Long-Term Metformin Use and Vitamin B12 Deficiency in Diabetes |

March 16, 2016
The Journal of Clinical Endocrinology and Metabolism

TAKE-HOME MESSAGE

The risk of vitamin B₁₂ deficiency in diabetic patients treated with metformin was evaluated in the secondary analysis of the Diabetes Prevention Program (DPP)/Diabetes Prevention Program Outcomes Study (DPPOS). Both short-term and long-term metformin use were associated with combined low and borderline-low B₁₂ levels (≤298 pg/mL) when compared with placebo (19.1% vs 9.5% at 5 years; P < .01 and 20.3% vs 15.6% at 13 years; P = .02). Longer duration of metformin use predicted a higher risk of developing B₁₂ deficiency, which was associated with a higher prevalence of neuropathy.
This secondary analysis of DPP/DPPOS suggests that vitamin B₁₂ levels should be measured routinely in diabetic patients on metformin.
– Lisa Parikh, MD

Written by David Rakel MD, FAAFP

Metformin and B12 Deficiency

Metformin is a solid work horse used frequently in primary care, and we need to be aware of its potential harm. This is the largest and longest study to date to evaluate the severity of B12 deficiency caused by prolonged metformin use.

The Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study showed how lifestyle modifications reduced the progression to diabetes by about 58% while metformin 850 mg twice daily reduced it by about 28%.¹ For over 13 years, this study tracked B12, homocysteine, and hemoglobin levels in participants taking metformin.²

The longer someone was on metformin, the greater the risk of B12 deficiency. The risk went up 13% per year of total metformin use. But, to put this in perspective, the prevalence of B12 deficiency in the metformin group was 4.3% vs 2.4% in the type II diabetics on placebo. Homocysteine levels were elevated in those with low levels and there was more neuropathy, although total number of cases was small.

The metformin package insert suggests checking B12 levels every 2 to 3 years in patients on long-term metformin. The authors of this study support periodic monitoring. Below is a chart of other drug-induced nutrient depletions that we should be aware of. Proton pump inhibitors also inhibit the absorption of B12, but not in this study. Those individuals on acid suppressive therapy did not have more severe B12 deficiency than those on metformin alone.

Drug	Depleted Nutrient	Notes
Metformin	B12, Folate, Thiamine (B1)	Elevated homocysteine suggests more severe B-vit deficiency in the tissues
Proton Pump Inhibitors	B-vit, Mg, Iron, Calcium, Zinc, Vit C, Chromium	We need acid to absorb many key nutrients
ACE Inhibitors	Zinc	Think, “ACE to Zinc.” Be concerned in elderly with recurring infections or those with acne as zinc is needed to fight infections
Thyroid hormone	Calcium	Helps explain osteoporosis risk with over-treatment
Acetaminophen	Glutathione	The main amino acid that fuels health and repair of the gut lining (enterocytes)
Statins	Co-enzyme Q 10	The “spark plug” of the mitochondria, which may explain the risk of myositis
Insulin	Magnesium	Check levels in diabetics with cardiac arrhythmias. Red blood cell levels are more sensitive than serum levels.

References

Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-1350.
Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study [published online February 22, 2016]. J Clin Endocrinol Metab. DOI: http://dx.doi.org/10.1210/jc.2015-3754.

Abstract

This abstract is available on the publisher’s site.

CONTEXT

Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use.

OBJECTIVE

To assess risk of B12 deficiency with metformin use in the DPP/DPPOS Design: Secondary analysis from DPP/DPPOS. Participants were assigned to placebo (n=1082, PLA) or metformin (n=1073, MET) for 3.2 years; MET received open-label metformin for an additional 9 years.

SETTING

27 study centers in the US Patients: DPP eligibility: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. Analytic population: participants with available stored samples. B12 levels were assessed at 5 (n=857, n=858) and 13 years [n=756, n=764] in PLA and MET, respectively.

INTERVENTIONS

Metformin 850 mg twice daily versus placebo (DPP); open-label metformin in MET (DPPOS) Main Outcome Measures: B12 deficiency, anemia, peripheral neuropathy Results: Low B12 (≤203 pg/ml) occurred more often in MET than PLA at 5 years (4.3% vs 2.3%, p=0.02) but not at 13 years (7.4% vs. 5.4%, p=0.12). Combined low and borderline-low B12 (≤298 pg/ml) was more common in MET at 5 (19.1% vs 9.5%, p<0.01) and 13 years (20.3% vs 15.6%, p=0.02). Years of metformin use was associated with increased risk of B12 deficiency (OR B12 deficiency/year metformin use, 1.13, 95% CI 1.06-1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels.

CONCLUSIONS

Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.

Story Source

Journal Abstract

Long-Term Metformin Use and Vitamin B12 Deficiency in Diabetes