Abstract

The objective of this study was to evaluate the scientific evidence on stevia, including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. This review serves as a clinical support tool. Electronic searches were conducted in 10 databases, 20 additional journals (not indexed in common databases), and bibliographies from 50 selected secondary references. No restrictions were placed on the language or quality of the publications. All literature collected pertained to efficacy in humans, dosing, precautions, adverse effects, use in pregnancy and lactation, interactions, alteration of laboratory assays, and mechanisms of action. Standardized inclusion and exclusion criteria were used for selection. Grades were assigned using an evidence-based grading rationale. Based on the availability of scientific data, two indications are discussed in this review: hypertension and hyperglycemia. Evaluation of two long-term studies (1 and 2 years in length, respectively) indicates that stevia may be effective in lowering blood pressure in hypertensive patients, although data from shorter studies (1-3 months) did not support these findings. A pair of small studies also report positive results with respect to glucose tolerance and response, although the relatively low methodological rigor of these experiments limits the strength of these findings. Further investigation is warranted in both indications.

The drugs come with ‘an unacceptable risk’ of causing type 2 diabetes, and they are only half as effective as newer hypertension drugs such as the ACE inhibitors, according to practice guidelines issued by the National Institute for Health and Clinical Excellence (NICE) last month.

The announcement, described as the ‘most significant’ in NICE’s history, was forced on the advisory group by reports last autumn that beta-blockers had killed tens of thousands of hypertension patients when a more benign and effective therapy was available.

The dangers of beta-blockers were already being highlighted 16 years ago.

One study discovered that hypertension patients who suddenly stopped taking a beta-blocker were very likely to suffer a heart attack and death (JAMA, 1990; 263), while another study, published eight years ago, discovered they were no more effective than a sugar pill (JAMA, 1998; 279: 1903–7).

But it has been the continued revelations from ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) that finally forced NICE’s hand. ASCOT, which recruited 19,257 hypertension patients aged between 40 and 79 years, has been pointing out for years both the dangers and shortcomings of the beta-blockers, but NICE decided to form a review committee only after a damning study was published in September 2005 (Lancet, 2005; 366: 895–906).

This trial established that the beta-blockers were reducing the risk of stroke by 19 per cent compared with the 38 per cent effectiveness of the ACE inhibitors. Beta-blockers were also responsible for the deaths of 3 per cent more patients than other anti-hypertensives.

Beta-blockers (beta-adrenergic antagonists) are designed to decrease the heart’s need for blood and oxygen by reducing its workload. They also help the heart to beat more regularly.

Nobel prize winner Sir James Black developed the drug in the 1950s as a way of combating heart diseases such as angina after he realized that adrenaline, our ‘fight or flight’ hormone, puts a sudden demand on the heart.

Adrenaline triggers the release of glucose reserves into the blood. They bind to receptors on the membrane of the heart cells that cause the heart to beat faster. The hormone also constricts arteries to increase the rate at which blood is pumped around the body.

It took another ten years before the first beta-blocker—propranolol—was licensed for use. Ironically, Black and his team at Glasgow never developed it as an antihypertensive, but it was quickly used as this and for many other conditions that can be worsened by a sudden restriction of the arteries.

Within just a few years of it appearing on the market, propranolol was being used to treat migraine, glaucoma, tremor, hyperthyroidism, and performance anxiety and enhancement.

Propranolol quickly established itself as the beta-blocker for all ills. Not surprisingly, the American Association of Poison Control Centers (AAPCC) each year receives reports of 2.4 million adverse reactions to the drug in the USA alone, and 1,184 fatalities associated with the drug.

Tragically, it is also the ‘drug of choice’ for people attempting suicide, while its widespread use means that almost every home has some, and 510 children under the age of six die every year after swallowing drugs prescribed for their parents.

What now for the beta-blocker? The drug industry has a wonderful way of reinventing drugs that have been finally discredited, and the beta-blockers are no exception.

One researcher at Baylor College of Medicine in Houston, Texas, believes they could be the answer to osteoporosis. Prof Gerard Karsenty believes that the drug could block bone destruction (Nature, 20 Feb 2005), a theory that has been supported by another trial, which found that people taking beta-blockers also suffered fewer fractures (JAMA, 2004; 292: 1326–32).

And psychiatrists at Cornell University believe they could be used to help suppress disturbing memories in people who witnessed a traumatic event such as 9/11 or the London terrorist bombings. Propanolol has the ability to block the neurotransmitters involved in laying down memory, and so it could be used for victims of post-traumatic stress disorder (PTSD), the researchers postulate.

The Cornell team wants to recruit 60 volunteers who would be prepared to take the drug whenever they experienced a PTSD symptom, such as increased heart rate or breathing difficulties.

It’s a therapy that has not been met with universal approval.

Dr Paul McHugh, a psychiatrist at Johns Hopkins University in Baltimore, says: “If soldiers did something that ended up with children getting killed, do you want to give them beta-blockers so that they can do it again?”

Bryan Hubbard

Now, I’m taking a ‘water pill’, bendroflumethiazide (2.5 mg), which does not hurt my stomach, and does not interfere with my kidney function (so far). And my blood pressure is more or less normal.

But I can’t help feeling that I’ve been treated as a guinea pig, and might have ended up with stomach ulcers or similar if I’d carried on with all the stuff I was being given. – Brigitte French, via e-mail

WDDTY replies: We’re sorry to say that bendroflumethiazide, a diuretic, comes with its own problems. In fact, around 3 per cent of patients using diuretics find the accompanying side-effects unacceptable (Pharmacotherapy, 2001; 21: 940-53). These include impotence, dizziness on standing (due to too-low blood pressure), blood disorders, skin reactions, gout, pancreatitis, and depleted levels of potassium, magnesium, coenzyme Q10 and zinc. There is also evidence that diuretics may be ‘harmful’ in people with coronary heart disease (J Cardiovasc Pharmacol, 1990; 16: 58-63). For safer ways to keep blood pressure in check, see WDDTY vol 14 no 8.

Accutane works by preventing acne from developing, while most other treatments (such as antibiotics and Retin-A) attempt to control acne once it has appeared. And there’s no doubt that it’s effective. Approximately 85 per cent of patients treated with a single course of Accutane have a positive response in terms of acne reduction (Adv Dermatol, 2003; 19: 1-10).

However, because it’s a high-risk treatment, with side-effects ranging from impaired hearing to fatal haemorrhagic pancreatitis, Accutane is supposed to be the last-chance saloon of acne medicines, reserved for cases where all other treatments have failed.

But like many drugs, the drug is overprescribed for all forms of acne, despite major concerns that it is teratogenic (able to damage the fetus when used in pregnancy). But now, there’s an even more immediate concern – the possibility that Accutane causes depression and even suicide in its users (Am J Ther, 2004; 11: 507-16).

According to American congressman Bart Stupak, whose son committed suicide while taking Accutane, French health authorities required Roche to add “suicide attempt” to the drug’s list of side-effects in 1997. Roche, however, neglected to inform the US Food and Drug Administration (FDA) of this side-effect. The FDA only became aware of these side-effects when its MedWatch received reports of people taking Accutane who either committed suicide or were hospitalised for suicide attempts or severe depression (see below). These made isotretinoin the third highest on the MedWatch list of the most frequently reported drugs.

In February 1998, the FDA insisted that Roche add a bold-face warning to its physician package insert regarding depression and suicidal thoughts (with the UK and Ireland following suit a month later). By 2000, the full psychiatric warnings – in bold, and covering depression and suicide as well as intracranial hypertension – were included on the package label itself. The FDA stated that “patients treated with Accutane should be observed closely for symptoms of depression or suicidal thoughts”. Patients and their caregivers are warned to discontinue treatment and seek further evaluation if symptoms of depression – such as irritability, acting on dangerous impulses, weight changes and aggression – develop.

The depression connection
Among the voluntary FDA reports received, 37 were suicides, 110 were cases where patients had been hospitalised for depression or suicidal tendencies, and 284 were cases of general depression. In all of these cases, there was a time link between use of the drug and onset of depression (J Am Acad Dermatol, 2001; 45: 515-9).

Individual case reports have also drawn attention to the link between Accutane and suicidal depression. In one instance, five men developed manic psychosis following exposure to the drug. In three of them, the psychosis lasted for more than six months. Three of the men also attempted suicide (Int Clin Psychopharmacol, 2005; 20: 39-41).

In another case, a young man developed symptoms of acute depression just two weeks into the therapy. His symptoms improved as the dosage was reduced, and worsened as it was increased. He eventually attempted suicide. When he finally stoppped the medication, his suicidal depression resolved (World J Biol Psychiatry, 2001; 2: 159-61).

Although Accutane is now among the FDA’s top-10 list of drugs associated with suicide – and Britain’s Medicines and Healthcare Products Regulatory Agency (MHRSA) is currently assessing reports of suicide or suicidal attempts associated with the medication – a link between Accutane and suicidal depression has yet to be clinically proven (Int Clin Psychopharmacol, 2005; 20: 39-41).

Nevertheless, studies have found that the drug decreases brain metabolism in a part of the brain that regulates mood. Furthermore, depression and suicide can occur in patients using Accutane who don’t have a personal or family history of either (Am J Psychiatry, 2005; 162: 983-91; Am J Ther, 2004; 11: 507-16).

It has long been known that Accutane can damage fetuses, but this hasn’t stopped it being handed out to women of childbearing age. Indeed, a number of cases of fetal abnormalities and miscarriages have been linked to the drug (J Clin Pharmacol, 1989; 29: 463-5).

To Dr David J. Graham, mph (Masters in Public Health), Associate Director for Science in the FDA’s Office of Drug Safety, the solution is clear-cut. In testimony to the US Senate Committee on Finance last November, the veteran scientist stated that, of 12 drugs for which he has recommended market withdrawal during his career, Accutane is one of the two that remain available.

Last month, the FDA approved a strengthened risk-management programme called ‘iPLEDGE’ to reduce possible Accutane exposure during pregnancy. The programme will ensure that US prescribers and patients agree to specific responsibilities so that women do not fall pregnant while taking Accutane (and aren’t given prescriptions if they are already pregnant). For example, women of childbearing age must have with a negative pregnancy test to receive the drug, and prescribers must assume responsibility for their pregnancy counselling. As of 31 December 2005, all potential prescribers and patients must be registered on the iPLEDGE system.

The UK and France have led a recent European initiative, the Pregnancy Prevention Programme (PPP), with prescriptions limited to only 30 days and only valid for a week.

In the UK, only specialists in dermatology – and not GPs – are currently allowed to prescribe oral isotretinoin.

Kim Wallace

Researchers found that patients whose blood pressure was measured by ambulatory monitoring where levels are recorded throughout the normal working day with a device strapped to the patient needed fewer drugs than people whose blood pressure is monitored in the normal way.

Ambulatory monitoring avoids the “white coat effect”, when blood pressure is raised unnaturally when a patient gets to the hospital. It is also more accurate than the standard testing, and is not open to interpretation from the operator (JAMA, 1997; 278: 1065-72).

A survey of 300 GPs by the London School of Tropical Medicine found that most of them were using equipment which falls below standards set by the British Hypertension Society.

Quite simply, the cuffs they were using to wrap around the patient’s arm to measure blood pressure were too small to give accurate readings. A too small cuff will overstate a patient’s blood pressure.

The mean length of the cuff used on normal weight or lean people was 11cm shorter than the recommended length. Only 7 per cent of respondents were able to say what the correct sizes should be.

A high sodium to potassium ratio has been shown to increase extracellular fluid volume, which hinders blood pressure regulation (Am J Clin Nutr, 1984; 39: 963-8).

Other studies have demonstrated that magnesium levels are consistently low in those with hypertension, and supplementation can help. In a double blind study, magnesium supplementation lowered blood pressure by an average of 12/8 mm/Hg in 95 per cent of the treatment group (Br Med J, 1983; 286: 1847-9).

Diets that are low in animal fats but high in polyunsaturates also reduce high blood pressure (J Am Med Ass, 1990; 263: 688-92; Ann Med, 1989; 21: 251-4).

This seems to be due to the normalization of the E-series pros taglandins, which are known to be low in patients with high blood pressure (Clin Exp Hypertension, 1981; 3: 27-38).

This effect stops when aspirin is taken, so that hypertensives who take daily aspirin are doing exactly the wrong thing (Acta Biol Med, 1978; 37: 879-83).

Giving up alcohol also has been shown to decrease blood pressure within a week (Proc Nutr Soc, 1988; 47: 111-4).

Because a high sucrose diet seems to impede the uptake of potassium, blood pressure usually drops on a low sugar diet ( J Am Coll Nutr, 1987; 5: 79).

Higher dietary fibre can also lower blood pressure. For a half a year, 32 patients consumed about two thirds of their calories in the form of uncooked food. Diastolic blood pressure was reduced by an average of 17.8 mm/Hg, there was a mean weight loss of 3.8 kg and, most astonishingly, those who smoked or habitually drank alcohol spontaneously abstained (South Med J, 1985; 78: 841).

Besides general dietary measures, other naturopathic measures have helped. In a large randomized, blinded, controlled trial, high blood pressure patients were given daily portions of guava fruit, a good source of vitamin C, fibre, potassium and magnesium. Those on the guava diet showed an increase in plasma ascorbic acid, a reduction in the serum total cholesterol and triglycerides, a substantial lowering in systolic and diastolic blood pressure, as well as a net increase in high density lipoprotein cholesterol (the “good”variety) (J Nutr & Envir Med, 1997; 7: 5-14).

An infusion (or tincture type preparation) of the evergreen leaves of Olea europaea (Olive tree) have been used as an effective anti hypertensive since the turn of the century. Such a decoction contains the substance oleuropein, which not only helps reduce hypertension, but also dilates coronary blood vessels and regulates heartbeat (Am J Chin Med, 1979; 7: 197-236).

Quitting smoking will also get your pressure down. Cadmium has been shown to raise blood pressure. Tobacco smokers, and ex tobacco smokers, have more cadmium in their bodies than others, and hypertensives tend to have cadmium levels about three times higher than those with normal blood pressure (Lancet, 1976; i: 717-8).

Lose weight and root out food allergies. A number of epidemiological studies have shown the link between excess weight and hypertension (Ann Int Med, 1983; 98: 855-9). Food allergies have often been found to underlie hypertension (Mackarness, R, Not all in the Mind, London, Pan Books, 1976).

It’s also better to drink hard water, which contains more magnesium and calcium than soft water, Absorption of these minerals from drinking water is twice that from foods, where chelating agents have a hindering effect (Prog Food Nutr Sci, 1985; 9: 109-47).

!AHarald Gaier

Harald Gaier is a registered naturopath, homeopath and osteopath.

* Circulatory problems, including a reduced or increased platelet count (J Eur Acad Dermatol Venereol, 2004; 18: 718-20).

* Nasal-tip deformities in patients who have had nasal surgery (Aesthetic Plast Surg, 2005; 29: 102-6).

* Heart palpitations (Pacing Clin Electrophysiol, 2005; 28: 348-9).

For safe alternative treatments for acne, see WDDTY vol 15 no 1.

The Stop 2 trial concluded that among hypertensive people aged 70 to 84 the reduction in blood pressure and the risk of a major cardiovascular events were the

same, whether patients were given conventional therapy (defined as a hydrochlorothiazide/

amiloride combination and/or one of three beta blockers) or a newer therapy such as a calcium channel blocker (in this case felodipine) or an ACE inhibitor (enalapril or lisinopril).

The trial was large 6614 patients and was conducted over a reasonably long period of time. Apart from the main conclusions, some other interesting things came out of the trial such fact that nearly half of all the patients in the study were taking more than one drug. By the time of their last visit, only two thirds of the patients were still taking the same medications they were taking at the beginning of the trial.

Being overmedicated or switched between medications, often without a rational reason, continues to be a problem for

elderly patients. It was also a problem for the researchers, too making it difficult to ascertain the true impact of the drugs studied.

Across all three drug groups, side effects were common. More than a quarter of patients in all three groups suffered dizziness, and ACE inhibitors produced a dry cough in a third of patients (Lancet, 1999; 354: 175 -6).

l Another smaller trial has also added to the debate about heart medicines. The ELITE-2 trial, which was designed to show the superiority of sartans (losartan) over ACE inhibitors (captopril) found that there was not much difference between them. Although the patients in the ACE inhibitor group had a slightly lower mortality rate and a lower prevalence of sudden death, the difference between the two types of drug did not really reach significance (Lancet, 1999; 354: 1797).

Researchers reckon that 78 per cent of the hypertension in men and 65 per cent in women is directly caused by obesity. Prevention is better than cure, say the researchers, and there needs to be a strong emphasis on weight control among young and middle aged adults.

!ANew Eng J Med, 1996; 334: 1571-6.