Metformin and vitamin D

Metformin is a commonly prescribed first line intervention in NIDDM management and its mechanisms of action include decreased intestinal sugar absorption, increased glucose uptake in liver and skeletal muscle, modulation of lactate production, inhibition of gluconeogenesis and protein synthesis, activation of fatty acid β-oxidation, and reduction in appetite.

Functions

Vitamin D is essential for many functions including –

• as an anti-inflammatory agent it modulates the immune system response by affecting both innate and adaptive immunity,
• regulating bone homeostasis including stimulating osteoid mineralization and regulating bone turnover,
• regulating calcium–phosphorus homeostasis such as regulating calcium absorption in the gut and maintaining serum calcium and phosphate concentrations,
• optimizing musculoskeletal system functioning such as regulating muscle function, decreasing oxidative stress, regulating muscle tone and contraction,
• optimizing mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial oxygen consumption and dynamics,
• being an effective antioxidant,
• impacting occurrence and course and treatment of asthma,
• increasing insulin sensitivity and protects against high-glucose-induced ß-cell dysfunction,
• cardiovascular function,
• muscle energy metabolism.

Deficiencies

Deficiency in vitamin D is now being called a pandemic disease by some authors. Further some authors claim that its deficiency is a contributor to the increased risk of NIDDM.

Vitamin D deficiency manifests as decreased insulin secretion and increased insulin resistance, NIDDM, metabolic syndrome, obesity, cardiovascular risk, neurodegeneration, Alzheimers dementia, depression, inflammation, skeletal muscle atrophy, osteoporosis and rickets, increased risk of graft rejection post-transplant, and others.

One author commented that while vitamin D deficiency enhances oxidative stress (in muscles), overcorrection of vitamin D status may also negatively impact skeletal muscle.

Guidelines for Preventing and Treating Vitamin D Deficiency: A 2023 Update in Poland (https://doi.org/10.3390/nu15030695) advise these ranges for total serum 25-hydroxyvitamin D concentration indicating -

• vitamin D deficiency < 50 nmol/L,
• suboptimal status 50 - 75 nmol/L,
• optimal concentration 75 - 125 nmol/L.

These ranges are noticeably different from Australia’s current recommended ranges. Being recent, these ranges likely reflect recent research findings.

The research is limited in relation to transporters, and the focus is primarily on intestinal absorption and excretion. Evidence in relation to other membrane transporters seems to be difficult to locate -

• proximal jejunum and distal ileum to epithelium - cholesterol membrane transporters including the scavenger receptor class B type I (SR-BI), CD36 molecule (CD36), NPC1-like transporter 1 (NPC1L1), and ATP-binding cassettes A1 and G1 (ABCA1 and ABCG1),
• Epithelium to intestinal lumen – MDR1 (P-gp).

MDR1 moves vitamin D out of the lumen and into the bloodstream, and moves it from the bloodstream to the lumen.

Direct evidence in relation to interactions between metformin and vitamin D is quite limited. The (typically) older evidence generally indicates no interaction. In the late twenty noughties the lower acceptable limit for vitamin D was significantly increased, and since then the evidence has more commonly indicated metformin having a negative impact on vitamin D status.

Metformin downregulates MDR1 and upregulates MRP1, whilst vitamin D downregulates MDR1 and MRP1. If a vitamin D intervention is to be administered then timing of administration needs to be considered. Vitamin D's management of MRP1 and MDR1 is likely to minimise risks of toxicity and deficiency, consequently the greater risk to vitamin D status is from metformin. Consequently vitamin D and metformin should be administered at significantly different times from each other.

Clinical Questions

What actions will you initiate when you see someone prescribed metformin, will you -

• recommend clarifying current vitamin D status?
• recommend regular monitoring of vitamin D status on an annual or 6-monthly basis whilst metformin is prescribed?
• recommend vitamin D interventions be administered at a significantly different time from metformin, and from food intake?

Conclusions

Metformin’s negative impact on vitamin D status is quite profound and as the negative impact is on both absorption and excretion it could increase the risks of deficiency and toxicity.

Case study

The comments refer to the drug-nutrient, drug-food, and PharmacoNutrition effects only.

Data summary

Medical History with Nutritional Aspect

Biochemistry with Nutritional Aspect

Medications That May Adversely Affect Nutritional Status

Transporter-mediated interactions and nutrients

Biochemistry

Relatively recent biochemistry indicates

   - low albumin - typical indicator of nutritional status; influenced by inflammatory response; advisable to recheck status,

   - marginal vitamin D status - advisable to recheck status and if low then review current management strategy.

Pharmaconutrition

Doryx associated with negative impact on B12, D and thiamine.

Bowel management

   No regular intervention prescribed,

   Oral PRN aperient prescribed,

   No Nurse Initiated interventions administered.

Staff comments

Staff advise Mr AGQ eats well at breakfast and has a variable, mostly minimal intake at midday and evening meals.

Observations

Mr AGQ is a tall, big-framed man who was dozing in the Day Room when I went to speak to him - he woke to his name and told me he likes mince (meat), and his eyes lit up when I asked if he likes ice cream. I asked if he was given some ice cream now would he eat it and he agreed he would - ice cream was produced and he is eating it with enjoyment.

Pharmaconutrition assessment

Mr AGQ’s diagnoses include falls - nutritional factors that may be useful to consider in falls management include -

   - loss of weight – doxycycline side effects include poor appetite, altered taste, dry mouth, nausea and vomiting – a combination that could significantly negatively impact food intake and consequent weigh loss;

   - vitamin D – doxycycline negative impact likely due to inhibiting MDR1;

   - low folate – mechanism unknown; doxycycline negatively impacts renal uptake likely due to inhibiting OAT1 which is more likely to result in higher levels rather than lower levels. However, doxycycline has a hypofolataemia effect therefore there is another mechanism of interference.

What else would you include?

Download free pdf

Please read this as it is important …

The information in this article is provided to support Health Professionals. It is not an exhaustive protocol and Health Professionals are advised that adequate professional supervision is accessed to ensure that Duty of Care obligations with respect to safe administration of medicines is met for each consumer.