Targeting atherogenic dyslipidemia to reduce residual microvascular risk

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7 December 2012

Despite best evidence-based medicine, there is a high residual risk of microvascular complications, including retinopathy, nephropathy or neuropathy, in type 2 diabetes patients. This analysis of data from more than 70,000 subjects showed that targeting atherogenic dyslipidemia may offer the potential to impact this high burden of disease.

Toth PP, Simko RJ, Palli SR et al. The impact of serum lipids on risk for microangiopathy in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2012;11:109

STUDY SUMMARY

Objective

To evaluate associations between the levels of lipid subfractions (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and non-HDL cholesterol) and the incidence of diabetic retinopathy, peripheral neuropathy and nephropathy.

Study design

Observational cohort study based on data from the HealthCore Integrated Research Database (2004-2010).

Study population

72,267 patients (mean ± SD age 49.9 ± 9.4 years, 48.7% female), with newly-diagnosed type 2 diabetes or a first claim for prescription of a glucose-lowering medication (2005-20010), and at least one full lipid panel 12 months previously. Baseline lipids (mg/dL) are summarised.

Lipid	Mean ± SD	% at goal
LDL cholesterol	116 ±36	64%
HDL cholesterol	47 ± 14	50%
Triglycerides	187 ± 177	60%
Non-HDL cholesterol	151 ± 44	57%

Primary variable

Microvascular complications, i.e. diabetic neuropathy, retinopathy and nephropathy, defined according to International Classification of Diseases 9, Current Procedural Terminology or revenue service codes. Diabetic nephropathy was also identified using estimated glomerular filtration rate calculated from serum creatinine values.

Secondary variables

Lipids: LDL, HDL and non-HDL cholesterol and triglycerides
Guideline-defined lipid targets
- LDL cholesterol <100 mg/dL (2.5 mmol/L)
- HDL cholesterol >40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women
- Triglycerides <150 mg/dL (1.7 mmol/L)
- Non-HDL cholesterol <130 mg/dL ( mmol/L)

Methods

Multivariate Cox proportional hazards models were used to investigate the relative significance of lipid subfractions and achievement of lipid goals on the risk of diabetic microvascular complications. Univariate sensitivity analysis was used to investigate the independence of the association between the triglycerides/HDL and risk for microvascular complications.

Main results

Over a mean follow-up of 21.7 months, there were 5.21 microvascular events (1.44 cases of diabetic retinopathy, 1.26 cases of diabetic neuropathy and 2.61 cases of diabetic nephropathy) per 1000 patient-months
Patients achieving each lipid goal had a significantly lower risk of microvascular complications (see Table).
Notably, patients achieving target HDL cholesterol level had an 11% decrease in risk compared with non-achievers; those achieving target triglyceride level had a 15% decrease in risk versus non-achievers

	Microvascular events/ 1000 patient-months		RR (95%) for event	p-value
	At goal	Not at goal	RR (95%) for event	p-value
LDL-C	5.17	5.24	0.91 (0.87-0.96)	0.0001
TG	4.71	5.97	0.85 (0.81-0.89)	<0.001
Non-HDL-C	4.83	5.52	0.83 (0.79-0.87)	<0.001
HDL-C	4.73	5.76	0.89 (0.85-0.94)	<0.001

TG triglycerides; RR relative risk

Irrespective of attainment of LDL-C goal, reduction in the risk of microvascular events was greatest (22-24%) in patients who achieved both HDL cholesterol and triglyceride target levels

Author's conclusion

Goal-attainment of atherogenic dyslipidemia components beneficially may impact the risk for microvascular events among patients with type 2 diabetes.

COMMENT

Previous evidence has highlighted the relationship between atherogenic dyslipidemia, the combination of elevated triglycerides and low HDL cholesterol, with microvascular risk in type 2 diabetes.1-4 In a study by Zoppini et al (2012),2 previously highlighted by the R3i, the triglycerides-HDL cholesterol ratio was shown to be an important prognostic index of risk for microvascular disease, beyond blood glucose and blood pressure, in patients with type 2 diabetes. Individuals with a high triglycerides-HDL cholesterol ratio had about twice the risk of new-onset microvascular events compared with those with a lower ratio.

Adding to these findings, the current study shows that in a real-world managed care setting achieving recommended targets for triglycerides and HDL cholesterol has the potential to substantially impact the risk of diabetic microvascular complications. Even in patients with type 2 diabetes at LDL cholesterol goal, there was a further 24% reduction in risk of microvascular events. Indeed, the study showed no clear association between achievement of the recommended goal for LDL cholesterol and risk for diabetic microvascular events.

The study does have a number of limitations, including the possibility of miscoding of claims (and hence events), and limited duration of follow-up (<2 years). Despite these caveats, the data highlight the relevance of expanding lipid treatment goals beyond LDL cholesterol in this predominantly working-age patient population. Thus, effective management of atherogenic dyslipidemia, in addition to current standards of care for LDL cholesterol, blood pressure and glycaemia, has the potential to impact the substantial burden of residual microvascular risk in type 2 diabetes.

Given the escalating epidemic of type 2 diabetes, with more than 371 million currently affected world-wide,5 these data provide new support for targeting atherogenic dyslipidemia to reduce the high residual microvascular risk that persists in patients with type 2 diabetes.

References

1. Press release. New Insights Link Low HDL-Cholesterol and Elevated Triglycerides with Coronary Heart Disease and Microvascular Complications in Patients at Goal for LDL-Cholesterol. Available from http://www.r3i.org/press/pressreleases.asp
2. Zoppini G, Negri C, Stoico V, Casati S, Pichiri I, Bonora E. Triglyceride-high-density lipoprotein cholesterol is associated with microvascular complications in type 2 diabetes mellitus. Metabolism 2012;61:22-9.
3. Fioretto P, Dodson PM, Ziegler D, Rosenson RS. Residual microvascular risk in diabetes: unmet needs and future directions. Nat Rev Endocrinol 2010;6:19-25.
4. Teramoto T, Shirai K, Daida H, Yamada N: Effects of bezafibrate on lipid and glucose metabolism in dyslipidemic patients with diabetes: the JBENEFIT study. Cardiovasc Diabetology 2012, 11:29.
5. International Diabetes Federation. IDF Diabetes Atlas, 5th edition. Available at http://www.idf.org/diabetesatlas/5e/Update2012. Accessed 11 December, 2012.