CAM for Diabetes: Thousands of years of use and counting

Tanya Dougherty, PharmD, BCPS Clinical Pharmacy Specialist, Ambulatory Care

University of Pennsylvania

Department of Family Medicine & Community Health

Objectives

• Compare and contrast the efficacy and safety of various herbal medications and supplements for the treatment of diabetes.

• Recommend an herbal medication or supplement for a patient with diabetes considering patient specific parameters.

• Disclosure – I have no actual or potential conflicts of interest in

relation to this presentation.

Question 1

• Which of the following diabetes medications can be traced to natural sources?

A. Metformin

B. Glipizide (Glucotrol)

C. Empagliflozin (Jardiance)

D. Exenatide (Byetta)

Biguanide isolated from Galenga officinalis (goat rue)

GLP-1 isolated from Gila Monster saliva (exenatide)

Active constituent phorizin isolated from bark of apple tree modified to SGLT-2 Inh (canagliflozin)

Background

• Among US adults in 2012, 57% used some form of herbal therapy in the past year

• National Health Interview Survey

– 22% of diabetes patients use herbal products

• 63% of older adults with diabetes used some for of herbal product in the past year

– 67% of adult patients with diabetes used some type of vitamin or supplement

Clin Ther 2005:27:1847–1858 Diabetes Care 2006;29:15–19 Diabetes Care. 2018 Jun;41(6):e95-e96

Product Selection & Recommendation

• Verify that it meets USP standards • Contains the ingredients listed on the product label, in the declared strengths

and amounts.

• Does not contain harmful levels of contaminants.

• Will break down and release ingredients in the body within a specific amount of time.

• Has been made under Good Manufacturing Practices (GMPs).

• Consumer Labs – Provides independent testing from products off the shelf

• Tests for identity, strength, purity and disintegration

– Requires subscription

Importance of Product Selection

What do the guidelines say?

• AACE/ACE Health Eating for Prevention & Treatment of Metabolic/Endocrine diseases – Insufficient evidence on use of micronutrients or

supplements.

• ADA Nutrition Therapy Recommendations for Management of Adults with Diabetes – Conflicting evidence on use of micronutrients or

supplements.

AACE/ACE Endo Prac Vol 19 (Suppl 3) September/October 2013 Diabetes Care 2014;37(suppl 1): S120-143

ADA Recommendations: Nutrition

Micronutrients and herbal supplements:

• There is no clear evidence that dietary supplementation with vitamins, minerals, herbs, or spices can improve diabetes, and there may be safety concerns regarding the long-term use of antioxidant supplements such as vitamins E and C and carotene. C

American Diabetes Association Standards of Medical Care in Diabetes.

Lifestyle Management. Diabetes Care 2017; 40 (Suppl. 1): S33-43

American Diabetes Association Standards of Medical Care in Diabetes.

Lifestyle Management. Diabetes Care 2017; 40 (Suppl. 1): S33-432017; 40 (Suppl.

1): S33-43

Fiber

• Guideline recommendations

– AACE/ACE

• 20-35 grams daily from raw vegetables and whole grains

– ADA

• 25-38 grams/day

AACE/ACE Endo Prac Vol 19 (Suppl 3) September/October 2013 Diabetes Care 2014;37(suppl 1): S120-143

Fiber

• Associated with reduced mortality with high fiber compared to low fiber diet

– Nurses Health Study showed reduced risk of mortality by 16-31% with highest whole grain consumption

– European Prospective Investigation in Cancer and Nutrition study showed reduce risk of mortality by 17% and CVD mortality by 24%

Circulation 2010;121:2162–2168 Plos ONE 2012;7:e43127

Fiber

• Proposed mechanism of action – Improves insulin sensitivity

– Carbohydrate absorption inhibitor

• Effectiveness – Meta-analyses and systemic reviews show 5-50

grams daily in divided doses of fiber for up to 1 year produces a modest reduction in FBG by 16 mg/dL, PPG by 22 mg/dL and Hgb A1C by 0.2-0.3%.

– Limitations: small samples, short mean duration

JABFM 2012;25(1): 16-23 Am J Clin Nutr 2015;102(6): 1604-14

Fiber

INSOLUBLE FIBER

INSOLUBLE FIBER SOLUBLE FIBER

MOA Insoluble in water to increase peristalsis through the GI tract

Dissolves in water in the large intestine to form a gel and promote peristalsis to reduce transit time

Examples Whole grains, wheat cereal/bran, carrots, celery

Barley, oats, beans, nuts, fruit OTC products • Blond psyllium (Plantago ovata), whole

psyllium husks) • Metamucil Multifiber health • Konsyl

• Benefiber (wheat dextrin) • Citrucel (methylcellulose) • Fibercon (polycarbophil calcium)

Food sources of insoluble fiber and soluble fiber are both associated with a reduction in CVD and CVD related mortality*.

Fiber: Clinical Pearls

• Product selection – Psyllium might be associated with the largest benefit

but based on small studies ( FBG 14-20%)*

• Drug interaction precaution – One soluble fiber active ingredient to avoid!!

• Patient instruction – Take with meals and at least 8 ounces of water

– Monitor for constipation, bloating

Am J Nutrition 2015;102(6): 1604-14

Question #2

• Which of the following OTC Fiber Supplement is listed as an adjunct for maintaining healthy blood sugar levels?

A. psyllium husk (ex: Metamucil Fiber Health)

B. wheat dextrin (ex: Benefiber)

C. methylcellulose (ex: Citrucel)

D. polycarbophil (ex: Fibercon)

Fenugreek

• Recognized as a general safe substance by the FDA

• Seeds (whole and powdered) and extract have been studied

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=182; Accesssed October 11th, 2018

Fenugreek

• MOA: – Slows absorption of carbohydrates from GI tract – Might enhance insulin release – Hypoglycemic effect

• Dose: – 5-100 grams daily in single or divided doses with

meals for up to 3 years (powdered seeds 5-10 twice daily)

• ADE: – Mild (dyspepsia, GI upset) – Rare (dizziness, headache)

Fenugreek

• Effectiveness

– Based on meta-analyses of low quality, heterogeneous studies

– Benefit occurs only in the presence of food

– FBG 18 mg/dL

–PPG 22-40 mg/dL

–A1C 0.85-1.16%

• Low risk of adverse effects

Fenugreek: Clinical Pearls

• Product selection – Powered seeds have the most data

• Avoid in the following patients: – Pregnant or lactating women

– Concurrent use of antiplatelets or anticoagulants? • Some constituents have antiplatelet properties but not to a

clinically meaningful effect

– Allergies to legumes, peanuts, chickpeas

• Patient counseling – May cause urine to smell like maple syrup

Cinnamon

• Recognized as a general safe substance by the FDA

• 3 different types of cinnamon

– Cassia cinnamon most common

– Majority of trials in diabetes use cassia cinnamon

• MOA

– Increases insulin sensitivity through insulin receptor phosphorylation

Cassia Cinnamon

• Effectiveness – Analysis of 10 RCT shows that 120 mg – 6 grams daily

for 4 months reduces FBG by 25 mg/dL but no effect on Hgba1c

– Encapsulated dose forms may be more effective than powdered forms

• ADE: rarely rash or allergic skin reaction

• Contains coumarin – Avoid in hepatic insufficiency or patients taking

warfarin

• Encourage use of cinnamon in food

• Safe for use up to 4 months J Pharm Pract 2017;30(6):631-38

Chromium

• Trace element

– Found in Brewer’s yeast, whole wheat bread, animal fats, meat, fish, coffee, tea and some spices

• IOM Adequate Intake Level: 25-35 mcg daily

Institute of Medicine, Food and Nutrition Board. National Academy Press, Washington, DC, 2001

Chromium

• MOA – May prolong insulin receptor activity

– May up regulate insulin receptors

– Improves insulin binding and beta-cell sensitivity

• Dose: 200-1000 mcg daily for up to 6 months

• ADE (many) – Headache, insomnia, sleep disturbances,

irritability, mood changes, kidney damage, weight gain, hepatoxicity

J Pharm Pract 2017;30(6):631-38

Chromium

• Effectiveness – Analysis based on 18 small, heterogeneous, low

quality trials – FBG 18 mg/dL – A1C 0.6%

• Avoid use in patients with renal or hepatic insufficiency

• Must separate dose by 1-4 hours of levothyroxine • Safe at doses up to 1000 mcg daily for 6 months • Risks > Benefits

Natural Medicines. Chromium monograph. Retrieved from https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=932#effectiveness on October 14th, 2018.

Vitamin D

• Low levels (< 20 ng/mL) have been associated with worse glycemic control

– Seasonal variations (winter) also associated with worse glycemic control

• Proposed MOA

– Low vitamin D levels increases PTH secretion which impairs insulin resistance

– May have a role in regulating insulin secretion

Vitamin D

• Conflicting evidence regarding the effects of vitamin D supplementation on diabetes control – Analysis of 15 trials showed no effect on HgbA1C

– Small reduction in FBG 6 mg/dL and insulin resistance by 25%

• Limitations: population level data, various preparations and vitamin D status

• Lack of studies evaluating the effect of vitamin D in patients with diabetes who have vitamin D deficiency (25, OH-vitamin D level < 20 ng/mL).

Diabet Med 2012;29:e142-150

Vitamin D

• Recommendations

– Reasonable to check levels in patients at risk of Vitamin D deficiency

• Older institutionalized patients

• Obesity

• Hyperpigmented/dark skin patients

• Treat accordingly

– Single dose Vitamin D3 (ergocalciferol) 100-200,000 IU

– Vitamin D3 20,000-40,000 IU weekly for 6-12 months

AACE/ACE Endo Prac Vol 19 (Suppl 3) September/October 2013

Magnesium

• Hypomagnesium occurs in 25-38% of people with diabetes

• More prevalent in uncontrolled diabetes

• RDA 310-420 mg daily

• Vicious cycle – Mg causes insulin resistance and insulin resistance Mg concentrations

• Treatment of hypomagnesmia improves glucose metabolism and insulin sensitivity

Magnesium

• Evaluate medications as a causative factor – ≥ 1 year of PPI use (especially with diuretics)

– Loop and thiazide diuretics

– Aminoglycosides

– Cisplatin

– Calcineurin inhibitors (cyclosporine, tacrolimus)

– Digoxin

• Other risk factors – Gastrointestinal diseases (Crohn’s, celiac disease),

chronic alcohol use, older adults

ADA guidelines: Supplements to Avoid

• Vitamin E – Large RCT (HOPE study) showed that taking 400 IU

daily for up to 7 years is associated with increased risk of heart failure in patients with diabetes

– Population study showed taking vitamin E was associated with a higher rate of mortality in patients with severe CVD

• Vitamin C – Taking vitamin C 300mg associated with higher

CVD mortality in postmenopausal women

JAMA 2005;293(11):1338-47 Am J Med 2007;120:180-84

Am J Nutr 2004;80(5):1184

ADA Guidelines 2017 New Recommendation: Pharmacologic Therapy For T2DM

• Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy. Grade B recommendation

American Diabetes Association Standards of Medical Care in Diabetes.

Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74

American Diabetes Association Standards of Medical Care in Diabetes. Lifestyle Management. Diabetes Care 2017; 40 (Suppl. 1): S33-4320

Metformin and B12

• Taking metformin for ≥ 5 years is associated with a 10-50% (mean 25%) reduction in B12 levels

– Dose and duration dependent

• May cause or worsen diabetic neuropathy

• Consider checking a B12 level in patients taking metformin for > 5 years or with symptoms of neuropathy

J Clin Endocrinol Metab 2016;101(4):1754 DM Care 2012;35(2):327-33.

Depression

• Patients with diabetes who have depression have a larger burden of disease (hypo/hyperglycemic symptoms)

• Patients with diabetes are twice as likely to have or develop depression – High risk after 10 years of having diabetes

• Lack of large RCT studies focusing on effects of adherence to antidepressant treatment and diabetes control

Family Practice, 2015, Vol. 32, No. 3, 317–322 DM Care 2001;24(6):1069-1078

Depression

• Positive outcomes associated with integrated collaborative care management – 50% more likely to achieve A1C < 7% and 30% more

likely to achieve depression remission after 12 weeks. – Analysis of 7 RCT shows a 0.33% reduction in A1C and

30% improvement in depression scores – May be most effective with holistic approach to

treating both conditions simultaneously

• Pharmacists call to action – PHQ9 Depression assessment – Access to adherence measures for antidepressants

Ann Fam Med 2012;10(1):15-22 BMJ Open 2014;4(4):e004706

Yoga

• Analysis of 17 small, low quality RCT

• Associated with a A1C reduction of 0.6%, FBG 23 mg/dL and PPBG 15 mg/dL

– Practice for most days of the week

– Study duration up to 6 months

Resources

• General – FDA Dietary Supplements:

https://www.fda.gov/Food/DietarySupplements/default.htm

– National Center for Complimentary and Integrative Health: https://nccih.nih.gov

• CAM – Natural medicines:

https://naturalmedicines.therapeuticresearch.com – Cochrane Complementary Medicine:

https://cam.cochrane.org

Patient Evaluation for CAM

• What patient specific data would you need?

• What lab results would you need?