www.alineanutrition.com - Alinea Nutrition
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
SEPTEMBER 2021 www.alineanutrition.com
TABLE OF
CONTENTS
What We Know, Think We Know, or Are Starting to Know 03
Geek Box: Network Meta-Analysis 04
The Study 04
Results 05
The Critical Breakdown 06
Key Characteristic 06
Interesting Finding 07
Relevance 07
Application to Practice 08
References 09
02 www.alineanutrition.comZhao H, Xing C, Zhang J, He B. Comparative efficacy of oral insulin
sensitizers metformin, thiazolidinediones, inositol, and berberine in
improving endocrine and metabolic profiles in women with PCOS: a
network meta-analysis. Reprod Health. 2021 Aug 18;18(1):171.
What We Know, Think We Know, or Are Starting to Know
In a previous Deepdive, we have seen how combination therapies between nutritional
supplements and pharmaceutical treatments are of interest for Polycystic Ovary Syndrome
[PCOS]. This may reflect the complexity of the underlying pathophysiology, in particular
the relationship between androgens and insulin (1). For example, it has been observed
that both anti-diabetic drugs that are also used in treatment of PCOS - metformin and
thiazolidinediones [TZDs, of which troglitazone, rosiglitazone, and pioglitazone, and the
three main drugs in use] - may also result in increased ovulation rates (2,3).
Both of these class of drugs increase insulin sensitivity (2,3). This is instructive, as high insulin
levels drive the production of androgens, which may in turn adversely effect ovulatory
function (1). Metformin has an effect on both increasing insulin sensitivity and lowering
androgens (2). Similarly, TZDs have also been shown to lower androgens, increase insulin
sensitivity, and result in spontaneous pregnancy (3). Collectively, this evidence indicates
that for reproductive health, a concomitant reduction in androgens and increase in insulin
sensitivity may be important.
Certain nutrient supplements have also shown promise in this regard, in particular
inositol, which has two components. Myo-inositol acts as a “second messenger” for
hormonal signalling, i.e., produces signals for follicle signalling hormone [FSH] and glucose
uptake, and d-chiro-inositol, which enhances responsiveness to insulin and glycogen
synthesis (4,5). Myo-inositol alone has been shown to have beneficial effect on reproductive
function, whereas d-chiro-inositol may be superior for lowering androgens (5,6). Finally,
berberine [a plant compound], has been shown to result in significant improvements in
insulin sensitivity and blood glucose levels (7).
Thus, the question begs: for PCOS, what is the effect size of these interventions, and the
effect of potential combinations? The present study conducted a network meta-analysis* of
metformin, TZDs, inositol, and berberine in treatment of PCOS.
www.alineanutrition.com 03*Geek Box: Network Meta-Analysis
In a traditional meta-analysis, single studies are compiled together to obtain an overall summary
of effect for the particular treatment/exposure and outcome being investigated. In a network
meta-analysis, the effects of three or more interventions may be compared. This is achieved by
combining what is known as ‘direct’ and ‘indirect’ evidence. For example, let’s say we have Drug
A, Drug B, and Drug C. And let’s say that a number of studies have compared Drug A vs. Drug
C; this would be direct evidence. Now let’s say other studies have compared Drug B vs. Drug C;
a network meta-analysis would allow for an indirect comparison between Drug A and Drug B,
as they had both been compared to Drug C in other studies. This means that a network meta-
analysis is particularly useful for analysing the comparative effects of different interventions,
and can estimate how these interventions rank in effectiveness. An important assumption for
the validity of a network meta-analysis is what is known as “transitivity”. This means that there
are no systematic differences in the comparisons other than the treatments being compared,
i.e., it is as if participants could have been randomised to any of the treatments in a study and
the remaining factors would be similar. Network meta-analysis is a relatively new statistical
approach, and is a promising method for determining effectiveness of comparative treatments
on a specific condition or outcome.
The Study
The investigators conducted a network meta-analysis of the following interventions in women
with PCOS:
• Metformin
• TZDs
• Inositol
• Berberine
The outcomes were ovulatory cycle frequency, androgens [testosterone and hirsutism], and
metabolic markers [in particular insulin sensitivity, blood cholesterol].
A traditional meta-analysis was conducted, followed by the network meta-analysis. The
network meta-analysis combined the direct and indirect effects of all 4 treatments. The results
below are reported for the network meta-analysis.
04 www.alineanutrition.comResults: 22 randomised controlled trials with a total of 1,079 participants were included in
the final analysis.
Figure from the paper
which illustrates the
‘network’ of comparisons.
The size of the blue circle
represents the number
of participants, and the
width of the green line
represents the number
of included trials.
• Menstrual Frequency: The odds of improving menstrual frequency were greatest with
the combination of myo-inositol and d-chiro-inositol, which was superior to metformin or
myo-inositol alone.
• Androgens: Combination treatments were shown to be superior to individual treatments.
The combinations of metformin + berberine and metformin + TDZs were superior to
metformin alone for reducing total testosterone. The combination of myo-inositol and
d-chiro-inositol also was superior to metformin, myo-inositol or d-chiro-inositol alone for
reducing total testosterone. None of the interventions showed any difference in levels of
sex hormone-binding globulin [SHBG] or hirsutism scores.
• Insulin Sensitivity & Blood Glucose: For improving insulin sensitivity, TDZs alone, the
combination of TDZs + metformin, and the combination of myo-inositol and d-chiro-
inositol, were superior to metformin alone. The combination of myo-inositol and d-chiro-
inositol was ranked the best out of these treatments. There were no significant differences
of the treatments on fasting blood glucose levels.
• Body Weight: The combination of metformin + berberine was ranked the best among the
treatments, and was superior to other combination treatments, specifically metformin +
TDZs.
• Blood Lipids: The combination of metformin + TDZs was the most effective at reducing
triglyceride levels, while berberine was superior than metformin alone. For increasing HDL
and lowering LDL, TDZs ranked best among the treatments.
www.alineanutrition.com 05The Critical Breakdown
Pros: The participants in the included studies represented diverse ethnic populations from
Europe, South and East Asia, and the Middle East. The interventions were clearly defined - all
were insulin-sensitising agents - and measured similar outcomes. The comparative efficacy of
the different treatments is the biggest strength of the study, providing more nuanced evidence
for potential combination therapies.
Cons: As would be expected given the differences in conducting nutrition vs. pharma research,
the included studies on inositol and berberine were very small, both in number of studies
and numbers of participants. Overall, many of the comparisons were based on 1 or 2 studies.
It is arguable that the analysis failed the assumption of transitivity, as participants in the
included studies were commonly on oral contraceptives and ovulation-inducing drugs [e.g.,
clomiphene citrate], which were not treatments of interest in the analysis.
Key Characteristic
The key characteristic is the novel use of a network meta-analysis to compare the effects of
4 different types of insulin-sensitising treatments, particularly when different combinations
may be more effective than single treatments. For example, take a look at the table below for
the data for menstrual frequency:
You can see the comparisons in the far-left column; and you can see the odds of menstrual
frequency from the traditional meta-analysis [the middle column highlighted in green] and
the network meta-analysis [the far-right column highlighted in orange]. The effects were
largely similar, but looking at the overall data is it clear that the combination of myo-inositol
and d-chiro-inositol was superior to both metformin alone and myo-inositol alone. That said,
it is based on only 2 studies with 44 participants...so caveats apply!
06 www.alineanutrition.comInteresting Finding
Although we must begin with the caveat that this is based on a single study, the combination
of myo-inositol and d-chiro-inositol was superior to metformin at improving insulin sensitivity,
and was ranked the best out of these treatments.
Table from paper illustrating the effect of combination myo-inositol and d-chiro-inositol
compared to metformin alone on HOMA-IR, a measure of insulin resistance. Overall the
combination of inositol had the greatest effect on improving insulin sensitivity [i.e., lowering
the measure of insulin resistance].
This is interesting because both myo-inositol and d-chiro-inositol influence glucose tolerance
through different mechanisms. As standalone therapies, myo-inositol generally has stronger
evidence for improving glucose tolerance and insulin sensitivity (8). However, d-chiro-inositol
levels have been shown to be low in people with type-2 diabetes, and it is possible that levels
of d-chiro-inositol in cells are important for responses to insulin to take glucose into the
cell (4,5). Interestingly, metformin actually increases levels of d-chiro-inositol (9).
Relevance
Although the present analysis suggests a number of combinations which may be effective for
treatment of PCOS, it is important to bear in mind the small number of trials and small sample
sizes of those trials, and the potential for bias to influence the results.
With that caveat, however, at the broadest level this is further support for potential effects of
both nutritional supplements and pharmacotherapy, alone or in combination, for improving
a range of metabolic and hormonal outcomes in women with PCOS. This is supported by the
wider research. For example, in women with PCOS who are resistant to clomiphene [used
for induction of ovulation], the addition of metformin is effective at inducing ovulation and
achieving pregnancy (10).
Similar effects of inducing ovulation in clomiphene-resistant women with PCOS have been
shown with TDZs. It should also be noted that TZDs are potentially teratogenic, i.e., may cause
harm to foetal development (3). Thus, while they may result in increased ovulatory cycles and
spontaneous pregnancy, it is recommended these drugs are discontinued while pregnant (3).
In thinking about this line of evidence, and the effects of these treatments, it lends support to
the relationship between insulin and androgens in PCOS, and the effects of this interaction on
menstrual health. While much of the foregoing relates to drugs that are outside our scope of
practice, increasing insulin sensitivity and reducing circulating androgens may be addressed
through a number of nutritional approaches: supplemental inositol, flaxseed oil, and high-
protein, lower glycemic index diets (4-6,11-13).
www.alineanutrition.com 07Application to Practice
Ok, let’s think about the nutritional supplements in the present study that are within our
scope of practice. For berberine, however, the main effects with PCOS in this study have been
shown only with addition to metformin (7). At this juncture, current evidence for an isolated
therapy would favour inositol over berberine.
The current position supports combined therapy of myo-inositol and d-chiro-inositol
administered in the physiological ration of 40:1, which ensures better clinical results,
including the reduction of insulin resistance, blood androgen levels, cardiovascular risk, and
regularization of menstrual cycle with spontaneous ovulation (4,5).
D-chiro-supplementation alone may not be beneficial, because while myo-inositol may
be converted to d-chiro, d-chiro-inositol cannot raise levels of myo-inositol. Thus, the
combination therapy has the advantage of providing the small physiological levels of d-chiro-
inositol required, while providing higher levels of myo-inositol for both actions of myo-inositol
and further converstion to d-chiro-inositol (4).
The primary application of the present study is confirming the superiority of combined inositol
supplementation for improve insulin and androgen levels in women with PCOS.
08 www.alineanutrition.comReferences
1. Kayampilly P, Wanamaker B, Stewart J, Wagner C, Menon K. Stimulatory Effect of Insulin on
5α-Reductase Type 1 (SRD5A1) Expression through an Akt-Dependent Pathway in Ovarian
Granulosa Cells. Endocrinology. 2010;151(10):5030-5037.
2. Diamanti-Kandarakis E, Economou F, Palimeri S, Christakou C. Metformin in polycystic ovary
syndrome. Annals of the New York Academy of Sciences. 2010;1205(1):192-198.
3. Froment P, Touraine P. Thiazolidinediones and Fertility in Polycystic Ovary Syndrome (PCOS).
PPAR Research. 2006;2006:1-8.
4. Lepore E, Lauretta R, Bianchini M, Mormando M, Di Lorenzo C, Unfer V. Inositols Depletion
and Resistance: Principal Mechanisms and Therapeutic Strategies. International Journal of
Molecular Sciences. 2021;22(13):6796.
5. Unfer V, Porcaro G. Updates on the myo-inositol plus D-chiro-inositol combined therapy in
polycystic ovary syndrome. Expert Review of Clinical Pharmacology. 2014;7(5):623-631.
6. Iuorno M, Jakubowicz D, Baillargeon J, Dillon P, Gunn R, Allan G et al. Effects of D-Chiro-Inositol
in Lean Women with the Polycystic Ovary Syndrome. Endocrine Practice. 2002;8(6):417-423.
7. Wei W, Zhao H, Wang A, Sui M, Liang K, Deng H et al. A clinical study on the short-term effect
of berberine in comparison to metformin on the metabolic characteristics of women with
polycystic ovary syndrome. European Journal of Endocrinology. 2012;166(1):99-105.
8. Pizzo A, Laganà A, Barbaro L. Comparison between effects of myo-inositol andd-chiro-
inositol on ovarian function and metabolic factors in women with PCOS. Gynecological
Endocrinology. 2013;30(3):205-208.
9. Baillargeon J, Iuorno M, Jakubowicz D, Apridonidze T, He N, Nestler J. Metformin Therapy
Increases Insulin-Stimulated Release ofd-Chiro-Inositol-Containing Inositolphosphoglycan
Mediator in Women with Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology
& Metabolism. 2004;89(1):242-249.
10. Abu Hashim H, Anwar K, El-Fatah R. N-Acetyl Cysteine Plus Clomiphene Citrate Versus
Metformin and Clomiphene Citrate in Treatment of Clomiphene-Resistant Polycystic Ovary
Syndrome: A Randomized Controlled Trial. Journal of Women’s Health. 2010;19(11):2043-
2048.
11. Mirmasoumi G, Fazilati M, Foroozanfard F, Vahedpoor Z, Mahmoodi S, Taghizadeh M et al.
The Effects of Flaxseed Oil Omega-3 Fatty Acids Supplementation on Metabolic Status of
Patients with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled
Trial. Experimental and Clinical Endocrinology & Diabetes. 2017;126(04):222-228.
12. Gower B, Chandler-Laney P, Ovalle F, Goree L, Azziz R, Desmond R et al. Favourable metabolic
effects of a eucaloric lower-carbohydrate diet in women with PCOS. Clinical Endocrinology.
2013;79(4):550-557.
13. Goss A, Chandler-Laney P, Ovalle F, Goree L, Azziz R, Desmond R et al. Effects of a eucaloric
reduced-carbohydrate diet on body composition and fat distribution in women with PCOS.
Metabolism. 2014;63(10):1257-1264.
www.alineanutrition.com 09You can also read
