Can I Take Vitamin B12 with Tresiba (Insulin Degludec)?

What the Tresiba label actually lists

The Tresiba prescribing information has a drug-interaction table with four groups of medicines and other substances [1].

• Drugs that may increase the risk of hypoglycemia: other antidiabetic agents (including GLP-1 receptor agonists, DPP-4 inhibitors and SGLT-2 inhibitors), ACE inhibitors, angiotensin II receptor blockers, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs such as octreotide, and sulfonamide antibiotics [1].
• Drugs that may decrease the glucose-lowering effect: atypical antipsychotics such as olanzapine and clozapine, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens, protease inhibitors, somatropin, sympathomimetic agents such as albuterol, epinephrine and terbutaline, and thyroid hormones [1].
• Drugs and other substances that may increase or decrease the effect: alcohol, beta-blockers, clonidine and lithium salts. Pentamidine may cause hypoglycemia, sometimes followed by hyperglycemia [1].
• Drugs that can blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine and reserpine [1].

How insulin degludec and vitamin B12 work

Insulin degludec is an ultra-long-acting human insulin analog. After a subcutaneous injection it forms multi-hexamers in the tissue and creates a depot; its long action comes mainly from delayed absorption out of that depot, plus some binding to albumin [1]. At steady state the label reports a median time to peak of 9 hours and a half-life of about 25 hours, with steady state reached after 3 to 4 days [1].

Vitamin B12 (cobalamin) is a water-soluble vitamin sold as oral supplements and prescription injections [3]. Getting it out of food needs stomach acid to release it from protein, and uptake in the ileum needs intrinsic factor made by stomach parietal cells [3]. Inside cells it is a cofactor for methionine synthase, which converts homocysteine to methionine, and for methylmalonyl-CoA mutase [4]. When B12 is low, homocysteine and methylmalonic acid rise, which is why those two are used as functional markers [4].

The B12 issue that does show up: metformin

If you take metformin alongside Tresiba, metformin is the drug in your regimen with a documented effect on B12 status [2].

In the Diabetes Prevention Program Outcomes Study, adults with prediabetes (not people using insulin) took metformin 850 mg twice daily or placebo for 3.2 years, then open-label metformin. B12 at or below 203 pg/mL was found in 4.3% on metformin versus 2.3% on placebo at 5 years (p=0.02), and 7.4% versus 5.4% at 13 years (not significant) [2]. Low or borderline B12 (at or below 298 pg/mL) was 19.1% versus 9.5% at 5 years and 20.3% versus 15.6% at 13 years [2]. Each year of metformin use raised the odds of deficiency (odds ratio 1.13 per year, 95% CI 1.06 to 1.20), and neuropathy was more common in metformin users with low B12 [2]. The authors suggested considering routine B12 testing in metformin users [2]. Metformin use for more than four months is also listed as a risk factor that may justify screening [5].

What is less settled is how much that lab change matters. A 2018 review concluded that metformin, proton pump inhibitors and H2 blockers clearly lower serum B12 by reducing absorption, but it is unclear whether this raises the risk of true functional or clinical deficiency, and randomized trials using multiple-analyte testing are still needed [4].

Timing and what to watch for

The Tresiba label directs adults to inject once daily at any time of day, with at least 8 hours between consecutive injections [1]. In a label trial that deliberately alternated dosing intervals between 8 and 40 hours, HbA1c results were similar to insulin glargine [1]. The glucose-lowering effect lasted at least 42 hours after the last of 8 daily injections, and steady state takes 3 to 4 days [1].

The label warns that hypoglycemia can be severe or life-threatening, and awareness of symptoms can be reduced by beta-blockers, neuropathy or longstanding diabetes [1]. It also lists serious hypersensitivity, hypokalemia, and fluid retention with thiazolidinediones such as pioglitazone [1].