CHICAGO – Serum osteoprotegerin is an independent predictor of both cardiovascular complications and peripheral vascular disease in type 1 diabetes, according to an analysis of a large prospective Finnish cohort.

Previous studies have suggested that high levels of the glycoprotein are associated with cardiovascular mortality in patients with diabetes, but the Finnish Diabetic Nephropathy (FinnDiane) study is the first to show an independent link between osteoprotegerin (OPG) and incident peripheral vascular disease. The findings come from a retrospective analysis of 1,939 patients with type 1 diabetes in the FinnDiane database.

Baseline serum OPG levels were significantly higher in the 80 patients who underwent amputation or peripheral revascularization than in those who did not (2.0 vs. 1.6 mg/L).

Increased OPG was a significant, independent risk marker for amputation or peripheral revascularization in multivariate analysis after adjustment for other associated factors (hazard ratio, 1.46), Dr. Daniel Gordin reported at the annual scientific sessions of the American Diabetes Association.

Baseline OPG levels were also significantly elevated in the 166 patients who suffered a first-ever cardiovascular event, compared with those with no event (2.2 vs. 1.6 mg/L). This association remained significant after adjustment for factors associated with cardiovascular disease and OPG concentrations.

Osteoprotegerin, a member of the inflammatory tumor necrosis factor superfamily, is increased in patients with coronary artery disease and is associated with the degree of arterial stiffness, explained Dr. Gordin of the division of nephrology, Helsinki (Finland) University Central Hospital.

A recent study reported that a high OPG level was an independent risk marker of all-cause mortality in hemodialysis patients and cardiovascular disease (Clin. Nephrol. 2013 Apr 2 [Epub ahead of print]).

In the current study, serum OPG levels were elevated only in patients with macroalbuminuria and/or moderate to severe renal disease. Patients with end-stage disease were excluded from the analysis.

Patients with established cardiovascular disease also had higher OPG concentrations, but this was attributable to an excess of patients with chronic kidney disease and eliminated after adjustment for renal function.

OPG remained independently correlated, however, after adjustment for renal function, with high C-reactive protein, a marker of systemic inflammation, and with hemoglobin A_1c, according to study data simultaneously published online (Diabetes Care 2013;36:1827-33).

The investigators followed patients for an average of 10.4 years, and verified events and mortality from hospital discharge registries and the Finnish National Death Registry.

To no surprise, patients with macroalbuminuria and high levels of OPG at baseline were at the highest risk for cardiovascular disease events, while those with normoalbuminuria and low OPG levels were at lowest risk, Dr. Gordin said.

"However, patients with a normal urinary albumin excretion rate and high OPG concentrations, and microalbuminuric patients with high OPG concentrations, were at a similar risk for cardiovascular disease events, suggesting a predictive role of OPG on top of the associated covariates," he added.

Although patients with incident coronary heart disease and stroke had elevated baseline OPG levels, the association with OPG was not significant after correction for associated covariates.

Finally, OPG concentrations were significantly higher in the 566 patients who died during follow-up than in those who stayed alive (2.0 vs. 1.6 mg/L, but, again, the association between OPG and all-cause mortality lost statistical significance after adjustment.

Dr. Gordin observed that experimental data support a causal link between OPG and the development of cardiovascular complications. Thus, it’s possible that blocking the actions of OPG slows the development and progression of vascular disease in diabetes. In mice, however, complete blockage of OPG causes early onset of osteoporosis and arterial calcification, suggesting that a better target for prevention may be to augment its ligands, RANKL (receptor activator of nuclear factor-kappa B ligand) and TRAIL (tumor necrosis factor-alpha–related apoptosis-inducing ligand). Indeed, studies using TRAIL in apolipoprotein E knockout mice with type 1 diabetes have already reported promising reductions in atherogenesis, the authors noted.

Session moderator Dr. William Cefalu, chief and professor of endocrinology, diabetes, and metabolism at Louisiana State University, New Orleans, said in an interview that the results are interesting but that more information is needed, particularly on the impact of glucose control on OPG levels over time.

"HbA_1c is going to vary day to day, so when you talk about one measure that predicts something over 7-10 years, what’s going to be the yearly variation because of glycemic control? That’s my question," he said.

The study was supported by grants from several Finnish foundations, Helsinki University Central Hospital, the Finnish Medical Society, and the Diabetes Research Foundation. Dr. Gordin reported having no financial disclosures.

pwendling@frontlinemedcom.com

Osteoprotegerin ups risk of vascular events in type 1 diabetes