Determinants of vitamin B12 deficiency in patients with type-2 diabetes mellitus - A primary-care retrospective cohort study

Abstract

Background: Like many developed nations, the prevalence of both older people and type-2 diabetes mellitus (T2DM) in Singapore is rising. This demographic shift predisposes the population to greater risks of both frailty and its complications that can be further aggravated by vitamin B12 deficiency -a highly prevalent associated variable that is potentially modifiable. Indeed, B12 deficiency adversely impacts the neuro-cognitive, haematological, and even the immune systems; jeopardizing our aspirations for successful aging. Despite this, many patients with T2DM in primary care remain unscreened due to a lack of clear guidelines for regular B12 screening. We therefore investigated the determinants of B12 deficiency in community-dwelling patients with T2DM, with the aim of profiling patients most in need of B12-deficiency screening.

Methods: B12 deficiency was evaluated using a retrospective cross-sectional cohort of 592 primary-care patients with T2DM, recruited from 2008 to 2011 from a Polyclinic in Singapore.

Results: B12 deficiency (serum B12 < 150 pmol/L) was present in 164 (27.7%) patients and was associated with a higher "metformin daily dose" (OR = 2.79; 95% CI, 2.22-3.48, P < 0.001); "age ≥ 80 years" (OR = 2.86; 95% CI, 1.31-6.25, P = 0.008); "vegetarianism" (OR = 21.61; 95% CI, 4.47-104.44, P < 0.001); and "folate deficiency" (OR = 2.04; 95% CI, 1.27-3.28, P = 0.003). Conversely, "Prescribed B12 supplementation" was associated with a lower odds of B12 deficiency (OR = 0.37; 95% CI: 0.22-0.61, P < 0.001). The area under the receiver operating characteristic curve was 0.803 (95% CI: 0.765-0.842). "Metformin daily dose" correlated interchangeably with "Metformin 1-year cumulative dose" (r = 0.960; P < 0.01), and also associated linearly with "duration of diabetes" (B = 0.113, P < 0.0001). Independent of the duration of T2DM, 29.3% of the B12-deficient patients needed > 1 screening test before the detection of B12 deficiency.

Conclusions: Primary-care screening for B12 deficiency should be part of the annual laboratory review of patients with T2DM regardless of the duration of T2DM -especially when they are prescribed ≥ 1.5 g/day of metformin; ≥ 80 years old; vegetarian; and not prescribed B12 supplementation. Concurrent evaluation for associated folate (vitamin B9) deficiency is essential when addressing T2DM-associated B12 deficiencies. Current "Metformin daily dose" is an accurate proxy of both cumulative metformin exposure and duration of T2DM.

Keywords: COVID-19; Elderly; Folate deficiency; Metformin; Vegetarianism; Vitamin B12 deficiency.

Fig. 1

Correlation of “Metformin daily dose” and “Metformin 1-year cumulative dose” (n = 592). The 1^st variable gives a convenient cross-sectional estimate of metformin exposure whilst the 2^nd variable gives a more accurate cumulative measure of metformin exposure

Fig. 2

Box plot of Metformin daily dose (g/day) by age groups (n = 592). This shows the oldest age group (age ≥ 80 years) taking significantly less metformin daily than the youngest age group (age < 60 years) (P < 0.001); Age is thus a confounder in Metformin daily dose’s association with B12 deficiency

Fig. 3

Adjusted probability of “B12 deficiency” by “metformin daily dose” (g/day) (with 95% confidence intervals; n = 592). The probabilities are adjusted for age groups, vegetarianism, folate deficiency and prescribed B12 supplementation; showing increasing probability of B12 deficiency at higher daily doses of metformin

Fig. 4

Scatterplot of serum B12 levels and their corresponding daily metformin doses (g/day) (n = 592). This shows the mean serum B12 levels (with 95% confidence intervals) of patients decreasing consistently as they take higher daily doses of metformin

Fig. 5

Mean “Metformin daily dose” by the “duration of type-2 diabetes mellitus” (with 95% confidence intervals; n = 592). This shows a strong linear association in bivariate regression (B = 0.113, F(1,590) = 99.74, P < 0.0001)

Fig. 6

Number of additional screening tests needed before the diagnosis of B12 deficiency (through the “reference B12 test”) by duration of type-2 diabetes mellitus (n = 164 B12-deficient patients). This indicates the need for repeated screening of these patients for B12 deficiency