Medline was started in 1966 but has been expanded to record journal papers back to 1950. There are already 768 RCT metformin references listed on Medline since 1969; and 323 on metformin double blind RCTs (compare lithium- since the first in 1968, respectively 611 and 335 reports). Obviously many of these RCTs refer to it simply as background or previous or exclusion therapy or alternatives. In the 50 latest of the 323, metformin was distinctly involved in 42% as one of the trial arms; in the 50 earliest, 52% involved diabetes as one of the primary trial arms.
Thus there are perhaps 150 published double blind RCTs of metformin itself, (which after lithium- (used from about 1850) must thus be the longest (over 40years) and still regularly used and tested single chronic “drugs”. Reserpine (isolated in 1952 from a centuries-old medicinal plant) dating from the first report in 1966 is still like metformin and lithium the gold standard in it’s field of hypertension, but with only 74 and 47 reports respectively reflecting the concerted collusion of drug regulators and the drug industry to try to suppress it by no longer using it as a gold standard for comparison. All three are uniquely safe and effective in their fields provided doses are appropriately tailored. Since these old drugs have been in clinical use already for > 50years, there may be more RCTs than those listed.
Paracetamol has been in use almost the longest of any synthetic drug (from 1886), but ( unlike metformin, lithium and reserpine ) is contraindicated for long term chronic daily prevention.
But the centuries-old appetite-overweight–diabetes-reducing plant galega officinalis finally yielded up it’s unique antihyperglycemic guanide secret when dimethylguanidine- metformin was isolated 86 years ago in Dublin, Ireland by Werner and Best, the same year that insulin was isolated in Canada under the leadership of another visionary Celtic British Isles physiologist, John Macleod from Aberdeen.
If Banting and Macleod deserved the 1923 Nobel prize for insulin for DM1, more so did Werner and Bell for isolating metformin for DM2 when almost 95% of diabetics are now type 2. But hindsight is great. DM2 was only recognized a decade after insulin and metformin’s extraction (Himsworth, the Lancet 1936), like gout a relatively rare disease of lazy overindulgence for obvious reasons until the fast foods and prosperity – expanding waistlines from the 1950. So there was no impetus to develop metformin commercially in it’s first 30 years, in obvious contrast to the need for insulin for the scourge of wasting juvenile diabetes mellitus type 1 DM1 in millions of young sufferers already in the 1920s.
Werner and Bell need to be honoured as isolating by far the most important chronic drug of our time for the epidemic chronic degenerative diseases of aging in the increasingly overweight since the 1950s, (and especially with AIDs and ARVs increasing metabolic syndrome). It is a prohormone that in the overweight improves the function of the vital hormone insulin, if started preventively before diabetes and obesity develop, largely preventing obesity and metabolic syndrome MBS, and thus more than halves the incidence and mortality of diabetes and it’s fellow scourges: vascular disease, cancer, infection, arthritis etc. It has also been shown to be a prohormone in lowering TSH without affecting thyroid hormone levels, thus further reducing the tendency to obesity- related high SHBG in women with PCOS. Metformin, like lithium and reserpine, is thus bad news indeed for the Disease and Undertaking industries, to be blocked and replaced by new designer drugs at any cost.
Insulin by contrast cannot be swallowed, and works well and extends life long term only in DM1. The longest (20year – mean 13.6yrs – from 1978 to 1998) drug trial ever – on metformin and sulphonylureas, the UKPDS, has just had the 10year follow-on published.But Chakrabarti and Fearnley in UK already in 1965 described the fibrinolytic effect of metformin in coronary artery disease- and the USA chose to obstruct obstruct metformin till 1995.
So while DM1 was conquered in Canada, it was in the British Isles that DM2 was first delineated (Himsworth 1936), and metformin isolated(1922) and established for coronary artery disease (1965) and and uniquely validated for DM2 and lipidemia and all-cause mortality protection (1978-2008 – Holman ea).
But the trials confirming metformin’s unique role in improving function and outcomes in PCOS and infertility(Glueck ea), and in reversing peripubertal obesity- growth delay- DM2 (Freemark ea) , and the delineation of PCOS (Stein & Levinthal, Chicago 1935) were mostly done in USA;
and the landmark Diabetes Prevention Program DPP trials in primary prevention in the overweight, showing that metformin can more than halve the incidence of new diabetes, were carried out the past decade in China (Wenying ea 2001), USA (Knowler ea 2002) and India (Ramachandran 2006) if built up slowly from low dose (eg 125mg/day up to tolerance – a mean of about 2.7gm/d in caucasoids.
METANALYSIS of metformin effect on CRP C reactive protein: if one counts just abstracts and full papers on metformin and CRP reported on Medline and the internet, a study this month from Univ College London is at least the 14th prospective study. These studies- from USA(4), UK(2), Saudi Arabia, Finland, Greece, Bosnia, Italy, Brazil, Mexico and Israel, looked at metformin’s effect on inflammation – CRP, between 2002- and now -the paper by Chu, Reaven ea at Univ Calif San Diego; in +- 4000 subjects (20 to 3234); 6 studies with diabetes mellitus DM2; 5 studies with PCOS polycystic ovary syndrome, and 3 in metabolic syndrome MBS. These papers – including 4 RCTs- exclude those which looked futilely at burnt-out – advanced- resistant DM2 ie in those who refused to comply and reduce obesity.
This metanalysis confirms that metformin in effective dose (they tested between 850-2000mg/day for 1 to 12 months)- not even titrated to tolerance – reduces inflammation (reactive oxygen species, VLDL , raised white cell count, fibrinogen and CReactive Protein CRP); which partly explains why it is the only drug ever discovered which lowers both appetite, overweight, abdominal girth, hypertension, leptin, insulin resistance; hot flashes (due to everyday insulin resistance); cancer, hepatitis, fatty liver, blindness, kidney failure, neuropathy, gout, infectivity, CVD, stroke, arrhythmia, heart-attack, heart failure, dementia; and halves both CVD and non-CVD mortality and new diabetes; while promoting nitric oxide, HDL, fertility, successful pregnancy, normal infants and childhood growth.
It is the only drug ever tested in an RCT lasting 20years; and the only drug that in numerous RCTs has never shown a serious unpredictable adverse effect let alone related fatality.
But ignoring overweight, hypertension and PCOS, waiting till obesity let alone diabetes mellitus DM2 develops before starting metformin is negligence, since DM2 already increases risk of the many complications and death fourfold; and waiting till DM2 is severe before reversing weight gain with metformin, now requiring hypoglycemic drugs, is a criminal, terrible risk of heart, brain, kidney, limb and eye failure and premature death.
Titrated from low starter dose to tolerance – ideally with blood metformin level monitoring like many other chronic drugs – with sensible diet and without hypoglycemic drugs- metformin has no serious adverse effects ie risks. Tendency to diarrhoea and raised homocysteine can easily be prevented by both sensible dose titration and some supplement of calcium carbonate, folic acid B12 and B6- which should anyway be taken regularly as part of multisupplement for prevention of the whole group of interrelated chronic major degenerative diseases of aging .
Since it is eliminated exclusively by the kidneys, the absolute contraindications to metformin are temporary and obvious on simple observation – oligoanuria and/or acidosis (unexplained rapid breathing/ hyperventilation); and it should be stopped for a few days around xray contrast media injections.. As with any other drug, it should be briefly reduced to low dose (and if no rapid improvement, stopped) and the doctor consulted if new symptoms eg nausea, bloating, abdominal pain, faintness, confusion, unstable urinary output, rapid breathing or diarrhoea develop; and the dose re-titrated more cautiously to tolerance.
Strangely, a Statement by the American Heart Association and the NHLBI on Diagnosis and Therapy of the Metabolic Syndrome as recently as 2005 negligently failed to mention metformin as the only agent that safely and effectively lowers all inflammatory markers and risks – despite three crucial abstracts/papers already Medline-listed by 2003.
But given the universal availability of Medline, clinicians are bound first by their primary duty to practice evidence-based medicine that matters to patients. They cannot hide behind the ignorance, regulations, omissions and smokescreens of Big Pharma, regulators- bureaucrats; and especially academics who are heavily influenced by conflicts of vested interests.
$Billions are spent futilely by Big Pharma to invent and dishonestly register and market risky raincheck designer chronic drugs that attempt without success to give the crucial healthspan-prolonging multisystemic benefits of metformin (and fish oil, and appropriate vigorous supplements- vitamins, minerals and human biologicals like CoQ10 and non-oral sexhormone replacement), – including sulphonylureas, glitazones, gliptins, statins, fibrates, oral xenohormones, appetite suppressants NSAIDS and antithrombotics, ACEIs and ARBs.
Statins for example – which now gross perhaps $20billion a year in sales- have just been shown in a UK 1991-2006 analysis (compared to controls) to increase myopathy/myalgia by 10fold at 3 months, 20fold by 6 months and 27-fold at 1 year; with 10year incidence of about 0.7%. This compares with the 10year risk of hospitalized rhabdomyolysis in USA patients on modern statins of 0,044%.
But a 2007 analysis from Boston of the 23 large statin RCTs in 300 000 patient years showed inverse relation between LDL lowering and cancer – and in the recent Hong Kong study (Yang, Chan ea 2008), the cancer and death rates rose progressively when LDLC levels fell below a mean of 3.28mmol/L, while in the 2008 Baltimore statin meta-analysis in people from 60yrs upwards, cancer increased by 6% on statin.
Few of these wannabe new drugs are subjected to even 2 years of RCT, let alone the 20year RCT of metformin, before being launched on the innocent casualties, the public, by Big Pharma’s for-profit-at-any-cost War against Humanity.
Everything in life is potentially dangerous in excess, from food to love to oxygen to water; but common sense- experience- soon teaches safe doses. There is a criminal, hypocritical regulatory obsession that insists that metformin must be reserved only for PCOS and DM2 but is too dangerous to prescribe to prevent increasing overweight and disease – when it is the most-proven and safest modern drug for prevention of overweight and obesity that fuels the chronic major degenerative diseases.
A recent innovative study from the Hatter CVD Institute at University College London shows that metformin almost halves myocardial infarction size in both normal and diabetic rats. So why is it’s use so restricted, when cigarettes, the statins and NSAIDs- with multiple serious adverse effects- are allowed over-the-counter?
Metformin seems to be the only drug which addresses all organ systems that appear to be involved in the primary pathophysiology of DM2 -metabolic defects in liver and in peripheral target tissues, such as fat and muscle and pancreatic β cells.
One need look no further than the overwhelming profit motive that drives the $trillion disease industry to prefer diseases that pay to effective prevention which would more than halve the need for common drugs and acute care, that avoids banning the sale of eg cigarettes and sugar, and avoids mandatory immediate long jail term and confiscation both of driver’s license and vehicle and gun license for drunken driving especially with a weapon.
This paradox is especially obvious in the most violent warmongering “civilized” country in the world this decade under the Bush Gang- the USA – that confiscates even houses of those who grow proven medicinal cannabis for personal use, when cannabis has been long proven to have perhaps one thousandth of the toxicity of sugar or cigaretes, and a fraction of the risks of alcohol overuse .
This is the self-styled 1st-world country that leads the world – especially it’s parent Europe- in trying to suppress natural proven nutritional supplements – eg the (pro)hormones metformin and non-oral human estrogen, testosterone and progesterone, which work against the causes and mortality of common degenerative disease.
They do this so as to favour their own costly but risky and inferior chronic designer drugs and acute disease industry that rarely help resolve the chronic major aging diseases. . As usual, they promote diseases that pay, while preaching the opposite.