Metformin and proton pump inhibitors
The invisible danger: micronutrient robbers
According to the Drug Commission of the German Medical Association, drug therapy safety – AMTS for short – is the totality of measures to ensure an optimal medication process with the aim of reducing medication errors and thus avoidable risks for patients during drug therapy(Action Plan for Drug Therapy Safety in Germany 2021-2024). Anyone aiming to provide holistic therapy for their patients cannot ignore possible micronutrient deficiencies caused by pharmacotherapy.
This is because drugs can disrupt the micronutrient balance through both pharmacokinetic and pharmacodynamic mechanisms. Pharmacokinetic interactions, for example, disrupt absorption or increase excretion, while pharmacodynamic interactions occur due to the pharmacological effect and, for example, enzyme inhibition.
Numerous interactions between individual active ingredients, classes of active ingredients and micronutrients are now known and well documented. In 2022, for example, the Drug Commission of the German Medical Association warned of the consequences of an undetected vitamin B12 deficiency that can occur during metformin therapy. The Drug Saftey Mail 2022-34(information from the British Medicines Agency) recommends monitoring patients at risk. According to the Medicines Commission, the risk of B12 deficiency increases with increasing dose, duration of treatment and other risk factors for vitamin B12 deficiency. These are older age, a vegetarian/vegan diet, co-medication with proton pump inhibitors and certain gastrointestinal diseases such as Crohn’s disease and other inflammatory bowel diseases. The Drug Commission further writes: “Vitamin B12 (cobalamin) is important for various metabolic functions such as cell proliferation, energy production and the function of the nervous system. Symptoms of vitamin B12 deficiency can include macrocytic anemia, glossitis or neuropsychiatric deterioration such as neuropathy.” Treacherously, some clinical symptoms of vitamin B12 deficiency can thus also be misinterpreted as age- or diabetes-related polyneuropathy and, in the worst case, a cascade of prescriptions may result.
Fortunately, if the active absorption of vitamin B12 is impaired, a sufficient supply can still be ensured with sufficiently high doses of oral preparations. This is because around 1% of the dose is passively absorbed independently of the intrinsic factor and gastric acid. In prevention, daily doses of 500 to 1000 ug or more of vitamin B12 per day make sense. The cyanocobalamin frequently used in preparations is a purely synthetic form of B12 bound to hydrocyanic acid and does not occur naturally in the body. High-dose lozenges with the body’s own hydroxocobalamin (e.g. 500ug per lozenge) can be a useful supplement in the case of appropriate medication and/or risk factors, which also support compliance by simply being taken as a lozenge.
Example: Absorption of vitamin B12
Diagnosis of B12 deficiency: measure HoloTC and not B12!
Symptoms of B12 deficiency can be very unspecific and can also manifest themselves, for example, in unsteady gait or fatigue, which could be wrongly attributed to advanced age in elderly patients. However, early diagnosis is not only relevant because of the quality of life and consequential damage caused by falls, but also because neurological damage is reversible in the initial phase.
Vitamin B12 is present in plasma in two forms: The majority (70 to 90 %) is bound to haptocorrin. However, only liver cells are able to take up B12 bound to haptocorrin via specific receptors. It is therefore considered metabolically inactive. Only vitamin B12 bound to transcobalamin, or holo-transcobalamin (HoloTC) for short, is biologically active. Only this can be absorbed by all cells and ensures the cellular supply.
If only the B12 level is determined in the serum, the laboratory does not differentiate between metabolically active and inactive B12. A total B12 value in the lower third of the reference interval may already indicate a holoTC deficiency that is not detected. This applies in particular to vitamin B12 values < 350 pg/ml.
It is therefore better to measure the HoloTC. A lower value indicates a depletion of the vitamin B12 store. According to the IMD laboratory in Berlin(diagnostics of vitamin B12 deficiency), the determination of homocysteine and methyl malonic acid (MMA) has also proven useful in diagnostics. Both metabolites increase as part of the methionine/homocysteine level if there is an intracellular and therefore clinically manifest B12 deficiency. According to the IMD, clinical signs of B12 deficiency have already been detected in vitamin B12 levels within the reference range (> 191 pg/ml) with a lower holoTC ( < 35 pmol/l) and increased MMA. The measurement of a normal B12 level should therefore not lull you into a false sense of security. Elevated homocysteine also represents an independent risk factor for osteoporosis, dementia, cardiovascular disease and much more.
Proton pump inhibitors also interfere with vitamin B12 absorption, albeit by a different mechanism: on the one hand they impair B12 release and cleavage from food by inhibiting acid secretion, on the other hand they block binding to the transport factor (intrinsic factor) and thus the formation of the IF-vitamin B12 complex. The result is the same as when taking metformin: Long-term intake in particular threatens an undersupply of vitamin B12 with all the associated consequences.
Hypomagnesemia also occurs with proton pump inhibitors. This is what it says in the prescribing information for Pantozol® 40 mg (click here ): “Serious manifestations of hypomagnesemia with fatigue, tetany, delirium, convulsions, dizziness, and ventricular arrhythmias may occur, but they may develop insidiously and then be overlooked. Hypomagnesemia may lead to hypocalcemia or hypokalemia (see section 4.8). In most affected patients, hypomagnesemia (and hypocalcemia or hypokalemia associated with hypomagnesemia) improved after administration of Magnesium and discontinuation of the PPI. In patients for whom prolonged treatment is planned or who are taking PPIs with digoxin or other drugs that may cause hypomagnesemia (e.g. diuretics), the physician should consider monitoring magnesium levels before and periodically during treatment with PPIs.” Many studies now indicate that even a suboptimal supply of Magnesium is associated with an increased risk of depression, for example, and can also worsen glucose tolerance or promote insulin resistance.
But that’s not all. The resorption of Calcium is also impaired by the reduced HCl secretion, so that the information for healthcare professionals warns about long-term use (> 1 year): “Observational studies suggest that proton pump inhibitors may increase the risk of fractures by 10 – 40%, although this increased risk may also be partly due to other risk factors. Patients at risk of osteoporosis should be treated according to current clinical guidelines and receive adequate vitamin D and Calcium.” In addition, taking a proton pump inhibitor interferes with iron absorption and thus increases the risk of developing iron deficiency(Use of proton pump inhibitors and risk of iron deficiency: a population-based case-control study). Organically bound iron compounds and vitamin C are recommended for optimal tolerability(see iron text).
In short: Targeted supplementation adapted to illnesses and medication should be a fixed pillar of drug therapy safety.
Source: Uwe Gröber, Arzneimittel und Mikronährstoffe, Medikationsorientierte Supplementierung, 4th edition, Wissenschaftliche Verlagsgesellschaft Stuttgart