The Use of Complementary and Alternative Medicine in Hospitalized Patients with Type 2 Diabetes Mellitus in Israel

Abstract

Introduction:

The use of complementary and alternative medicine (CAM) has been on the rise in recent years in the general population, as well as among patients with chronic diseases such as diabetes mellitus. The aim of this study was to add information regarding the use of CAM in patients with type 2 diabetes mellitus (DM2) in Israel and explore possible interactions between CAM and prescription medication (PM).

Methods:

Results:

Out of 111 diabetic patients, 23.4% used CAM. There was no significant difference between the consumers and nonconsumers in terms of age, education, income, smoking, or alcohol habits. Only 11 of the 26 CAM consumers informed their physician regarding the use. We found possible drug–herb interactions in 19 of the 26 CAM consumers. A major interaction was found between omega-3 and antiaggregants and was encountered in 7 (26.9%) of the CAM consumers. Other minor and major interactions were found with vitamin E, ginkgo-biloba, co-enzyme Q10, green tea, fenugreek seeds, pyridoxine, and dandelion.

Conclusions:

Since CAM consumption is on the rise, it is desirable to improve our knowledge concerning their potential effects and adverse effects, especially in conjunction with PM. Given the complexity of pharmaceutics in patients with chronic diseases, among them patients with DM, the use of supplementary medicine cannot be ignored.

Introduction

The use of complementary and alternative medicine (CAM) has been on the rise in recent years.¹ Rates of use differ according to different studies, populations, and variable definitions of CAM.² User characteristics also have a wide range, with most studies suggesting a higher prevalence of consumption among women and older adults, people with a higher degree of education and socioeconomic status, those who are physically active, and nonsmokers.^3

–9

Type 2 diabetes mellitus (DM2) is a worldwide epidemic; prevalence is growing and is expected to increase greatly in the following years.¹⁰ Patients with chronic diseases were found to have a higher prevalence of supplement use than healthy subjects.^11,12 In one study, the use of CAM was found to be 30.9% among diabetic patients. However, only 3.43% of them used it for the management of diabetes.¹³ In another study, 63% of diabetic patients used CAM, with only 29% of them informing their physician.¹⁴ CAM use was not associated with a better quality of life in this subgroup of patients.¹⁵ The aim of this study was to add information regarding the use of CAM among patients with DM2 in Israel and explore possible interactions between CAM and prescription medication (PM).

Methods

This is a cross-sectional study based on questionnaires. The study included type 2 diabetic patients who were hospitalized in an internal medicine department at Assaf Harofeh Medical Center, Zerifin, Israel, between December 2013 and December 2014. The Medical Center, which is affiliated with the Sackler Faculty of Medicine at Tel Aviv University, serves a rural and urban population of about 1 million citizens and has over 800 hospital beds. Inclusion criteria were patients 18 years or older admitted for reasons other than for diabetic complications (diabetic ketoacidosis or hyperglycemic hyperosmolar state). All patients signed an informed consent before participation in the study. CAM was considered to be any vitamin, mineral, amino acid, herb, or other substance or their constituents. We did not include acupuncture, energy therapies like reiki, manipulative and body-based systems like chiropractic or massage, and mind–body interventions like tai chi or yoga. Patients were excluded from participation if they could not sign an informed consent or comprehend the questionnaire. The protocol was approved by the Assaf Harofeh Medical Center Helsinki Committee for Human Experiments (approval number 102/11).

Questionnaire

The questionnaire was designed by the authors for the purpose of this study. The authors were familiar with the study population and the implications of herbal consumption. The first section included demographic data (age, gender, education, income, etc.); the second section included information on medical history and the use of PM; the third section included information regarding diabetes: disease duration, blood glucose balance, and PM for diabetes control; the fourth section included all relevant history of CAM use, including the interest of the medical team in the supplements. The questionnaires were filled in by one of the researchers.

Drug–herb interactions

Possible interactions between CAM and PM were evaluated by a clinical pharmacist and a clinical pharmacologist. We used two websites in order to find possible interactions: clinicalpharmacology.com and naturaldatabase.therapeuticresearch.com.

Interactions were rated as follows: major, combination is contraindicated and a serious adverse outcome could occur; moderate, use cautiously or avoid combination, a significant adverse outcome could occur; minor, there is a chance of an interaction.

Statistics

Data analysis was performed with the SPSS v22.0 package. Continuous data are expressed as mean±standard deviation (SD) or as a median and interquartile range (IQR) if they were not normally distributed. Categorical data are expressed as frequencies and percentages. Normal distribution was evaluated by the Kolmogorov–Smirnov test and QQ plot.

The Mann–Whitney test was used to compare continuous variables. The chi-square and Fisher's exact tests were used for categorical variables. All statistical tests were two sided. Differences were considered significant when the p-value was less than 0.05.

Results

General characteristics

One hundred and eleven patients with DM2 were evaluated, 23.4% of who used CAM. There was a small male predominance in the overall study population, with no difference among CAM consumers (53.8%) and nonconsumers (56.5%, p=0.814). The mean age of the study population was 70.5±10.4 years with no difference between consumers (median±IQR 69.9±7.45) and nonconsumers (70.7±11.2, p=0.68). Out of the CAM consumers, 69.2% were well educated, in comparison to 51.8% of nonconsumers, though this was not statistically significant (p=0.117). We found the level of income to be average and above in 38.5% and 23.55% of CAM consumers and nonconsumers, respectively (p=0.134). There were no differences in exercise, alcohol, or smoking habits between groups. There was no statistically significant difference in the level of diabetes control between groups in terms of HBA1c levels [6.85 (6.4–9.3) in consumers and 7.9 (7.2–8.4) in nonconsumers, p=0.24]. However, patients using CAM were more likely to report that they were well controlled (46.2% vs. 26.2%, p=0.054). Eleven of the 26 CAM consumers informed their physician regarding the use. The main reason for CAM consumption was general health (10 patients), 2 of the patients used CAM for diabetes control and the rest for malnutrition, urinary tract infection prevention, osteoarthritis, kidney or liver disease, or for unknown reasons. Patient characteristics are presented in Table 1.

Table 1.

Baseline Characteristics of Consumers vs. Nonconsumers

	Consumers, 23.4% (n=26)	Nonconsumers, 76.6% (n=85)	p
Age	69.9±7.45	70.7±11.2	0.695
Gender (male)	53.8 (14)	56.5 (48)	0.814
Family status			0.998
Married	53.8 (14)	54.1 (46)
Single	3.8 (1)	3.5 (3)
Widow/er, divorced	42.3 (11)	42.3 (36)
Level of education			0.117
Below 8 years	30.8 (8)	48.2 (41)
Above 8 years	69.2 (18)	51.8 (44)
Income			0.134
Below average	61.5 (16)	76.5 (65)
Average & above	38.5 (10)	23.5 (20)
Current smoking	15.4 (4)	14.1 (12)	0.985
Alcohol			0.39
Abstinence	73.1 (19)	89.2 (74)
Occasional/regular	26.9 (7)	10.8 (9)
Physically active	11.5 (3)	7.1 (6)	0.745
BMI	29.9 (26.7–31.7)	28.4 (25.2–32.8)	0.136
Years with DM	12 (4.5–27.5)	13 (8.25–20)	0.683
HBA1c (%)	6.85 (6.43–9.3)	7.9 (7.2–8.4)	0.247

p-Value was considered significant if <0.05; continuous data are expressed as mean±SD, or as median and IQR if they were not normally distributed; categorical data are expressed as frequencies and percentages.

BMI, body mass index (weight/height²); DM, diabetes mellitus; HBA1c, hemoglobin A1c.

Association with chronic diseases and PM

There was no association between consumption of CAM and comorbidities, except for peripheral arterial disease (none for consumers and 14.3% in the nonconsumer group, p=0.041). CAM consumers were less likely to use benzodiazepine (3.8% vs. 23.5%, p=0.024) and more likely to use nitrates (11.5% vs. 1.2%, p=0.039). Interestingly, 34.6% of CAM consumers used antidepressants, in comparison to only 17.6% of nonconsumers, although this difference was not statistically significant (p=0.066). CAM consumers were more likely to use glucagon-like peptide 1 (GLP-1) agonist (11.5% vs. 1.2%, p=0.039); there was no difference regarding other antidiabetic medications. Information regarding comorbidities and PM is presented in Table 2.

Table 2.

Diseases and Prescription Medications Associated with Complementary and Alternative Medicine Consumption

Disease	Consumers, % (n)	Nonconsumers, % (n)	p
PAD	0	14.3 (12)	0.041
Nitrates	11.5 (3)	1.2 (1)	0.039
PPIs	57.7 (15)	36.5 (31)	0.055
Antidepressants	34.6 (9)	17.6 (15)	0.066
GLP1 agonist	11.5 (3)	1.2 (1)	0.039

p-Value was considered significant if <0.05; categorical data are expressed as frequencies and percentages.

GLP1, glucagon-like peptide1; PAD, peripheral arterial disease; PPI, proton pump inhibitor.

Herb–drug interactions

A potential herb–drug interaction was encountered in 19 out of 26 CAM consumers (73%). A total of 44 drug–herb interactions (out of 151 drug–herb combinations) were found, 1 was major, 30 moderate, and 13 minor. The major interaction was between omega-3 and antiaggregants and was encountered in 7 (26.9%) of the CAM consumers.

Out of the 19 CAM consumers with the potential drug–herb interaction, 11 (58%) notified their family doctor about the use; however, in only 3 (15%) was the information mentioned in the patient's medical file.

Fish oil and omega-3 fatty acids particularly at high doses can inhibit platelet aggregation^16,17 and may increase the risk of bleeding, particularly in combination with antiaggregants.¹⁸ Seven patients consumed both antiaggregants and omega-3. Five of them (71%) notified their family doctor, but merely in one was it mentioned in the patient's medical files. Vitamin E also seems to inhibit platelet aggregation and antagonize the effects of vitamin K-dependent clotting factors. These effects appear to be dose dependent, and are probably only likely to be clinically significant with high doses of vitamin E.¹⁹

Several clinical studies have suggested that omega-3 may cause mild, dose-dependent reductions in blood pressure.²⁰ Therefore, it is possible that additional reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. Eight of the nine patients taking omega-3 also consumed antihypertensive drugs and six of them used two different antihypertensive agents. Six patients notified their family doctor about the consumption, but only in one was it mentioned in the medical file.

Some animal studies suggest that pyridoxine (B6) can decrease systolic blood pressure,^21
–23 which might increase the risk of hypotension when used in combination with antihypertensive agents. Four patients consumed pyridoxine, all using antihypertensive drugs as well. These patients notified their family doctor about the use, but it was mentioned in only one of the medical files. Co-enzyme Q10 can also decrease blood pressure and might have additive blood pressure-lowering effects when used with antihypertensive drugs.²⁴ One patient in our study used a combination of Co-enzyme Q10 and antihypertensive PM.

Ginkgo leaf extract seems to alter insulin secretion and metabolism, and might affect blood glucose levels in people with type 2 diabetes.²⁵ In patients with hyperinsulinemia who are treated with oral hypoglycemic agents, taking ginkgo seems to decrease insulin levels and increase blood glucose following an oral glucose tolerance test. This could be due to a ginkgo-enhanced hepatic metabolism of insulin. One patient in this study consumed ginkgo together with antihypertensive medications.

Main interactions are presented in Table 3.

Table 3.

Main Drug–Herb Interactions

Herbal supplement	Type of interaction	Interacting drug	Interaction description	Reference
Omega-3	Major	Antiaggregates	↑ Bleeding risk	^14,15
	Moderate	Antihypertensive	↓ Blood pressure	¹⁷
Pyridoxine	Moderate	Antihypertensive	↓ Blood pressure	^18,19
Vitamin E	Moderate	Antiaggregates	↑ Bleeding risk	¹⁶
Ginkgo-biloba	Moderate	Metformin	↑ Blood glucose levels	²²
	Moderate	Beta blockers	↓ Drug level	³²
Q10	Moderate	Antihypertensive	↓ Blood pressure	²¹
Green tea	Moderate	Antiaggregates	↑ Bleeding risk	^33,34
	Moderate	H2 blockers	↑ Effect of caffeine	³⁵
Fenugreek seeds	Moderate	Metformin	↓ Blood glucose levels	³⁶
Dandelion	Moderate	Antiaggregates	↑ Bleeding risk	³⁷
Cranberry	Minor	Cyp2c9 met. agents^a	Alters agents metabolism	³²
Glucosamine	Minor	Metformin	↑ Blood glucose levels	³⁸

CYP 2C9 metabolized agents including statins, angiotentsin inhibitors, antiepileptics, benzodiazepines, and antidepressants.

We found no differences between the groups of patients with versus those without interactions regarding age, gender, comorbidities, or number of PMs (data are presented in Table 4).

Table 4.

Patients With vs. Without Interactions

	Interaction (n=19)	No interaction (n=7)	p
Gender (% male)	78.6 (11)	21.4 (3)	0.665
Age (years)	69.63 (64–76)	70.57 (62–79)	0.821
Number of PM	3.29 (6–12)	3.35 (2–9)	0.107
Number of comorbidities	4.94 (3–6)	4.285 (3–6)	0.461
Notified family doctor (%)	57.9 (11)	71.4 (5)	0.668
Written in medical file (%)	15.8 (3)	28.8 (2)	0.588

Discussion

A recent study suggests that CAM consumption has increased significantly in recent decades, from 40% to over 50%.²⁶ Other studies conducted in the United States and Europe found a prevalence of 15–20%.^27
–29 A higher prevalence of consumption was recorded among women, older adults, and highly educated patients. Chronically ill patients tend to use CAM more often than do healthy subjects. In a recent trial,¹² chronic obstructive pulmonary disease and anxiety were associated with mind–body therapy use. Diabetic patients also use CAM frequently; Odegard et al.³⁰ found that over half of the patients with DM used CAM, with higher consumption rates among patients with DM2. Interestingly, the HBA1c level of consumers was lower than that of nonconsumers. In Israel, 6% reported to use CAM in a survey conducted on a random sample of the Israeli population. In this survey, no association between CAM users and DM was found. Another questionnaire-based trial establish that Israeli Arabs used herbal medications more often than Ashkenazi Jews (35% vs. 28%).³¹ As in other parts of the world, in Israel, CAM consumption is on the rise.³²

Although more data are required, dietary supplements for glucose control are considered safe.³³ Several supplements have been better studied than others and have been shown to be beneficial, such as coccinia indica and American ginseng. Dietary supplements currently being studied include Gymnema sylvestre, aloe vera, vanadium, Momordica charantia, and nopal.

Our study found that almost every fourth diabetic patient uses CAM. There were no statistically significant differences between CAM consumers and nonconsumers in terms of gender, level of education, or income. CAM consumers did use GLP-1 agonists more often—a more expensive drug among antidiabetic agents in Israel. This could imply a better socioeconomic status of these patients. CAM consumers reported their diabetes to be well controlled more often than did nonconsumers. We solely recruited hospitalized patients, who might have additional comorbidities in comparison with the nonhospitalized population; this could bias our results since these patients are prone to use CAM more frequently than other DM2 patients.^11,13 Though the rate of CAM use in our study was somewhat lower than that found in DM2 patients in previous studies,^13,14,30 it is still higher than that found in the general population in several studies.^27
–29

Most patients did not inform their physician regarding the CAM consumption, as was found in previous studies.¹⁴ Nahin et al.¹³ found that diabetic patients with a more progressive disease were more likely to use CAM, yet Spinks et al.¹⁵ did not find a better quality of life among these patients. Moreover, the more CAM was used, the worse the impact on quality of life. In our study, CAM consumers were more likely to use antidepressants, a finding that might also indicate an attempt to improve quality of life (though this finding did not reach statistical significance).

Nineteen patients with 44 possible herb–drug interactions were found, some of them affecting blood glucose levels and most affecting platelet aggregation and blood pressure. DM2 patients, especially elderly ones, suffer comorbidities and are prone to polypharmacy.³⁴ Since CAM consumption is on the rise, it is desirable to improve our knowledge concerning their potential effects and adverse effects, especially in conjunction with PM. A complete database and its standardization is warranted, but until this can be achieved clinicians should inquire about CAM consumption and seek out potential drug–herb interactions.³⁵

Conclusion

Given the potential adverse effects and interactions of dietary supplements and herbal remedies, along with the potential beneficial effects,³⁶ the use of CAM cannot be ignored.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Ritchie

. Use of herbal supplements and nutritional supplements in the UK: What do we know about their pattern of usage?. Proc Nutr Soc, 2007; 66:479–482.

Harris

, Cooper

, Relton

, et al. Prevalence of complementary and alternative medicine (CAM) use by the general population: A systematic review and update. Int J Clin Pract, 2012; 66:924–939.

Messerer

, Johansson

, Wolk

. Sociodemographic and health behaviour factors among dietary supplement and natural remedy users. Eur J Clini Nutr., 2001; 55:1104–1110.

Nielsen

, Hansen

, Rasmussen

. Use of natural medicines in the Danish population: A national cross-sectional survey. Ann Pharmacother, 2005; 39:1534–1538.

Nilsson

, Trehn

, Asplund

. Use of complementary and alternative medicine remedies in Sweden. A population-based longitudinal study within the northern Sweden MONICA Project. Multinational Monitoring of Trends and Determinants of Cardiovascular Disease. J Intern Med, 2001; 250:225–233.

Radimer

, Bindewald

, Hughes

, et al. Dietary supplement use by US adults: Data from the National Health and Nutrition Examination Survey, 1999–2000. Am J Epidemiol, 2004; 160:339–349.

Kelly

, Kaufman

, Kelley

, et al. Recent trends in use of herbal and other natural products. Arch Intern Med, 2005; 165:281–286.

Rock

. Multivitamin-multimineral supplements: Who uses them?. Am J Clin Nutr, 2007; 85:277S–279S.

Bailey

, Gahche

, Miller

, et al. Why US adults use dietary supplements. JAMA Intern Med, 2013; 173:355–361.

10.

Shaw

, Sicree

, Zimmet

. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract, 2010; 87:4–14.

11.

Miller

, Bellizzi

, Sufian

, et al. Dietary supplement use in individuals living with cancer and other chronic conditions: A population-based study. J Am Dietetic Assoc, 2008; 108:483–494.

12.

Nerurkar

, Yeh

, Davis

, et al. When conventional medical providers recommend unconventional medicine: Results of a national study. Arch Intern Med, 2011; 171:862–864.

13.

Nahin

, Byrd-Clark

, Stussman

, et al. Disease severity is associated with the use of complementary medicine to treat or manage type-2 diabetes: Data from the 2002 and 2007 National Health Interview Survey. BMC Complement Altern Med, 2012; 12:193.

14.

Bhalerao

, Bolshete

, Swar

, et al. Use of and satisfaction with complementary and alternative medicine in four chronic diseases: A cross-sectional study from India. Nat Med J India, 2013; 26:75–78.

15.

Spinks

, Johnston

, Hollingsworth

. Complementary and alternative medicine (CAM) use and quality of life in people with type 2 diabetes and/or cardiovascular disease. Complement Ther Med, 2014; 22:107–115.

16.

Schoene

. Vitamin E and omega-3 fatty acids: Effectors of platelet responsiveness. Nutrition, 2001; 17:793–796.

17.

Moertl

, Berger

, Hammer

, et al. Dose-dependent decrease of platelet activation and tissue factor by omega-3 polyunsaturated fatty acids in patients with advanced chronic heart failure. Thromb Haemost, 2011; 106:457–465.

18.

Thorngren

, Gustafson

. Effects of 11-week increases in dietary eicosapentaenoic acid on bleeding time, lipids, and platelet aggregation. Lancet, 1981; 2:1190–1193.

19.

National Academy of Sciences. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: Institute of Medicine, Food and Nutrition Board, 2000.

20.

Howe

. Dietary fats and hypertension. Focus on fish oil. Ann NY Acad Sci, 1997; 827:339–352.

21.

Hatzitolios

, Iliadis

, Katsiki

, et al. Is the anti-hypertensive effect of dietary supplements via aldehydes reduction evidence based? A systematic review. Clin Exp Hypertens, 2008; 30:628–639.

22.

Vasdev

, Ford

, Parai

, et al. Dietary vitamin B6 supplementation attenuates hypertension in spontaneously hypertensive rats. Mol Cell Biochem, 1999; 200:155–162.

23.

Lal

, Dakshinamurti

, Thliveris

. The effect of vitamin B6 on the systolic blood pressure of rats in various animal models of hypertension. J Hypertens, 1996; 14:355–363.

24.

Langsjoen

, Langsjoen

, Willis

, et al. Treatment of essential hypertension with coenzyme Q10. Mol Aspects Med, 1994; 15 Suppl:S265–S272.

25.

Kudolo

. The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic beta-cell function in response to glucose loading in individuals with non-insulin-dependent diabetes mellitus. J Clin Pharmacol, 2001; 41:600–611.

26.

Gahche

, Bailey

, Burt

, et al. Dietary supplement use among U.S. adults has increased since NHANES III (1988–1994). NCHS Data Brief, 2011; 61:1–8.

27.

Kaufman

, Kelly

, Rosenberg

, et al. Recent patterns of medication use in the ambulatory adult population of the United States: The Slone survey. JAMA, 2002; 287:337–344.

28.

Garcia-Alvarez

, Egan

, de Klein

, et al. Usage of plant food supplements across six European countries: Findings from the PlantLIBRA consumer survey. PloS One, 2014; 9:e92265.

29.

Gardiner

, Graham

, Legedza

, et al. Factors associated with herbal therapy use by adults in the United States. Altern Ther Health Med, 2007; 13:22–29.

30.

Odegard

, Janci

, Foeppel

, et al. Prevalence and correlates of dietary supplement use in individuals with diabetes mellitus at an academic diabetes care clinic. Diabetes Educ, 2011; 37:419–425.

31.

Ben-Arye

, Lev

, Keshet

, et al. Integration of herbal medicine in primary care in Israel: A Jewish-Arab cross-cultural perspective. eCAM, 2011; 2011:401395.

32.

Shmueli

, Igudin

, Shuval

. Change and stability: Use of complementary and alternative medicine in Israel: 1993, 2000 and 2007. Eur J Public Health, 2011; 21:254–259.

33.

Yeh

, Eisenberg

, Kaptchuk

, et al. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care, 2003; 26:1277–1294.

34.

Caughey

, Roughead

, Vitry

, et al. Comorbidity in the elderly with diabetes: Identification of areas of potential treatment conflicts. Diabetes Res Clin Pract, 2010; 87:385–393.

35.

Rehman

, Choi

, Choe

, et al. Interactions between herbs and antidiabetics: An overview of the mechanisms, evidence, importance, and management. Arch Pharm Res, 2014. [Epub ahead of print]

36.

Moona

, Smits

, Kertesz

, et al. Clinical inquiry: Do complementary agents lower HbA1c when used with standard type 2 diabetes therapy?. J Fam Pract, 2014; 63:336–338.

37.

Catania

, et al. Hemmorrhagic cystitis induced by an herbal mixture. South Med J, 2010; 103:90–92.

38.

Giaccari

, et al. In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: possible relevance to the maladaptive responses to chronic hyperglycaemia. Diabetologia, 1995; 38:518–524.