The Why, What and Issues Clinicians Must Address
According to the National Center for Complementary and Integrative Health, complementary health approaches include natural products and mind and body practices.1 Health strategies involving mind and body practices or natural products are called complementary and alternative medicine (CAM). Natural products include probiotics, vitamins, minerals and herbals—these are available as dietary supplements. The U.S. Food and Drug Administration (FDA) does not stringently evaluate dietary supplements before marketing. However, the FDA requires manufacturers to use “good manufacturing practices” in the manufacture, packaging, labeling and storage of dietary supplements.2
Persons with diabetes, particularly those with type 2, often self-treat with CAM therapies.3 The primary drivers of CAM use include prevention3 quality of life and wellbeing.3,4 The 2012 National Health Interview Survey found that 26.2% of adults with diabetes used some type of CAM in the past year.5 Wellness or treatment were the major reasons for use in 56.7%, whereas 28.3% was only for treatment. Interestingly, 56.9% of CAM use was specifically for herbal therapies.
Issues with dietary supplements
When a patient takes supplements, clinicians must address the possibility of side effects, potential adulterants and drug interactions. Dietary supplements are not subject to FDA scrutiny since they are considered foods, not drugs. Thus, consumers may not be aware of consequences associated with their use, including side effects. However, one study found that 23,000 yearly emergency room visits and 2,000 hospitalizations in the U.S. were associated with dietary supplement use.6 Adulterants in the form of unapproved pharmaceutical ingredients are widespread.7 Unapproved ingredients may potentially be found in products that patients with diabetes may seek — for weight loss, sexual enhancement or muscle building. A further problem is that even if a product undergoes FDA recall for the presence of unapproved ingredients, researchers found that the product is still available for sale six months after the recall.8 Because patients do not consider that supplements contain active pharmaceutical ingredients, they may not realize the potential for drug interactions between supplements and prescription medications.9
Although there is no survey that describes the most popular dietary supplements used by people with diabetes, some of the most common include aloe vera, bitter melon, cinnamon, fenugreek, flaxseed and milk thistle.10,11
Aloe vera (Aloe vera L)
Aloe is a cactus-like succulent, and two major components are aloe latex and gel. Aloe contains various ingredients, including acemannan, aloeresin A and different phenolic and saponin constituents.12,13 The mechanism of glucose-lowering is unknown in humans; however, animal studies have shown an increase in pancreatic insulin production, increased hepatic gluconeogenesis and decreased insulin resistance by activation of adenosine monophosphate (AMP) active muscle protein kinase. Aloeresin may have possible alpha-glucosidase inhibition. Fiber content may delay or prevent glucose absorption, and acemannan may promote probiotic effects.13
Side effects have included gastrointestinal irritation, since some products may contain ingredients from the pericyclic cells obtained just beneath the leaf skin, which contains anthraquinones.12 Acute hepatitis has been noted in a few case reports. Possible drug interactions include elevated digoxin concentrations due to hypokalemia and increased risk of bleeding with sevoflurane.12,14
A 2016 meta-analysis found significant decreases in HbA1c (1.05%) in five studies and fasting glucose (47 mg/dL) in nine studies.15 Limitations with these studies included which plant part was studied, small sample size and heterogeneous study design. Aloe gel is called sábila in Spanish and is often included as an ingredient to prepare smoothies by Hispanic patients.
Bitter melon (Momordica charantia)
Bitter melon is used as a supplement, but the gherkin-like food is also consumed as a vegetable in Asia and India. Ingredients include momordin, momordicin, Polypeptide P and vicine.16 The mechanism of glucose lowering includes tissue glucose uptake, glycogen synthesis, increased AMPK activity, enhanced glucose oxidation of the G6PDH pathway and alpha-glucosidase inhibition.16
Side effects have included GI irritation, hypoglycemia, hemolytic anemia and possible miscarriage due to momocharin α and β—abortifacient constituents.17 Drug interactions include possible hypoglycemia if combined with secretagogues.12
Various forms of bitter melon have been studied. A 2012 meta-analysis of low-quality trials found no difference between bitter melon and placebo or between bitter melon and oral diabetes medications—including glyburide and metformin.18 A 2014 systematic review and meta-analysis found a small, non-significant benefit in decreasing fasting glucose (2.2 mg/dL) and HbA1c (0.13%).16 Thus, evidence supporting use of bitter melon is weak and therefore should not be recommended, especially in pregnancy.
Cinnamon (Cinnamomum cassia)
Cinnamon is a commonly used supplement for diabetes and hyperlipidemia. It contains procyanidin type-A polymers.12,19 Forms used include harvested bark quills or powder, bark-derived powder extracts or aqueous extracts. Mechanism of action is multi-modal and includes the following19 :
• Increased insulin sensitivity
• Enhanced insulin receptor phosphorylation and improved insulin signaling
• Glucose transporter-4 (GLUT-4) receptor synthesis and activation, which allows for glucose uptake
• Glycogen synthesis
• Alpha-glucosidase inhibition
• Peroxisome proliferator-activated receptor (PPAR) activation
• Delayed gastric emptying
Side effects include possible contact allergies or hepatotoxicity due to the coumarin content. Possible drug interactions include bleeding with anticoagulants and additive hepatotoxicity with known hepatotoxins.12 The 2012 Cochrane Review states there is insufficient evidence to support its use for diabetes.20 A 2013 systematic review and meta-analysis found that fasting glucose decreases significantly by 25 mg/dL and triglycerides by 30 mg/dL, but HbA1c decrease was not significant (0.16%).21
Controversy exists about the appropriate species, although cassia is the most used. The aqueous extract has shown a significant decrease in fructosamine, and many believe this is the most appropriate form for diabetes.19 Study design for clinical trials is heterogeneous, and cinnamon components vary. Overall, patients should expect decreased fasting glucose and triglycerides but modest HbA1c lowering.
Fenugreek (Trigonella foenum-graecum L.)
Fenugreek belongs to the Leguminosae family, along with chickpeas, green peas and peanuts. It is used for diabetes, hyperlipidemia and to promote lactation. It has a multimodal mechanism of action, which includes slowed carbohydrate absorption, delayed gastric emptying, increased insulin secretion and the promotion of peripheral glucose utilization.10,12
Side effects include gastrointestinal upset and possible “maple odor” smell of the urine or body.12 The major drug interaction is the possibility of bleeding if combined with agents having bleed risk.12
One major study found that when combined with sulfonylureas, the decrease in fasting and postprandial glucose was 33 mg/dL and 70 mg/dL, respectively, and HbA1c decreased 1.46%.22 A meta-analysis of studies for diabetes (and one for pre-diabetes) found that fasting and postprandial glucose decreased 15 mg/dL and 23 mg/dL, respectively, while HbA1c decreased 1.16%.23 Thus fenugreek may decrease fasting and postprandial glucose as well as HbA1c.
Flaxseed (Linum usitatissimum)
Flaxseed is a soluble fiber containing alpha linolenic acid (ALA), a plant omega-3 fatty acid, as well as lignans (a phytoestrogen).12 It is highly used by patients with and without diabetes for cardiovascular disease protection, weight loss (due to increased satiety) and constipation. Forms used include whole or ground flaxseed and oil. The mechanism of action is that soluble fiber delays glucose absorption and gastric emptying.12 Additionally, the lignan content, called secoisolariciresinol diglucoside, may reduce glucose concentration and delay postprandial glucose absorption.24 The ALA may improve insulin sensitivity and has antioxidant properties.12,24
Side effects include gastrointestinal irritation and possible bleeding if high doses are used. A theoretical drug interaction may occur with anticoagulants since high doses may decrease platelet aggregation.12
Studies have included various forms, such as whole or ground flaxseed, oil, and lignans. Research does not consistently demonstrate lowering of diabetes-related laboratory measurements. A 2018 meta-analysis found that whole flaxseed (not oil or lignans) significantly improves fasting glucose (weighted mean difference 3 mg/dL) but not HbA1c (nonsignificant 0.05% decrease).24
Milk thistle (Silybum marianum)
Milk thistle is a member of the Asteraceae/Compositae family, including daisies and thistles. It is used for hepatoprotection, nonalcoholic steatohepatitis (NASH), Amanita mushroom poisoning and diabetes.12 The mechanism of action involves decreasing insulin resistance, oxidative stress in pancreatic beta cells and malondialdehyde concentrations (a marker of oxidative stress).25
Side effects include possible allergies in those allergic to the daisy or ragweed family, as well as diarrhea.12 Drug interactions include possible additive hypoglycemia when combined with diabetes medications, possible bleeding in patients on warfarin and decreased concentrations of antiretroviral drugs.12
A 2016 systematic review and meta-analysis showed that routine administration significantly reduced fasting glucose by 27 mg/dL and HbA1c by 1.1%.25 However, trials were heterogeneous, with poor study design. Nevertheless, milk thistle has been widely used for centuries.
In spite of issues with potential side effects, adulteration and drug interactions, clinicians must have a non-judgmental attitude toward patients who use supplements. They should provide evidence-based information and allow patients to express their reasons for use of supplements. Clinicians and patients should collaboratively develop realistic goals and discuss possible side effects and drug interactions in a shared-decision manner. Clinicians should also help patients understand that supplements are not FDA- approved and are regulated as foods, not drugs. Clinicians may find evidence-based and useful information through the website available through NIH, the National Center for Complementary and Integrative Health1 and the Natural Medicines website.12
Access additional resources and practical information to enhance the care and treatment of your diabetes patients.
About our experts:
Laura Shane-McWhorter, PharmD, BCPS, BC-ADM, CDE, FASCP, FAADE
Professor (clinical) emeritus
Department of Pharmacotherapy
University of Utah College of Pharmacy
Salt Lake City, Utah
Reviewed by C. Brooke Boils, PharmD
University of Kentucky HealthCare clinical pharmacist
Good Samaritan Hospital