Interactions Between Complementary Therapies or Nutrition Supplements and Conventional Medications

Patients with diabetes frequently take complementary medicines and nutrition supplements. These patients use such therapies not only for diabetes-related conditions but also for other disease states.2–4 Hence, one of the most important considerations for clinicians who treat these patients is the possibility of drug interactions.

The case studies on p. 263 and 264 offer examples of possible interactions involving complementary therapies or nutrition supplements and conventional medications.

In our first case, several potential interactions may be responsible for the problems T.R. is experiencing. These problems include elevated blood pressure, recurrence of atrial fibrillation (including subtherapeutic digoxin serum concentration), and subtherapeutic International Normalized Ratio (INR). Furthermore, he has experienced increased nervousness and agitation, and his diabetes is not well controlled.

First, T.R.’s blood pressure is not at goal. Two potential interactions may be responsible. Ginseng has been noted to increase blood pressure6 and may theoretically attenuate the efficacy of T.R.’s antihypertensive medication. St. John’s wort has also been reported to interact with several medications. A constituent of St. John’s wort, hyperforin, may affect metabolizing enzyme production. Hyperforin binds to the pregnane X receptor, a nuclear receptor.7,8 This increases CYP3A4 activity and may increase the metabolism of drugs that are substrates in this isoenzyme system, including the angiotensin receptor blocker losartan. Thus, taking St. John’s wort could reduce the blood pressure–lowering effect of losartan.

The second problem for T.R. is the recurrence of atrial fibrillation and decreased digoxin serum concentration. St. John’s wort may be responsible for decreasing digoxin effects because it is a P-glycoprotein modulator. St. John’s wort has been reported to decreased digoxin serum concentrations by 18–25%.9,10 This could result in the recurrence of atrial fibrillation and diminished serum digoxin concentration.

Yet another problem in T.R.’s case is a subtherapeutic INR, which places him at risk for a thromboembolic event. A potential cause is the induction of warfarin metabolism by St. John’s wort, which has been reported to induce CYP2C9, the enzyme system for which warfarin is a substrate.6,11 Ginseng has also been reported to interact with warfarin with a resultant decrease in INR.12 

T.R. also reports feeling “down” and somewhat nervous even though he is taking an antidepressant. He may be experiencing an interaction between St. John’s wort and paroxetine.13,14 Concurrent use of these two agents may increase adverse effects such as the serotonin syndrome, which is characterized by nervousness, hyperactivity, and other symptoms. Patients who are elderly, such as T.R., are particularly predisposed to serotonin syndrome when combining St. John’s wort with a selective serotonin reuptake inhibitor.15 

In addition, an elderly patient with diabetes who is feeling “down” is likely to experience a declining appetite and lack of interest in food. This may lead the patient to try medical nutritional supplements in an effort to improve diabetes control and overall health. Specific medical nutritional supplements are promoted for patients with diabetes as snacks, supplements, and meal replacements. They are available in standard carbohydrate (50%) or lower-carbohydrate (33–40%) versions in the form of beverages, shakes, or snack bars. Although many patients do not consider such supplements to be “food,” these products may be fortified with at least 25–50% of the daily value of select vitamins and minerals. Some products contain 100% of the daily value of Vitamin C and E, as well as small amounts of chromium.

Health care providers should carefully question patients with diabetes about their use of medical nutritional supplements to determine the amount and types of products being consumed. Because these products contain calories and carbohydrate, their effect on body weight and blood glucose should be monitored. In addition, it is important to note the potential for excessive ingestion of vitamins and minerals when these products are combined with patients’ usual food and supplement intake.

The last problem in Case Study 1 is that T.R.’s diabetes is not well controlled. This may be caused in part by a drug-disease interaction. The patient is taking a glucosamine supplement, which may theoretically contribute to insulin resistance. A small study16 showed that glucosamine sulfate decreased glucose tolerance. Another in vitro evaluation17 showed that glucosamine may increase insulin resistance. This may result in the need to increase doses of diabetes medications or possibly add insulin.

There are two main issues in the case of E.M. First, she has experienced bleeding reactions and has a supratherapeutic INR. Second, she may also be exhibiting a phototoxic reaction. Several potential interactions with warfarin may have resulted in the bleeding reaction. All of the products E.M. is taking, including the supplemental vitamin E and the complementary therapies Ginkgo biloba, vanadium, and dong quai, may have antiplatelet effects6 and may therefore interact either with warfarin or with one another.

Doses >400 IU/day of vitamin E may interact with warfarin to enhance its antiplatelet effects.6,18,19 Vitamin E is a fat-soluble vitamin that has been used for a variety of disorders including menopausal symptoms and mastalgia. However, in high doses it may increase the risk of bleeding by inhibiting platelet aggregation and interfering with production of vitamin K–dependent clotting factors.6,18,19 Vitamin E may also interact with the other complementary products E.M. is taking to produce additive antiplatelet effects.

She is taking Ginkgo biloba for a possible diabetes complication—intermittent claudication. There are several reports of antiplatelet effects of Ginkgo biloba, and there is a potential for additive antiplatelet effects when it is combined with warfarin.6 Ginkgo biloba use has been associated with intracerebral20 and cerebral21 hemorrhage, subdural hematoma,22 subarachnoid hemorrhage,23 and spontaneous hyphema.24 

Vanadium is a trace element used for a variety of reasons, including diabetes and bodybuilding, although there are only a few published trials with a small number of patients evaluating its use in diabetes.6 The recommended dietary intake of vanadium is un-known,25 and the National Academy of Sciences has indicated that there is insufficient evidence to set a recommended daily allowance or an adequate intake level.26 An upper intake level based on renal toxicity in laboratory animals has been set at 1.8 mg.26 Because vanadium may possess anticoagulant activity,27 a theoretical interaction between vanadium and warfarin is potentiation of warfarin’s anticoagulant effects. This may be yet another factor that has contributed to E.M.’s elevated INR.

Dong quai is a botanical product used to treat menopausal symptoms.6 In a case report,28 dong quai doubled the INR in a woman also taking warfarin. In vitro data29 show that dong quai may inhibit cyclooxygenase activity and platelet aggregation. Furthermore, E.M. may also be exhibiting photosensitivity secondary to combined use of dong quai and the sulfonylurea. Dong quai contains the photoactive compounds, psoralens and bergapten, which may produce additive phototoxicity when combined with other photosensitizing agents30 such as sulfonylureas.

Less than 40% of patients tell their health care providers they are taking complementary therapies.1,5 Different surveys have reported varying reasons why patients do not provide this information. One survey31 indicated the following reasons:

• “It wasn’t important for the doctor to know.”

• “The doctor never asked.”

• “It was none of the doctor’s business.”

• “The doctor would not understand.”

It is imperative for clinicians to ask their patients whether they are taking any complementary products.

One reason patients may not let their providers know they are using these products is because patients often do not regard these products as medications.32 Or, they may not consider these products as potentially harmful since mandatory product labeling may suggest beneficial although nonmedical claims, such as St. John’s wort “helps to maintain a positive attitude” or “helps support healthy emotional balance.”33 

Patients are often reticent about admitting to using complementary therapies, and clinicians may not ask about specific use of these products.32 Effective provider-patient relationships require providers to have a nonjudgmental attitude. Without this, there may be a lack of trust, and patients may not be willing to tell providers what they are taking.

Using potentially toxic therapies may put patients at risk for adverse events. Cases have been reported in which individuals use unorthodox treatments to treat their diabetes. For instance “urine therapy” to prevent or treat diabetes is based on using patients’ own urine to develop an “autoimmune” solution that purportedly produces antibodies against patients’ own glucose without increasing pancreatic insulin production.34 Another example is substitution of complementary therapies for conventional diabetes medications. Diabetic ketoacidosis occurred in a patient with type 1 diabetes who was advised to stop insulin.35 Another patient was also advised by a reflexologist to stop insulin and was subsequently admitted to the hospital with acute hyperglycemia.3 

Many complementary products are on the market. There are >1,500 herbal products alone.36 Product ingredients and quality may vary considerably. Although use of standardized products is recommended, standardization is difficult to accomplish when active ingredients are unknown and there are no appropriate assays.37 For example, St. John’s wort has been standardized according to hypericin content. However, hypericin content may vary. Some products having labels that state that they contain 0.3% hypericin may have differing amounts of hypericin, such as 300 or 450 mg. Other formulations may be liquid preparations for which the label states the product “contains hypericins.” Other agents may not state contents at all other than that the product “contains St. John’s wort.”37 

Furthermore, hypericin has never been verified as the active ingredient. Hyperforin, another component of St. John’s wort, has been thought to be a more potent antidepressant than hypericin38 and is theorized to be the ingredient responsible for drug interactions.7,8 

Other products may contain a variety of different components, such as a combination of St. John’s wort, echinacea, kava, and other substances. Patients may believe that a combination product may provide the most value because they are obtaining many different ingredients for a single price.

Product variability may result in harm from a toxic product replacing a traditional product39 or from inadvertent contaminants.40 In 2000, the California Health Department announced that the sulfonylurea glyburide and the biguanide phenformin had been found as contaminants in some complementary products aimed at treatment of diabetes.41 Other publications have also reported lead contamination in Indian herbal remedies used for diabetes.42,43 

There are myriad products that patients with diabetes may use, and it is of utmost importance for clinicians to stay up to date on information regarding these products. Some references and web sites that may be useful for clinicians include:

• Jellin JM, Gregory P, Batz F, Hitchens K, Burson S, Shaver K, Palacioz K: Pharmacist’s Letter/ Prescriber’s Letter. Natural Medicines Comprehensive Database, Fourth Edition. Stockton, Calif., Therapeutic Research Faculty, 2002

• DerMarderosian A, Ed.: The Review of Natural Products. St. Louis, Mo., Facts and Comparisons, 2001

• Robbers JE, Tyler VE: Tyler’s Herbs of Choice: The Therapeutic Use of Phytomedicinals. Binghampton, N.Y., Hawthorn Herbal, 1999

• The Cochrane Library [electronic publication]. Oxford, U.K., Update Software, 2000. Available at: www.update-software.com

• National Institutes of Health Office of Dietary Supplements: IBIS Database. Available at: http://dietary-supplements.info.nih.gov/databases/ibids.html

Many patients with diabetes may take complementary therapies or nutrition supplements and conventional medicines concomitantly. Some of these combinations may lead to potentially harmful interactions. The education points listed throughout this article can help health care providers navigate these issues with their patients with diabetes.