FinnDiane study: atherogenic dyslipidaemia and diabetic retinopathy in type 1 diabetes

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13 January 2014

Findings from the FinnDiane study showed that mild non-proliferative diabetic retinopathy was independently associated with triglycerides in type 1 diabetes mellitus.

olonen N, Hietala K, Forsblom C, Harjutsalo V, Mäkinen VP, Kytö J, Summanen PA, Thorn LM, Wadén J, Gordin D, Taskinen MR, Groop PH; FinnDiane Study Group. Associations and interactions between lipid profiles, retinopathy and nephropathy in patients with type 1 diabetes: the FinnDiane Study. J Intern Med;274:469-79.

STUDY SUMMARY

Objective

To investigate the associations between lipid profiles and retinopathy in the large nationwide FinnDiane Study. Interactions between retinopathy, nephropathy and lipid variables were also investigated.

Study design

Cohort analysis of the Finnish Diabetic Nephropathy (FinnDiane) study, a multicentre, prospective observational study in patients with type 1 diabetes.

Study population

A total of 1,465 patients with type 1 diabetes (defined as diabetes onset <35 years and permanent insulin treatment initiated within 1 year of diagnosis) and with retinopathy status and complete lipid profiles were included in this analysis.

Primary variable

Association between lipid variables (triglycerides, total cholesterol, non-high-density lipoprotein (HDL) cholesterol, low-density lipoprotein [LDL] cholesterol, apolipoprotein [apo] B, HDL cholesterol, apoA-I, and ratios of total/HDL cholesterol, triglycerides/HDL cholesterol and apoB/apoA-I) and retinopathy status

Methods

The severity of diabetic retinopathy was graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, as none, mild nonproliferative diabetic retinopathy (NPDR), moderate to severe NPDR, or proliferative diabetic retinopathy (PDR). The eye with the more severe disease was used to determine retinopathy stage. Nephropathy status was based on measurement of the albumin excretion ratio (AER) in at least 2 of 3 consecutive overnight or 24-hour (h) urine collections, and was graded as normal (AER <20 μg/min or <30 mg/24 h); microalbuminuria (AER ≥20 and <200 μg/min or ≥30 and <300 mg/24 h); or macroalbuminuria (AER ≥200 μg/min or ≥300 mg/24 h).

Multiple logistic regression analyses were performed with PDR or mild NPDR as the dependent variables, using a model including diabetes duration, age at onset of diabetes, sex, HbA1c, systolic blood pressure, body mass index, history of smoking, estimated glomerular filtration rate (eGFR), AER and the lipid variables (included one at a time). Non-normally distributed values were logarithmically transformed before inclusion in the models (AER, triglycerides and the ratios of total/HDL cholesterol and triglycerides/HDL cholesterol). To investigate the effect of lipid variables on AER depending on the severity of DR, interaction terms between retinopathy status and lipid variables were included in linear regression models, with the natural logarithm (ln) of AER as the dependent variable.

Main results

Overall, more than 50% of patients had either no signs of DR or mild NPDR. These patients had a shorter duration of diabetes, lower systolic blood pressure, non-HDL cholesterol and AER and higher estimated glomerular filtration rate (eGFR) than those with PDR (Table 1).
Table 1. Patient characteristics

	No DR (n=381)	Mild NPDR (N=405)	Moderate-severe NPDR (n=186)	PDR (n=493)
Male	52%	44%	66%	54%
Mean age, yr	30.4	36.4	39.1	41.7
Mean duration of diabetes, yr	12.0	22.8	25.4	30.3
SBP, mmHg	127±14	130±17	136±18	143±20
Mean HbA1c, %	8.0	8.5	8.9	8.6
Lipids, mmol/L*
Non-HDL-C	3.25 ± 0.89	3.64 ± 1.00	3.86 ± 0.96	4.08 ± 1.13
LDL-C	2.77 ± 0.81	3.08 ± 0.87	3.22 ± 0.77	3.36 ± 0.95
HDL-C
Men	1.26 ± 0.29	1.19 ± 0.32	1.22 ± 0.34	1.14 ± 0.37
Women	1.43 ± 0.37	1.46 ± 0.40	1.37 ± 0.43	1.28 ± 0.32
Triglycerides	0.93 (0.70-1.27)	1.03 (0.77-1.40)	1.12 (0.83-1.50)	1.26 (0.94-1.90)
AER (mg/24 h)	8 (6-13)	11 (7-28)	31 (11-144)	135 (18-260)
eGFR (ml/min/1.73 m2)	93±20	82±21	79±28	59±31
Antihypertensive therapy	11%	27%	53%	78%
Lipid-lowering therapy	2%	7%	12%	20%

Data are given as mean ±SD or median (interquartile range) except where indicated
* To convert triglycerides to mg/dL multiple by 88.5; to convert other lipids to mg/dL multiply by 38.7.

Mild NPDR was independently associated with triglycerides and the triglycerides/HDL cholesterol ratio, and HDL cholesterol was inversely associated with PDR, independently of conventional risk factors and nephropathy status (Table 2).
Table 2. Factors associated with DR

	Factor	Hazard ratio (95% CI)	p-value
Mild NPDR	Diabetes duration	1.16 (1.12-1.19)	<0.001
	HbA1c	1.33 (1.14-1.56)	<0.001
	ln triglycerides	1.86 (1.18-2.93)	0.008
	ln AER	1.41 (1.14-1.75)	0.001
	eGFR	0.81 (0.71-0.93)	0.002

PDR	Diabetes duration	1.11 (1.09-1.14)	<0.001
	HDL cholesterol	0.45 (0.27-0.74)	0.002
	ln AER	1.57 (1.41-1.75)	<0.001
	eGFR	0.88 (0.81-0.96)	0.003

ln Logarithmically transformed data

In analyses exploring the interaction between retinopathy status, lipid variables and nephropathy (adjusted for other conventional risk factors), patients with triglycerides in the highest quartile (>1.52 mmol/L) or HDL cholesterol in the lowest quartile (<1.04 mmol/L) and moderate to severe NPDR or DR had a high AER.

Author's conclusion

Elevated blood triglycerides were dose-dependently associated with a greater risk of both CVD and all-cause mortality. These findings suggest that controlling triglycerides can help to prevent CVD and other causes of death.

COMMENT

Retinopathy due to type 1 diabetes mellitus is an important public health problem. Data from Denmark indicate that nine out of every ten patients diagnosed with type 1 diabetes develop DR over time, and that ~20-30% of these patients subsequently progress to proliferative DR in the long-term, despite guideline-recommended standards of care for glycaemic, blood pressure and LDL cholesterol control.1,2 Clearly there is an unmet need to address the residual risk of diabetic retinopathy in type 1 diabetes.

This report from the FinnDiane study, a large observational study in individuals with type 1 diabetes from a Northern European country has shown an association between triglycerides, a marker for triglyceride-rich lipoproteins, and HDL cholesterol - atherogenic dyslipidaemia - and DR. Of particular interest is the association between triglycerides and mild NPDR. The study findings are strengthened by the size and general homogeneity of the study cohort, robust definition of both DR and nephropathy and the use of a central laboratory to assess lipids. The study does not, however, provide any insights into possible mechanism(s) which may explain the association between triglycerides and early-stage DR.

Type 1 diabetes is differentiated from type 2 diabetes in that it is a chronic autoimmune disease characterised by insulin deficiency. While not typically associated with obesity, insulin resistance and hypertriglyceridaemia, the increasing prevalence of obesity and dyslipidaemia is also affecting individuals with type 1 diabetes. Indeed, in a recent study in type 1 diabetes patients, about 11% had triglycerides >1.7 mmol/L or 150 mg/dL; metabolic control was also worse in these patients than in those with low to normal triglycerides.3 This scenario suggests that considering the metabolic risk factor profile of patients as a whole, including non-LDL lipids, may contribute to better assessment of microvascular complications risk. Indeed, this strategy is further supported by data from Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) cohort, in which the severity of retinopathy was positively associated with triglycerides and negatively associated with HDL cholesterol.4 However, it is still unclear whether triglyceride-rich lipoproteins play a role in the pathogenesis of diabetic retinopathy, and if so, how they are involved.

In type 2 diabetes, there is robust evidence that fenofibrate, a peroxisome proliferator–activated receptor α (PPARα) agonist, has protective effects against DR,5,6 supporting its recent approval as an adjunctive therapy to prevent progression in early-stage DR. Whether fenofibrate has similar effects in patients with type 1 diabetes is not known, although studies in animal models of type 1 diabetes suggest potential benefit.7 Given that intraocular injection of fenofibrate reduced retinal vascular leakage in these models suggests that the protective effects of fenofibrate are independent of its systemic effects.

Thus, the current report is hypothesis-generating with respect to the role of triglycerides as a contributor to the residual risk of diabetic retinopathy in type 1 diabetes. The Residual Risk Reduction Initiative calls for further study to substantiate these findings; investigate whether targeting elevated fasting and/or postprandial triglycerides or the corresponding triglyceride-rich lipoproteins can impact the progression of DR in patients with diabetes; and if so, elucidate the underlying mechanisms.

References

1. Skrivarhaug, T.; Fosmark, D. S.; Stene, L. C.; Bangstad, H.-J.; Sandvik, L.; Hanssen, K. F.; Joner, G. Low cumulative incidence of proliferative retinopathy in childhood-onset type 1 diabetes: a 24-year follow-up study. Diabetologia . Oct2006, Vol. 49 Issue 10, p2281-90.
2. Broe R, Rasmussen ML, Frydkjaer-Olsen U, Olsen BS, Mortensen HB, Peto T, Grauslund J. The 16-year incidence, progression and regression of diabetic retinopathy in a young population-based Danish cohort with type 1 diabetes mellitus: The Danish cohort of pediatric diabetes 1987 (DCPD1987). Acta Diabetol 2013 Nov 6. [Epub ahead of print].
3. Alcantara LM, Silveira NE, Dantas JR et al. Low triglyceride levels are associated with a better metabolic control in patients with type 1 diabetes. Diabetology & Metabolic Syndrome 2011, 3:22 doi:10.1186/1758-5996-3-22.
4. Lyons TJ, Jenkins AJ, Zheng D, Lackland DT, McGee D, Garvey WT, Klein RL. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 2004;45:910-8.
5. Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d'Emden MC, Crimet DC, O'Connell RL, Colman PG, FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97.
6. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, Goff DC Jr, Cushman WC, Ginsberg HN, Elam MB, Genuth S, Gerstein HC, Schubart U, Fine LJ. . Effects of medical therapies on retinopathy progression in type 2 diabetes. New Engl J Med 2010;363:233-44.
7. Chen Y, Hu Y, Lin M, Jenkins AJ, Keech AC, Mott R, Lyons TJ, Ma JX. Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models. Diabetes 2013;62: 261-72.