High Lipoprotein(a) Levels in Type 1 Diabetes Add to CVD Risk

In an observational registry study of Swedish outpatients with type 1 diabetes, those who had high plasma lipoprotein(a) [Lp (a)] levels — defined as >120 nmol/L or approximately 50 mg/dL — were more likely to have albuminuria, calcified aortic valve disease, or a composite measure of cardiovascular disease.

And patients whose blood glucose level (A_1C<6.9%) was well controlled had lower Lp(a) levels.

The study, led by Karin Littmann, a PhD student in the Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden, was published December 18 in Diabetes Care.

"The identified CVD risk level for Lp(a) of 120 nmol/L and the association between Lp(a) and aortic valve disease are novel findings" for patients with type 1 diabetes, the group writes.

These results show that high levels of Lp(a) in patients with type 1 diabetes "add to [their] already elevated risk of developing cardiovascular disease," said Littman in a statement issued by the Karolinska Institute.

"Levels of these blood lipids should therefore be measured and should form part of [their] total risk assessment," according to Littmann.

Because there is currently no readily available therapy to effectively lower Lp(a) levels, "treatment of all other risk factors for cardiovascular disease should be optimized for patients with type 1 diabetes and high levels of lipoprotein(a)," she urges.

Lp(a) Levels in Type 1 Diabetes

Plasma Lp(a) levels are largely determined by genes and ethnicity and are much less affected by age, gender, or diet, the authors write.

High Lp(a) levels (>120 nmol/L or approximately 50 mg/dL) are associated with a significantly increased risk for coronary heart disease, calcified aortic valve disease, and peripheral artery disease.

In one other recent study, having type 2 diabetes and high Lp(a) levels was associated with a 3.5-fold higher risk for a cardiovascular event compared to having no diabetes or a low Lp(a) level (<24 nmol/L or approximately 10 mg/dL) (Jin JL et al. Diabetes Care . 2019;42:1312-1318), Littmann and colleagues note.

To study this relationship in type 1 diabetes, they identified 1860 outpatients with type 1 diabetes who were seen in their hospital clinic from August 2017 to October 2018 and who underwent testing to determine plasma Lp(a) levels.

The median age of the patients was 48 years, and they had had diabetes for a median of 25 years. The cohort included slightly more men (56%) than women.

Although most patients (69%) had never smoked, 18% were current smokers, and 13% had smoked in the past.

The patients' median A_1C level was 7.7%.

A third of the patients had very low plasma Lp(a) levels (<10 nmol/L); 27% had low levels (10 – 30 nmol/L); 23% had intermediate levels (30 – 120 nmol/L), and 16% had high levels (>120 nmol/L).

Few patients had coronary heart disease (6.9%), cerebrovascular disease (3.4%), calcified aortic valve disease (4.7%), or diabetic foot disease (a surrogate for peripheral artery disease; 4.1%); 13% had albuminuria.

After correcting for age and smoking, compared to patients who had very low levels of Lp(a), those with high Lp(a) levels were significantly more likely to have calcified aortic valve disease (adjusted risk ratio, 2.03), diabetic foot ulcer (1.51), albuminuria (1.68), or a composite of coronary heart disease, cerebrovascular disease, and diabetic foot ulcer (1.51).

The researchers acknowledge that study limitations include the fact that it was observational, so it cannot show cause and effect.

In addition, only nine patients exhibited overt cardiovascular disease, and for 5% of patients, Lp(a) measurements were made in a different laboratory using a test other than an immunoassay.

Antisense Oligonucleotide, a Potential Future Therapy?

Littmann and colleagues nevertheless point out that Lp(a) is "emerging as a clinically important target with new pharmacologic treatments with antisense oligonucleotides currently being developed to significantly reduce Lp(a) levels."

As previously reported, promising phase 2b trial results of antisense oligonucleotide AKCEA-APO(a)-LRX (Akcea Therapeutics/Ionis Pharmaceuticals) were presented at the American Heart Association Scientific Sessions 2018.

Such a therapy "would, if proven effective and safe, possibly be a treatment option for this patient group with [type 1 diabetes and] high inherent CVD risk," Littman and colleagues conclude.

The study was supported by grants from the Swedish Heart-Lung Foundation, the Swedish Research Council, the Karolinska Institute, and Sanofi. The authors have disclosed no relevant financial relationships.

Diabetes Care. Published December 18, 2019. Abstract

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