Vitamin B12 deficiency in long-term metformin treated type 2 diabetic patients: Prevalence and risk factors in a Tunisian population

Abstract

Objectives: To determine the prevalence of vitamin B12 deficiency in a Tunisian population with type 2 diabetes (T2D) on metformin treatment for more than three years and to identify its risk factors. Methods: This is a cross-sectional study conducted on 257 patients with T2D treated with metformin for at least three years. Patients were divided into two groups according to their vitamin B12 status. Low vitamin B12 was defined as ≤ 203 pg/mL. Results: The mean age of the patients was 59.8 ± 7.9 years. The mean duration of metformin use was 10.2 ± 5.2 years. The mean vitamin B12 level was 294.9 ± 156.4 pg/mL. The prevalence of vitamin B12 deficiency was 28.4%. Male gender, HbA1c < 7% and hyperhomocysteinemia were significantly associated with vitamin B12 deficiency (respectively p = 0.02, p < 0.001, p < 0.001). Homocysteine level was negatively correlated with vitamin B12 level ( r = −0.2, p = 0.001). Dose and duration of metformin treatment, peripheral neuropathy and anemia were not associated with vitamin B12 deficiency. On multivariate analysis, HbA1c < 7% and hyperhomocysteinemia were independently associated with vitamin B12 deficiency (respectively OR = 3.2, 95%CI = [1.6–6.3] and OR = 2.3, 95%CI = [1.2–4.2]). Discussion: The prevalence of vitamin B12 deficiency in patients with T2D on metformin treatment was high. Hyperhomocysteinemia is associated with vitamin B12 deficiency suggesting that the deficit occurs at the tissue level.

Serum vitamin B12, distal symmetrical polyneuropathy and anaemia in type 2 diabetes: the Fremantle Diabetes Study Phase 2

“…The use of mostly over-the-counter vitamin B12 supplementation by FDS2 participants was low (<4%) and not significantly different by serum vitamin B12 status, suggesting that this was not a confounding factor. Although consistent with most previous studies, [9][10][11][12][13][14][15][16] we found no evidence that metformin therapy was associated with DSPN, whether through vitamin B12 deficiency or other mechanisms, there was a graded relationship between metformin dose category and both vitamin B12 deficiency and anaemia that was independent of confounding factors in our participants. Such a dose-response relationship has been found previously for serum vitamin B12 deficiency, 1 especially daily doses ≥2000 mg, but the association between metformin therapy and anaemia is less clear.…”

“…Although some of our participants with a total vitamin B12 <200 pmol/L had an active B12 >35 pmol/L and were thus not categorised as deficient, this is below the 7.4-28.8% range in published studies employing a similar <200 pmol/L total serum vitamin B12 concentration cut point. 5,6,14,16 In a developed country such as Australia, greater nutritional sources likely counteract metformin-associated vitamin B12 malabsorption (and the additional potential influence of PPI use) compared to the situation in the developing world where the highest rates of metformin-associated deficiency have been reported. 14,16 As a corollary to this, vitamin B12 deficiency severe enough to cause DSPN and/or megaloblastic anaemia is (as in the present study) likely to be relatively rare in Australia compared with other countries.…”

“…5,6,14,16 In a developed country such as Australia, greater nutritional sources likely counteract metformin-associated vitamin B12 malabsorption (and the additional potential influence of PPI use) compared to the situation in the developing world where the highest rates of metformin-associated deficiency have been reported. 14,16 As a corollary to this, vitamin B12 deficiency severe enough to cause DSPN and/or megaloblastic anaemia is (as in the present study) likely to be relatively rare in Australia compared with other countries. The use of mostly over-the-counter vitamin B12 supplementation by FDS2 participants was low (<4%) and not significantly different by serum vitamin B12 status, suggesting that this was not a confounding factor.…”

“…While some found a positive association between metformin-associated vitamin B12 deficiency and DSPN complicating type 2 diabetes, [5][6][7][8] a larger number have found no such relationship. [9][10][11][12][13][14][15][16] Studies assessing the relationship between metformin-associated vitamin B12 deficiency and anaemia have all proved negative. 6,11,16 The available data from studies examining the relationship between vitamin B12 and DSPN and/or anaemia have limitations.…”

“…[9][10][11][12][13][14][15][16] Studies assessing the relationship between metformin-associated vitamin B12 deficiency and anaemia have all proved negative. 6,11,16 The available data from studies examining the relationship between vitamin B12 and DSPN and/or anaemia have limitations. All relevant studies have recruited from outpatient clinics rather than utilising communitybased samples, and some important potentially confounding variables have not been available.…”