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04(19/2003 20:45 252-945-5985 WASHINGTON EYE PAGE 02

Carbonated Soft Drinks and Diabetic Retinopathy- Are there Any

Effects?

by

Dennis A. O'Neal, 0.0. 04/14/03

A Master's paper submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Master of Public Health in

the School of Public Health, Public Health Leadership Program.

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ABSTRACT

The purpose of this study is to test whether or not drinking moderate quantities of carbonated soft drinks has any effects on diabetic retinopathy in patients with Insulin-dependent diabetes Mellitus.

Based on personal observations, diabetic retinopathy, especially if accompanied with diabetic macular edema, seems to improve when discontinuing moderate quantities of carbonated soft mdrinks1. Therefore it was hypothesized that carbonated beverage consumption may have an adverse effect on patients with diabetic retinopathy, specifically those with diabetic macular edema.

Diabetic Macular Edema

Dietary salt is responsible for raising blood pressure, thickens and stiffens conduit

arteries and thickens and narrows resistance arteries. It also increases the number of strokes, and the tendency for platelet aggregation37. An increased total body sodium and enhanced vascular reactivity are found in people with diabetes and most type 2 diabetics are salt sensitive. Similar to a subset of patients with essential hypertension, type 2

diabetics manifest dietary salt-induced exacerbation ofhypertension36.

Sympathetic nerve overactivity is crucial in the pathogenesis of hypertension in diabetes.

It is related to the activation of the rennin-angiotensin-aldosterone (RAA) system in.

Sympathetic overactivity stimulates RAA activity, promotes sodium reabsorption, and increases heart rate, stroke volume, and peripheral vascular resistnce, thus inducing

Diabetic Retinopathy

Diabetic retinopathy remains a major cause ofloss ofvision.2 Overall, diabetic retinopathy is estimated to be the most frequent cause of new blindness in the U.S.

among adults between the age of20-74 years8. Diabetic retinopathy is characterized by

microaneurysms, hemorrhages, and lipid accumulation referred to as hard exudates,

within the retina. Microaneurysms are thin-walled dilations of the capillaries that develop

in diabetic patients as the pericyte cells which line the capillaries, die off and weaken the

capillaries, causing a "ballooning", of the capillaries, or microaneurysm. Macular edema

(retinal thickening) is an important manifestation of diabetic retinopathy as it is the

leading cause of legal blindness in diabetic patients. Retinal thickening of macular edema

is a result of intercellular fluid derived from both leaking micro aneurysms and diffuse

capillary leakage9. patients with diabetic macular edema have a significant impaired

visual acuity. Diabetic maculopathy is closely associated with diabetic nephropathy and

neuropathy and with several atherosclerotic fisk factors which suggest that these factors

may have an important role in the pathogenesis ofmaculopathy4•

Medical treatment of macular edema with carbonic anhydrase inhibitors have been

known effective treatment of cystoid macular edema in patients with diabetic macular .L '

edema in nonproliferative retinopathy, even though mechanisms remain obscure20•

although it may facilitate the transport of water across the retinal pigment epithelium

from the subretinal space24. Carbonic anhydrase inhibitors have also been shown to have

acidification of the subretinal space, a decrease ofthe standing potential as well as an

increase in the retinal advesiveness25 .. The enzyme carbonic anhydrase catalyzes the

conversion of carbon dioxide and hydroxide ion into bicarbonate22.Acetazolamide, a

diuretic, is a carbonic anhydrase inhibitor, primarily effects the kidneys by inhibiting

carbonic anhydrase. Its mechanism of action is inhibits caarbonic anhydrase, which in

turns catalzses the haydration of bicarbonate at the proximal tubule in the kidneys,

facilitating the resorption of virtually all of the sodium21. By inhibiting hydrogen ion

secretion by the renal tubules, carbonic anhydrase inhibitors cause increased excretion of

electrolytes, sodium, potassium, bicarbonate, and H20, thus producing alkaline diuresis 23

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As carbonic anyhdrase inhibitors increase the excretion of sodium, potassium,

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bicarbonate, and water, and improve diabetic macular edema, discontinuation of

carbonated soft drinks (which contain the above electrolytes), may have a similar

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effect1.Carbonated soft drinks have been part of American lifestyle for more than 100 years. Soft drinks contain between 90% water in regular soft drinks, up to 99% water in

diet soft drinks. Carbon dioxide is the essential ingredient in all carbonated beverages.

Soft drinks also contain flavors, coloring, caffeine, acidulants, preservatives, potassium,

phosphorous, sodium, sucrose or high fructose com syrup in regular (non-diet) soft

drinks, and aspartame, saccharin, sucralose and acesulfame Kin diet soft drinks. One out

of every four beverages consumed in America is a carbonated soft drink, which averages

io over 57 gallons of soft drinks per year for every man, woman and child 7. T'nis is

equivalent to more than 576 12-oz. servings per year or 1.6 12 oz. cans per day for every

man, woman, and child28.Carbonated soft drinks account for more than 27% of

sales29. Carbonated soft drinks are the biggest source of refmed sugars in the American

Caffeine in soft drinks

Caffeine in soft drinks varies by brand, from 0 mg. in caffeine-free and 7-Up, to 58mg

per 12 oz.in Josta Cola. Most standard brands (Pepsi, Coca-cola) contain between 37.5 to

46.5 mg. per 12. can27

Caffeine, sodium, hypertension, and diabetes

Diabetes and hypertension are both relatively common diseases in westernized countries.

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I Both diseases increase with age. Hypertension is twice as frequent in diabetic patient than

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in the general population38. Essential hypertension accounts for the majority of

hypertension in people with type 2 diabetes, which what? Type 2 diabetes or essential

hypertension?] constitutes more than 90% of those with dual diagnosis of diabetes and

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hypertension. The benefit conferred per mmHg of Blood pressure reduction is greater in

persons with type 2 diabetes than with hypertensive patients without diabetes. Recent

guidelines have recommended that target blood pressure levels in patients with diabetes

should be lower than in other hypertensive groups31. It is currently recommended that

individuals with diabetes maintain a blood pressure ofless than 130/85 to maximize renal

protection33. An increased total body sodium and enhanced vascular reactivity are found

Caffeine raises blood pressure by elevating vascular resistance, and this effect is more

pronounced and prolonged in hypertensive patients than in normotensives32. Regular

coffee drinking raised blood pressure in older hypertensives35.

Known Risk Factors in Diabetic Retinopathy

The best predictor of diabetic retinopathy is the duration of the disease 10. Patients who

have had insulin-dependent diabetes mellitus (IDDM) for 5 or less years rarely show

evidence of diabetic retinopathy11• However, 27 of those who have had IDDM for 5-l 0

years and 71 to 90% of those who have had IDDM greater than 10 years have diabetic

retinopathy. After the diagnosis ofNon-insulin-dependent diabetes mellitus (NIDDM),

67% of patients had retinopathy and 10% had proliferative diabetic retinopathy (PDR) 12.

Systemic Factors

Control of blood glucose

The Diabetes Control and Complications Trial (DCCT), published in 1993, was the first

large, scientific, and clinical trial demonstrated a marked reduction in the development

and progression of diabetic complications in intensively treated patients3. More recently,

the U.K. Prospective Diabetes Study confirmed that intensively controlled patients with

type 2 diabetes had a significantly reduction in microvascular complications 4.

Patients with renal disease (proteinurea, elevated blood urea nitrogen, and elevated blood

creatine) almost always have retinopathy13. However, only 35% of patients with

retinopathy have proteinuria, elevated blood urea nitrogen, or elevated creatine14. [I don't

understand this]

Body Mass Index (BMI)

Body mass index, or BMI, [higher? Lower?]is a positive risk factor for diabetic

retinopathy19. Body mass index is expressed as weight in kilograms divided by the square

of the height in meters.

Systemic Hypertension

Elevated systolic blood pressure is a moderate risk for diabetic retinopathy14, whereas

other studies have shown that diastolic blood pressure is important for the development

of retinopathy in type 1 diabetes15. Control of systemic hypertension reduces the risk of

new onset diabetic retinopathy and slows the progression of existing diabetic

retinopathy15. Pulse raterate [high? Low?] may be an indicator of overall risk of diabetic

retinopathy, but is not an independent association with the condition16.

Race

The prevalence of diabetic retinopathy is more prevalent in blacks compared to whites 17• In addition, blacks have a higher rate of severe macular edema and blindness, probably because of a higher incidence of severe systemic hypertension and because of poorer

These studies demonstrate evidence that good metabolic control protects diabetic patients

against complications. However, clinicians are faced with individual variability of

diabetic patients in their practices, often wonder why some patients under good metabolic

control develop complications while others remain free of complications, despite poorly

controlled diabetic , remaincontrol5. Studies have shown that retinopathy develops in

about 10% of patients with type 1 diabetes under good metabolic control, whereas over

40% of patients with type 1 diabetes remain retinopathy-free despite poor metabolic

The present study is to observe if moderate consumption of carbonated soft drinks has

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any effects on diabetic retinopathy.

RESEARCH DESIGN AND METHODS

ii'-Records from a retina specialist's office were reviewed. Only patients with

insulin-dependent diabetes mellitus with diabetic retinopathy and macular edema during the

period of 1998 -2003 were selected. . A computer program was written in Hypercard 2.4

(Apple™) was designed to perform searches in patient records for all patients within the

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retina practice that include patients with IDDM, have documented word with "sodas" or

"carbonated drinks" and a diagnosis of "macular edema". All patients had diabetic

retinopathy at baseline and patients with previous laser treatments at initial visit were

historical cohort study design was within on patients within the retina clinic; using

patients with insulin-dependent diabetes mellitus with diabetic retinopathy who drink

carbonated drinks compared to a similar group of diabetic patients with retinopathy, but

did not drink carbonated beverages. The prevalence of diabetic macular edema in each

group was then compared.

From approximately I 0,000 medical records, about 3,500 patients with Insulin-dependent

Diabetes Mellitus (IDDM) were extracted. Of those patients, 1,849 patient records had

"soda" or "carbonated beverages" documented within the record. I ,278 patients had

macular edema and drank at least I -12 oz. can of soda per day, and had the diagnosis of

diabetic macular edema. 158 patients drank at least I can of soda per day and did have

diabetic macular edema. 355 patients had diabetic macular edema, but did not drink

sodas. 49 patients had IDDM and no macular edema, and had documented "no sodas" or

"does not drink sodas" in their medical records.

Calculation of the prevalence of disease in persons with exposure (sodas) and compare it

with the prevalence of disease (macular edema) without exposure. Odds Ratio in a 2 X 2

Table I.

Sodas No sodas

Odds Ratio • Macular Edema and Sodas

Controls

Macular edema No macular edema (exposed)

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12781 1581

(not exposed) 355 46

Odds Ratio= a/c =

bid

Odds Ratio= 58788 56090

Odds Ratio= 1.048101266

ad be

1:

1:

In addition, a survey was performed to estimate the carbonated beverage dinking

habits of diabetics, compared to non-diabetics. The survey included categories of age,

sex, race, no. of years having diabetes if diabetic. Efforts were made to include an

caffeine-average soda consumption, categories of sodas were tabulated, and pie graphs were

generated.

The study design has been submitted to the Institutional Review Board for approval.

Definition of carbonated soft drink users

In this study, the definition of a carbonate soft drink user was anyone who drinks 1 or

more, 12 oz. cans of soda or equivalent, each day.

Results

Of the sample surveyed, 88% of non-diabetics drank sodas, averaging 1.4 sodas per day,

while 70% of diabetics drank sodas, averaging 1.4% sodas per day. 60% of non-diabetics

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drink regular sodas, 28% drank diet, while in the diabetic group, 52% drank diet, and

18% drank regular sodas. (Figures 1 and 2).

Fig.l

Soda Consum tion: Non-diabetics

Fig.2

%non-diabetics who do not drink

sodas 12%

%non-diabetics who drink regular

sodas 60%

Soda Consumption: Diabetics

o % diabetics who do not drink sodas

30%

1111 % diabetics who drink regular sodas 18% %non-diabetics who drink diet sodas 28%

l!!ll % diabetics who drink diet sodas

52%

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~-Risk- Odds Ratio

The Odds Ratio in our group studied, or the ratio of the odds of development of disease

in exposed (to sodas) persons to the odds of development of disease (macular edema) in

non-exposed (no sodas), was 1.05 demonstrating that there is not an apparent association

between soda drinking and diabetic macular edema. If the exposure is not related to the

disease, the odds ratio will be equal to 1.

Conclusions

From this study, there is no clear association between drinking sodas and diabetic

macular edema, demonstrating a spurious association from observation noted above

within the retina clinic. However, due to confounding, we cannot rule out an association

between macular edema and soda consumption. As soda consumption was not quantified,

no dose-response was measured. Errors from selection bias may have a major impact on

the internal validity of the study. Information bias or inaccuracies of data acquisition

may have, at times, misclassified information regarding exposure status. Further

studies-prospective, case-controlled, and clinical trials studies are needed for more conclusive

evidence whether there is no association between carbonated beverage consumption and

diabetic macular edema.

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~-Acknowledgments

1. Personal communications, Peter VanHouten, M.D., retina specialist, East Carolina Retina Consultants, Greenville, NC 27834

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