Citrus bioflavonoids

What it is

Hesperidin is a flavonoid (a flavanone) found in citrus fruit; oranges and orange juice are rich sources, and hesperidin and naringin make up over 90% of sweet orange flavonoids. Gut bacteria convert hesperidin to hesperetin, its main metabolite. Diosmin is a related flavonoid used in 'phlebotonic' vein products, often combined with hesperidin.

What the research says

The evidence conflicts. A 2023 dose-response meta-analysis of 13 trials reported small reductions in LDL cholesterol and systolic blood pressure, but an earlier 2019 meta-analysis of 10 trials found no effect on cholesterol or blood pressure, and a meta-analysis of 6 trials found no effect on blood sugar control. For leg vein problems, a Cochrane review of phlebotonics (a class including diosmin) found they probably reduce swelling slightly but make little or no difference to quality of life or ulcer healing, and probably increase side effects slightly. Diosmin changed how the body handles the painkiller diclofenac in one small study.

Evidence grade: Disputed.

What goes wrong

Phlebotonics, a class that includes diosmin, probably increase adverse events slightly compared with placebo, mostly gastrointestinal. (Source 1)

• Systematic review, Moderate certainty.
• Size: 5,789 participants in 37 studies.
• Who: People with chronic venous insufficiency.
• How long: Short-term trials; medium- and long-term safety unknown.
• Result: Adverse events RR 1.14 (95% CI 1.02 to 1.27)
• Funding: Independent Cochrane review.

Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence).

In 12 healthy men, 9 days of diosmin 500 mg a day raised blood levels of the painkiller diclofenac, probably by blocking the liver enzyme CYP2C9. (Source 2)

• Case series, Low certainty.
• Size: 12 healthy male volunteers.
• Who: Healthy men.
• How long: 9 days of diosmin, then a single diclofenac dose.
• Result: Increased diclofenac AUC, Cmax and half-life; reduced clearance (numbers not captured). Before-and-after design, not randomized.
• Funding: Not stated in fetched text.

Diosmin pretreatment significantly enhanced AUC, C(max) and t1/2 with a concomitant reduction in CL/f.

The 2023 hesperidin review reported that most included trials found no side effects. (Source 3)

• Meta-analysis, Low certainty.
• Size: 13 RCTs.
• Who: Adults.
• How long: Varied.
• Result: Side effects not found in most studies (rates not given)
• Funding: Not stated in fetched text.

Side effects were not found due to hesperidin supplementation in most studies.

What the evidence supports

A 2023 dose-response meta-analysis reported that hesperidin supplements reduced triglycerides, total and LDL cholesterol, TNF-alpha and systolic blood pressure, while weight increased. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: 13 RCTs, 705 participants.
• Who: Adults.
• How long: Varied; the review reported benefit on insulin with more than 8 weeks.
• Result: Significant reductions in TG, TC, LDL, TNF-alpha and SBP; weight increased; effective dose around 1,000 mg/day (exact pooled numbers not captured)
• Funding: Not stated in fetched text.

The results showed that hesperidin supplementation had a significant effect on reducing serum triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL)

A Cochrane review of phlebotonics (including 11 trials of hidrosmine and diosmin) found moderate-certainty evidence they probably reduce leg swelling slightly. (Source 1)

• Systematic review, Moderate certainty.
• Size: 1,245 participants in 13 studies (oedema outcome); 56 studies, 7,690 participants overall.
• Who: People with chronic venous insufficiency.
• How long: Short-term trials.
• Result: Oedema RR 0.70 (95% CI 0.63 to 0.78); ankle circumference MD -4.27 mm (95% CI -5.61 to -2.93)
• Funding: Independent Cochrane review.

Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants)

What the evidence does not support

The 2023 review found no significant effect of hesperidin on HDL, waist, fasting glucose, insulin resistance, CRP, IL-6, BMI or diastolic blood pressure. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: 13 RCTs, 705 participants.
• Who: Adults.
• How long: Varied.
• Result: No significant pooled effect on these outcomes.
• Funding: Not stated in fetched text.

However, no significant effect was observed on high-density cholesterol (HDL), waist circumference (WC), fasting blood glucose (FBG), insulin

A 2019 meta-analysis of 10 trials found hesperidin had no effect on cholesterol, triglycerides or blood pressure. (Source 4)

• Meta-analysis, Certainty not rated.
• Size: 10 RCTs, 577 participants.
• Who: Adults in randomized trials.
• How long: Varied.
• Result: Total cholesterol WMD -1.04 mg/dl (95% CI -5.65 to 3.57); LDL WMD -1.96 mg/dl (95% CI -7.56 to 3.64); SBP WMD -0.85 mmHg (95% CI -3.07 to 1.36); DBP WMD -0.48 mmHg (95% CI -2.39 to 1.42)
• Funding: Not stated in fetched text.

Hesperidin supplementation might not improve lipid profile and blood pressure.

A meta-analysis of 6 trials found hesperidin did not improve blood sugar control in humans, despite animal studies suggesting it might. (Source 5)

• Meta-analysis, Certainty not rated.
• Size: 6 trials, 318 participants.
• Who: Adults in randomized trials.
• How long: Varied.
• Result: Fasting glucose WMD -1.10 mg/dL (95% CI -3.79 to 1.57); no effect on insulin, HbA1c, HOMA-IR or QUICKI.
• Funding: Not stated in fetched text.

Although several animal studies have proposed that hesperidin supplementation might improve blood glucose control, the present study could not confirm this benefit in humans.

The same Cochrane review found phlebotonics make little or no difference to quality of life or ulcer healing. (Source 1)

• Systematic review, Moderate certainty.
• Size: 1,639 participants (quality of life); 461 participants (ulcer healing)
• Who: People with chronic venous insufficiency.
• How long: Short-term trials.
• Result: QoL SMD -0.06 (95% CI -0.22 to 0.10); ulcer healing RR 0.94 (95% CI 0.79 to 1.13), low certainty.
• Funding: Independent Cochrane review.

Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo

Where the evidence is mixed

The same 2023 review rated evidence quality as good for LDL and systolic pressure, moderate for most other outcomes, and low for triglycerides, TNF-alpha and BMI. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: 13 RCTs, 705 participants.
• Who: Adults.
• How long: Varied.
• Result: GRADE: good (LDL, SBP), moderate (DBP, WC, weight, IL-6, CRP, HOMA-IR, insulin, FBG, HDL, TC), low (TG, TNF-alpha, BMI)
• Funding: Not stated in fetched text.

For LDL and SBP, the quality of the evidence was good. The quality of the evidence was moderate for DBP, WC, weight, IL-6, CRP, HOMA-IR, insulin, FBG, HDL, and TC but low for TG, TNF-α, and BMI.

Where the research disagrees

Whether hesperidin lowers cholesterol and blood pressure

• Khorasanian et al., 2023 (Frontiers in Nutrition), Dose-response meta-analysis of 13 RCTs: The results showed that hesperidin supplementation had a significant effect on reducing serum triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL) (Source 3)
• Mohammadi et al., 2019 (Phytotherapy Research), Meta-analysis of 10 RCTs: Hesperidin supplementation might not improve lipid profile and blood pressure. (Source 4)

How much

• Reference intake: No RDA or AI exists for hesperidin or other citrus flavonoids; they are not essential nutrients. None of the reviews we fetched cited an official reference intake. (Source 3)
• Upper limit: No upper limit for hesperidin or diosmin was found in the sources reviewed. The Cochrane phlebotonics review noted only short-term safety data exist. (Source 1)
• Studied: A 2023 meta-analysis reported that around 1,000 mg/day of hesperidin was the effective dose across trials. (Source 3)
• Studied: Diosmin 500 mg a day for 9 days was given in the diclofenac interaction study. (Source 2)

A common belief, and what the research shows

The belief: Hesperidin supplements reliably improve blood sugar and heart risk markers because animal studies show benefits.

What the research shows: Human trial pooling does not confirm this for blood sugar: 'Although several animal studies have proposed that hesperidin supplementation might improve blood glucose control, the present study could not confirm this benefit in humans.' For cholesterol and blood pressure, meta-analyses disagree: one concluded 'Hesperidin supplementation might not improve lipid profile and blood pressure.'

Questions and answers

What is it?

Hesperidin is a natural flavonoid found mainly in citrus fruit, especially oranges. In the gut, bacteria turn it into hesperetin, the main form the body absorbs. (Source 3)

What does it do in the body?

Its effects in people are uncertain. One meta-analysis found small drops in LDL cholesterol and systolic blood pressure; another found no effect on cholesterol or blood pressure; a third found no effect on blood sugar. (Source 3)

Is it good or bad for you?

Generally well tolerated in trials. In vein products (phlebotonics, including diosmin) side effects were slightly more common than with placebo, mostly stomach upset, and diosmin raised levels of the painkiller diclofenac in one small study. (Source 1)

How do you get more of it?

Studied sources are hesperidin supplements (trials clustered around 1,000 mg a day) and citrus, especially oranges and orange juice. (Source 3)

If it is harmful, what reduces it?

Does not apply. Hesperidin is not considered harmful at dietary levels; most trials reported no side effects. (Source 3)

Why might someone be low in it or missing it?

Intake depends on eating citrus. How much the body gets also depends on gut bacteria, which convert hesperidin before it is absorbed, and on absorption generally. (Source 3)

Which whole foods contain it or feed it?

Oranges and orange juice are the richest common sources; other citrus fruits also contain it. (Source 3)

What happens if you do not have it?

Nothing specific is known: hesperidin is not an essential nutrient and no deficiency state is described. Trials adding it did not consistently change cholesterol, blood pressure or blood sugar. (Source 4)

How can you test for it?

No clinical test for hesperidin status was found in the sources we searched. (Source 3)

We searched: WebSearch for hesperidin meta-analyses and interactions; Frontiers 2023 review; Cochrane phlebotonics review

References

1. Cochrane Database of Systematic Reviews. Phlebotonics for venous insufficiency. 2020. PMID 33141449, DOI 10.1002/14651858.CD003229.pub4. Read the source
2. Drug Metabolism and Drug Interactions. Bioavailability of diclofenac sodium after pretreatment with diosmin in healthy volunteers. 2007. PMID 17708066, DOI 10.1515/dmdi.2007.22.2-3.165. Read the source
3. Frontiers in Nutrition. The effects of hesperidin supplementation on cardiovascular risk factors in adults: a systematic review and dose-response meta-analysis. 2023. PMID 37502716, DOI 10.3389/fnut.2023.1177708. Read the source
4. Phytotherapy Research. Hesperidin, a major flavonoid in orange juice, might not affect lipid profile and blood pressure: A systematic review and meta-analysis of randomized controlled clinical trials. 2019. PMID 30632207, DOI 10.1002/ptr.6264. Read the source
5. British Journal of Clinical Pharmacology. Hesperidin supplementation has no effect on blood glucose control: A systematic review and meta-analysis of randomized controlled clinical trials. 2020. DOI 10.1111/bcp.14120. Read the source