbidity in many patient populations, although there are controversies on the overall benefits of intensive statin therapy [25, 26]. However, statin use seems to modestly increase the risk of new-onset type 2 diabetes in individuals with a pre-existing elevated risk for diabetes, probably because they increase insulin resistance and decrease insulin secretion [3, 4]. However, the benefits of reduced risk of cardiovascular disease probably outweigh the potentially increased risk of diabetes [1]. A recent large retrospective cohort study with a follow-up period of 6.5 years reported that statin use significantly increased the risk of new-onset diabetes and diabetic complications in healthy adults [5]. Thus, statin use may be a serious concern for individuals with predispositions for diabetes or pre-existing diabetes, but few studies have examined the effect of statins on diabetic microvascular complications, especially DR and diabetic macular edema.

The present study of patients with type 2 diabetes and DR shows that statin users have lower levels of LDL cholesterol than non-users. Notably, our results also show that statin therapy reduces the prevalence of diabetic macular edema in patients with type 2 diabetes and pre-existing DR, but does not contribute to the progression of DR. Considering that our statin users had a significantly longer duration of diabetes than non-users (Table 1), and that duration of diabetes is the strongest predictor for development and progression of DR [27], these results suggest that statins protect against the development of diabetic macular edema and progression of DR. Statins may protect against microvascular damage in patients with diabetes for several reasons. First, statins may benefit dyslipidemic patients with diabetes because they may reduce lipid leakage and improve lipid clearance in the eyes [28, 29]. Second, statins increase HbA1c in about 0.3% in patients with diabetes, so that may only cause relatively small exacerbations of diabetes [2]. Lastly, statins have anti-inflammatory effects, and this might slow the progression of microvascular complications in patients with diabetes [30, 31].

Previous studies showed that dyslipidemia is associated with diabetic macular edema [14, 32]. In addition, a global multicenter study reported that a high level of triglycerides and a low level of HDL cholesterol were associated with increased risk of diabetic microvascular diseases [33]. In our population, it is important to note that statin users with diabetic macular edema had a significantly higher level of triglycerides (p = 0.004) and a lower level of HDL cholesterol (p = 0.033) than those without diabetic macular edema, even though LDL cholesterol levels were well-controlled in both groups. A recent meta-analysis of cohort and case–control studies in patients with type 1 and 2 diabetes showed that serum triglyceride level was an independent risk factor for diabetic macular edema [20]. Moreover, a study of patients with type 1 diabetes reported no evidence of a relationship between oxidized LDL level and the incidence of diabetic macular edema or worsening of DR [34]. These findings motivated us to analyze the possible use of serum triglyceride level as a surrogate marker for macular edema in patients with type 2 diabetes. Indeed, serum triglycerides level at 6 months prior to the diagnosis of diabetic macular edema had a positive correlation with development of diabetic macular edema and with increased central retinal thickness in patients with diabetic macular edema. These results suggest that serum triglyceride level could be used as a surrogate marker for the development and severity of macular edema.

Our findings show that triglycerides and LDL cholesterol play important roles in the onset and severity of diabetic macular edema. Lipid lowering therapy with statins targets LDL cholesterol [7, 24, 25], but our findings indicate that the triglyceride level must also be controlled to prevent diabetic macular edema in patients with DR. Current treatment guidelines for dyslipidemia focus on LDL cholesterol and use of statin therapy [24, 25]. New guidelines released by the ACC/AHA in November 2013 recommend statin therapy for all patients with diabetes who are 40–75 years-old, have LDL cholesterol levels of 70 mg/dL or more, and have a 10-year risk of cardiovascular disease risk that is 7.5% or more, based on pooled cohort equations [7, 25]. These guidelines also suggest use of other therapies for patients with type 2 diabetes, such as fibrates, niacin, and/or fish oil, when the serum triglyceride level is moderately high despite statin use. Statin therapy can reduce triglycerides level by 10–20%, depending on the specific statins [35–39]. More specifically, rosuvastatin, atorvastatin, and especially pitavastatin are more effective in reducing triglyceride levels than the older statins [35–42]. The greatest benefit was seen in patients with high baseline triglyceride levels [35–42]. Furthermore, the combined use of statin and a fibrate (e.g. fenofibrate and bezafibrate) more effectively lowers serum triglycerides than statin therapy alone [43–45]. The ACCORD trial reported that fenofibrate provided no overall benefit for patients with type 2 diabetes when added to a statin, but it did improve outcomes in a subset of patients with elevated triglycerides (>204 mg/dL [2.30 mmol/L]) and low HDL cholesterol levels (<34 mg/dL [0.88 mmol/L]) [17, 46]. Based on these considerations, we suggest use of a statin with a supplemental therapy for patients with hypertriglyceridemia and DR to protect against diabetic macular edema.

Targeting triglycerides as a therapeutic indication for patients with type 2 diabetes would also help to reduce macrovascular complications such as cardiovascular events. Many epidemiological studies showed that DR is associated with macrovascular diseases in patients with type 2 diabetes [47]. Patients with type 2 diabetes and DR have an increased presence and number of plaques in the carotid territory [48]. The presence of dyslipidemia (elevated triglycerides and decreased HDL cholesterol) is associated with silent myocardial ischemia or angiographic coronary artery disease in asymptomatic patients with type 2 diabetes [49].

This study has several limitations. The small number of patients with diabetic macular edema is the major limitation. Thus, it might be difficult to generalize our results to other populations of patients with diabetic macular edema. However, our results showed significant relationships between serum triglycerides and diabetic macular edema, in agreement with the findings of the FIELD study and a recent meta-analysis of risk factors for diabetic macular edema [16, 20]. The present study also had a retrospective design, and the patients used different doses and different kinds of statins. These limitations could be overcome by performing a prospective randomized controlled trial. In addition, large and long-term randomized controlled prospective studies are needed to obtain a more complete risk/benefit assessment of the effect of statin therapy on DR and diabetic macular edema. Several previous trials have compared standard-dose versus high-dose statin therapy for prevention of cardiovascular diseases [50, 51]. Similar studies are needed for DR and diabetic macular edema.

Conclusions

In conclusion, use of statins by patients with type 2 diabetes and pre-existing DR did not increase the risk of DR progression, but was protective against development of diabetic macular edema. Hypertriglyceridemia is a potential surrogate marker for diabetic macular edema in patients with type 2 diabetes. Moreover, clinicians should closely monitor hypertriglyceridemia in patients with type 2 diabetes and taking statins. Use of a statin with a supplemental therapy (fenofibrate, niacin, and/or fish oil) should be considered for patients with DR to prevent the onset and reduce the severity of diabetic macular edema.

Notes

Abbreviations

ACC: 

American College of Cardiology

ACCORD: 

action to control cardiovascular risk in diabetes

AHA: 

American Heart Association

CI: 

confidence interval

DR: 

diabetic retinopathy

ETDRS: 

early treatment diabetic retinopathy study

FIELD: 

fenofibrate intervention and event lowering in diabetes

HDL: 

high-density lipoprotein

LDL: 

low-density lipoprotein

OCT: 

optical coherence tomography

OR: 

odd ratio

VEGF: 

vascular endothelial growth factor

Declarations

Authors’ contributions

YRC and SWP wrote the manuscript and performed the research. SYC, SWK and KYM performed the research. KL and JHK contributed to discussion of the results and reviewed/edited the manuscript. All authors read and approved the final manuscript.

Acknowledgements

This study was presented as a poster at the 2016 Annual Meeting of the American Society of Retina Specialists (ASRS), San Francisco, California, August 9–14, 2016.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable. The conclusions of the manuscript are based on relevant data available in the manuscript.

Ethics approval and consent to participate

This retrospective study was approved by the Institutional Review Board of Ajou University Hospital and complied with the Declaration of Helsinki.

Funding

This study was supported by the Pioneer Research Program of the National Research Foundation of Korea/Ministry of Education, Science and Technology (2012-0009544), and the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government, MSIP (NRF-2015M3A9E6028949).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Ophthalmology, Ajou University School of Medicine, 164 World Cup-ro, Yeongtong-gu, Suwon, 16499, South Korea
(2)
Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea
(3)
Department of Biomedical Sciences and Ophthalmology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea

References

  1. Robinson JG. Statins and diabetes risk: how real is it and what are the mechanisms? Curr Opin Lipidol. 2015;26:228–35.View ArticlePubMedGoogle Scholar
  2. Simsek S, Schalkwijk CG, Wolffenbuttel BH. Effects of rosuvastatin and atorvastatin on glycaemic control in Type 2 diabetes—the CORALL study. Diabet Med. 2012;29:628–31.View ArticlePubMedGoogle Scholar
  3. Shah RV, Goldfine AB. Statins and risk of new-onset diabetes mellitus. Circulation. 2012;126:e282–4.View ArticlePubMedGoogle Scholar
  4. Cederberg H, Stancakova A, Yaluri N, Modi S, Kuusisto J, Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015;58:1109–17.View ArticlePubMedGoogle Scholar
  5. Mansi I, Frei CR, Wang CP, Mortensen EM. Statins and new-onset diabetes mellitus and diabetic complications: a retrospective cohort study of US healthy adults. J Gen Intern Med. 2015;30:1599–610.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Nielsen SF, Nordestgaard BG. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol. 2014;2:894–900.View ArticlePubMedGoogle Scholar
  7. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1–45.View ArticlePubMedGoogle Scholar
  8. Bandello F, Lattanzio R, Zucchiatti I, Del Turco C. Pathophysiology and treatment of diabetic retinopathy. Acta Diabetol. 2013;50:1–20.View ArticlePubMedGoogle Scholar
  9. Wu L, Fernandez-Loaiza P, Sauma J, Hernandez-Bogantes E, Masis M. Classification of diabetic retinopathy and diabetic macular edema. World J Diabetes. 2013;4:290–4.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Madonna R, Giovannelli G, Confalone P, Renna FV, Geng YJ, De Caterina R. High glucose-induced hyperosmolarity contributes to COX-2 expression and angiogenesis: implications for diabetic retinopathy. Cardiovasc Diabetol. 2016;15:18.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Benarous R, Sasongko MB, Qureshi S, Fenwick E, Dirani M, Wong TY, Lamoureux EL. Differential association of serum lipids with diabetic retinopathy and diabetic macular edema. Invest Ophthalmol Vis Sci. 2011;52:7464–9.View ArticlePubMedGoogle Scholar
  12. Chew EY, Klein ML, Ferris FL 3rd, Remaley NA, Murphy RP, Chantry K, Hoogwerf BJ, Miller D. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early treatment diabetic retinopathy study (ETDRS) report 22. Arch Ophthalmol. 1996;114:1079–84.View ArticlePubMedGoogle Scholar
  13. Crosby-Nwaobi R, Chatziralli I, Sergentanis T, Dew T, Forbes A, Sivaprasad S. Cross talk between lipid metabolism and inflammatory markers in patients with diabetic retinopathy. J Diabetes Res. 2015;2015:191382.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Miljanovic B, Glynn RJ, Nathan DM, Manson JE, Schaumberg DA. A prospective study of serum lipids and risk of diabetic macular edema in type 1 diabetes. Diabetes. 2004;53:2883–92.View ArticlePubMedGoogle Scholar
  15. Romero-Aroca P, Baget-Bernaldiz M, Fernandez-Ballart J, Plana-Gil N, Soler-Lluis N, Mendez-Marin I, Bautista-Perez A. Ten-year incidence of diabetic retinopathy and macular edema. Risk factors in a sample of people with type 1 diabetes. Diabetes Res Clin Pract. 2011;94:126–32.View ArticlePubMedGoogle Scholar
  16. Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007;370:1687–97.View ArticlePubMedGoogle Scholar
  17. Knickelbein JE, Abbott AB, Chew EY. Fenofibrate and diabetic retinopathy. Curr Diab Rep. 2016;16:90.View ArticlePubMedGoogle Scholar
  18. Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363:233–44.View ArticlePubMedGoogle Scholar
  19. Action to Control Cardiovascular Risk in Diabetes Follow-On. Eye Study Group, action to control cardiovascular risk in diabetes follow-on study group. Persistent Effects of intensive glycemic control on retinopathy in type 2 diabetes in the action to control cardiovascular risk in diabetes (ACCORD) follow-on study. Diabetes Care. 2016;39:1089–100.View ArticleGoogle Scholar
  20. Das R, Kerr R, Chakravarthy U, Hogg RE. Dyslipidemia and diabetic macular edema: a systematic review and meta-analysis. Ophthalmology. 2015;122:1820–7.View ArticlePubMedGoogle Scholar
  21. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Ophthalmology. 1991;98:823–33.View ArticleGoogle Scholar
  22. Kinyoun J, Barton F, Fisher M, Hubbard L, Aiello L, Ferris F 3rd. Detection of diabetic macular edema. ophthalmoscopy versus photography—early treatment diabetic retinopathy study report number 5. The ETDRS Research Group. Ophthalmology. 1989;96:746–50.View ArticlePubMedGoogle Scholar
  23. Staurenghi G, Sadda S, Chakravarthy U, Spaide RF. Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: the IN*OCT consensus. Ophthalmology. 2014;121:1572–8.View ArticlePubMedGoogle Scholar
  24. Kim BK, Kim HC, Ha KH, Kim DJ. Application of new cholesterol guidelines to the Korean adult diabetic patients. J Korean Med Sci. 2015;30:1612–7.View ArticlePubMedPubMed CentralGoogle Scholar
  25. Phillips E, Saseen JJ. Current controversies with recent cholesterol treatment guidelines. J Pharm Pract. 2016;29:15–25.View ArticlePubMedGoogle Scholar
  26. Margolis KL, O’Connor PJ, Morgan TM, Buse JB, Cohen RM, Cushman WC, Cutler JA, Evans GW, Gerstein HC, Grimm RH Jr, et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial. Diabetes Care. 2014;37:1721–8.View ArticlePubMedPubMed CentralGoogle Scholar
  27. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL 3rd, Klein R. Retinopathy in diabetes. Diabetes Care. 2004;27(Suppl 1):S84–7.View ArticlePubMedGoogle Scholar
  28. Panagiotoglou TD, Ganotakis ES, Kymionis GD, Moschandreas JA, Fanti GN, Charisis SK, Malliaraki NE, Tsilimbaris MK. Atorvastatin for diabetic macular edema in patients with diabetes mellitus and elevated serum cholesterol. Ophthalmic Surg Lasers Imaging. 2010;41:316–22.View ArticlePubMedGoogle Scholar
  29. Gupta A, Gupta V, Thapar S, Bhansali A. Lipid-lowering drug atorvastatin as an adjunct in the management of diabetic macular edema. Am J Ophthalmol. 2004;137:675–82.PubMedGoogle Scholar
  30. Bu DX, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol. 2011;22:165–70.View ArticlePubMedGoogle Scholar
  31. Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012;18:1519–30.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Chew EY, Davis MD, Danis RP, Lovato JF, Perdue LH, Greven C, Genuth S, Goff DC, Leiter LA, Ismail-Beigi F, et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the action to control cardiovascular risk in diabetes (ACCORD) eye study. Ophthalmology. 2014;121:2443–51.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Sacks FM, Hermans MP, Fioretto P, Valensi P, Davis T, Horton E, Wanner C, Al-Rubeaan K, Aronson R, Barzon I, et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation. 2014;129:999–1008.View ArticlePubMedGoogle Scholar
  34. Klein BE, Myers CE, Howard KP, Klein R. Serum lipids and proliferative diabetic retinopathy and macular edema in persons with long-term type 1 diabetes mellitus: the Wisconsin epidemiologic study of diabetic retinopathy. JAMA Ophthalmol. 2015;133:503–10.View ArticlePubMedPubMed CentralGoogle Scholar
  35. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.View ArticlePubMedGoogle Scholar
  36. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–96.View ArticlePubMedGoogle Scholar
  37. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30.View ArticlePubMedGoogle Scholar
  38. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–7.View ArticlePubMedGoogle Scholar
  39. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas coronary atherosclerosis prevention study. JAMA. 1998;279:1615–22.View ArticlePubMedGoogle Scholar
  40. Chapman MJ. Pitavastatin: novel effects on lipid parameters. Atheroscler Suppl. 2011;12:277–84.View ArticlePubMedGoogle Scholar
  41. Ginsberg H. Statins in cardiometabolic disease: what makes pitavastatin different? Cardiovasc Diabetol. 2013;12(Suppl 1):S1.View ArticlePubMedPubMed CentralGoogle Scholar
  42. Jiang Z, Gong RR, Qiu L, Wang Q, Su M, Liu XJ, Hu MS, Lin J, Fang DZ. Efficacy and safety of pitavastatin versus simvastatin: a meta-analysis of randomized controlled trials. Clin Drug Investig. 2014;34:599–608.View ArticlePubMedGoogle Scholar
  43. Jones PH, Davidson MH, Kashyap ML, Kelly MT, Buttler SM, Setze CM, Sleep DJ, Stolzenbach JC. Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: a phase 3 study. Atherosclerosis. 2009;204:208–15.View ArticlePubMedGoogle Scholar
  44. Durrington PN, Tuomilehto J, Hamann A, Kallend D, Smith K. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia. Diabetes Res Clin Pract. 2004;64:137–51.View ArticlePubMedGoogle Scholar
  45. Arbel Y, Klempfner R, Erez A, Goldenberg I, Benzekry S, Shlomo N, Fisman EZ, Tenenbaum A. Bezafibrate for the treatment of dyslipidemia in patients with coronary artery disease: 20-year mortality follow-up of the BIP randomized control trial. Cardiovasc Diabetol. 2016;15:11.View ArticlePubMedPubMed CentralGoogle Scholar
  46. Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.View ArticlePubMedGoogle Scholar
  47. Papa G, Degano C, Iurato MP, Licciardello C, Maiorana R, Finocchiaro C. Macrovascular complication phenotypes in type 2 diabetic patients. Cardiovasc Diabetol. 2013;12:20.View ArticlePubMedPubMed CentralGoogle Scholar
  48. Alonso N, Traveset A, Rubinat E, Ortega E, Alcubierre N, Sanahuja J, Hernandez M, Betriu A, Jurjo C, Fernandez E, et al. Type 2 diabetes-associated carotid plaque burden is increased in patients with retinopathy compared to those without retinopathy. Cardiovasc Diabetol. 2015;14:33.View ArticlePubMedPubMed CentralGoogle Scholar
  49. Valensi P, Avignon A, Sultan A, Chanu B, Nguyen MT, Cosson E. Atherogenic dyslipidemia and risk of silent coronary artery disease in asymptomatic patients with type 2 diabetes: a cross-sectional study. Cardiovasc Diabetol. 2016;15:104.View ArticlePubMedPubMed CentralGoogle Scholar
  50. Ueshima K, Itoh H, Kanazawa N, Komuro I, Nagai R, Takeuchi M, Yamazaki T. Rationale and design of the standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy (EMPATHY) study: a randomized controlled trial. J Atheroscler Thromb. 2016.Google Scholar
  51. de Vries FM, Kolthof J, Postma MJ, Denig P, Hak E. Efficacy of standard and intensive statin treatment for the secondary prevention of cardiovascular and cerebrovascular events in diabetes patients: a meta-analysis. PLoS ONE. 2014;9:e111247.View ArticlePubMedPubMed CentralGoogle Scholar

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Cardiovascular Diabetology

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