It is obvious everywhere that, however one may arbitrarily and numerically define them, overweight let alone prediabetes and obesity impairs health and function.
The Importance of Treating Overweight and Prediabetes has been repeatedly stressed in this column.
More than ten new studies published the past month or so are further mandate for early and permanent metformin use to tolerance for major reduction of both infertility and pregnancy loss, overweight and new prediabetes/ metabolic syndrome, early hypertension, lipidemia, and thus cardiovascular disease, cancer, arthritis, depression, sexual dysfunction, hirsutism and cancer; as well as managing established diabetes of either type.
Metformin in sensible use never causes more than nuisance symptoms easily prevented by gradual upwards (and if necessary downwards) dose titration; and perhaps reduces risk of death even if (like any other drug) it is foolishly continued without reduction and consultation in the face of worsening illness.
Thus like often lethal aspirin, it should simply be available at health counters and pharmacies, in contrast to statins or black cohosh which can insidiously cripple; and alcohol and tobacco smoking which are the most lethal chronic d yet unscheduled recreational addictive drugs which actively and passively kill thousands every day.
And (never mind cigarettes) unlike the invaluable metformin, there is no indication for manufacture and marketing of paracetamol acetaminaphen with which the slightest overdose- 6 tablets at once- can kill, when there are many perfectly safe natural mild analgesic-anti-inflammatory substitutes for it.
IN RETROSPECTIVE STUDIES
Tian ea Beijing 2008 found that “metformin use for a mean of 6.6years is safe even in elderly diabetics”.
Monami ea Florence Italy 2008 found that “metformin use for more than 3 years for diabetes associates with 72% reduction in cancer”..
Fronstin ea USA 2008: “analysis of 63,000 patients in a USA 2007 Health Survey showed major impact on quality of life – loss of work productivity of 5.6 weeks per year for prediabetic patients compared to their healthy counterparts. Less than 40% of all prediabetic patients are even aware of their condition and therefore can’t take the steps necessary to prevent it from progressing to a full diabetes diagnosis.” This stigmatizes the overweight as patients, but the stark loss of productivity (in all spheres of life disussed below) requires this to bring home the obligation on health carers, families, parents and employers let alone the public to take early and sustained action.
Gundewar ea 2008 New York & Harvard show that “lowdose metformin given from the time of myocardial ischemia halves mortality from heart failure”.. as was shown in Canadian diabetics on metformin, whose mortality was halved;
Wang ea Shanghai China 2008 show that ”Metformin significantly inhibits cell proliferation and apoptosis in all human pancreatic cell lines”;
CARMOS (Greece 2008) was not a double-blind but an open randomised RCT “in 366 overweight / obese middle-aged subjects around 53yrs, BMI 32kg/sqm, bloodpressure around 140/89 but without cardiovascular disease CVD. Metformin just 850mg/day compared to standard management for 1 year lowered the incidence of new diabetes from 8.1% to 1.1% ie by 86%; lowered the incidence of new prediabetics from 18.5% to zero; and the incidence of metabolic syndrome from 15.5% to 2.6% ie by 83%; and significantly lowered LDL cholesterol. There was no significant fall in body mass index BMI compared to the controls.” The average tolerated Western dose of metformin in diabetics is 2.55gm/d, which in the obese produces a sustainable loss of about 6kg – up to 20kg; but in perhaps more out-door living Greeks on the legendary Mediterranean diet, even that moderate dose of metformin did wonders, so presumably their previous experience with it must have justified that dose. And of course, without some measurement of relative fat/lean mass,or of subcutaneous fat and waist girth, one cannot say if they showed meaningful fat loss with gain of lean mass. .
By contrast, in a Dumlupinar University trial 2008 in Turkey “324 mostly overweight patients [with white coat hypertension WCH, mean 47yrs (15 to 70yrs) , 42% overweight and 44% obese] self-selected themselves for a 6month open trial of standard care with or without metformin metformin up to 2.55gm a day. Compared to controls, those on metformin lost 6.6kg weight vs 2.1kg(C); WCH resolved in 69% (M)vs 26%(C); lipidemia in about 50% (M)vs 17%(C); normalization of fasting bld glucose occurred in 44%(M) vs 9%(C); and improvement from obesity to overweight or overweight to normal weight in about 20%(M) vs 4.5%(C).” Thus metformin at standard dose was 3 to 5 times as effective as standard therapy alone in reducing obesity, WCH and lipidemia.
Toronto University gave metformin 1500mg/day to 32 nondiabetic women with raised insulin and breast cancer for 6 months, showing that it significantly lowered risk factors for both CVD and cancer – insulin resistance, lipidemia and obesity.
A Johns Hopkins review (Nicholson 2009) confirms that, while metformin greatly improves fertility and pregnancy outcome, in gestational diabetes metformin gives far lower rates of neonatal hypoglycemia than insulin .
Resvanian ea Isfahan Iran 2008 show that metformin 1500mgday greatly enhances Intense-Pulsed-Light-Assisted Hair Removal in Patients with Polycystic Ovary Syndrome.
Ratner ea in the USA DPP 2008 show that after pregnancy diabetes, metformin halves the occurrence of later diabetes.
These studies thus add weight to the previous gold standard evidence making obligatory the early and permanent use of metformin to tolerance at any age in all who cannot keep their weight and waist girth within normal limits: ie estimated body fat (by bioimpedance analysis BIA scale, by Harpenden calipers or by calculation from BMI) below about 15kg (Knapik 1983), or waist girth below about 80cm in men, 75cm in women. Absolute body fat is more realistic than relative ie percentage fat since those who exercise regularly may have far higher lean mass %. Obviously 15kg of fat will be less obvious on a 2m tall 90kg person (ie 16.67% fat) than one of 1.5m (ie 30% fat).
While the average “first-world” middle-aged woman today measures a hefty ~33% body fat, and while no more than about 5kg of body fat seems essential for health (except in freezing climates), the exception (apart from a to-some desireable feminine full figure) is women trying to fall pregnant, in whom body fat of about 12-15kg ie 20-22% seems optimal for fertility (Rose Frisch’s hypothesis; debated by van der Spuy ea). At much above or much below this fat level, hypothalamic-pituitary- adrenal– gonadal regulation understandably skews away from fertility. There is obviously heavy controversy over whether mankind acquired it’s capacity for limitless adipocyte growth (and thus suicidal obesity) due to evolution via aquatic apes, as opposed to extended survival in ice ages- which except for eg the Esquimeaux, polar bears and walrusses, ended some 20 000 years ago – and the ice caps (and their obese denizens) are fast disappearing with global warming.
But the plant extract metformin is the only drug proven by centuries of use and 80 years of research that with sensible use to tolerance (like all other foodstuffs) if started early and permanently, reduces all common major chronic degenerative diseases by about half – and new diabetes by up to 90% – as reviewed repeatedly in this column, – other new studies from St Petersburg Russia (Anisimov ea), 80), Tennissee (Gosmanova ) , and UK – Bodmer, Holman UKPDS and Bailey about Metformin: A multitasking medication.
The 1-year CARMOS trial joins the three ±3year landmark (China – Wenying: Chin J Endoc Metab, 2001,17,131-6; USA 2002; & Indian 2006) Diabetes Pevention Program DPP trials showing what we see in Africa, that in very different races and regions (ie on all continents), metformin reduces the incidence of new diabetes (depending on baseline body build, energy intake /expenditure, and startup and final metformin dose) compared to placebo – by 27% in India (metformin 0.5gm/day) to 31% USA (1.7gm/d) to 60% China (0.75gm/d) to 83% Greece (0.85g/d). Thus in full tolerated dose (mean 2.55gm/d in the UKPDS) which none of these trials claim to use), metformin must add decades to health.
Both evidence and common sense show that:
i. there is much genetic variation in human metformin metabolism, and
ii. there is some metformin dose:body mass proportionality; and
iii. metformin complements, but does not replace the need for sensible diet and exercise, and
iv. metformin does not do away with the need for minimization of any drugs which reduce insulin sensitivity eg salt, cooked fat, alcohol, oral estrogen especially with progestin, sugars, betablockers, cortisones, psychotropes, diuretics, antidiabetics, and smoking/snuff (and arguably even aspartame- the infamous Canderal). Like tobacco use, refined sugar and cooked fats are anything but necessary and healthy foodstuffs – with alcohol overuse, they are the prime causes of the saccharine diseases -especially if combined with each more than about 10gms a day.. .
So to avoid early drop-out (25% in the USA DPP), metformin HCl – easily buffered by eg calcium carbonate- must always be started low eg at 125mg (1/4 tablet) twice a day, and built up to comfortable tolerance (by perhaps 25% increase in dose each day) over a few weeks; with in case of new symptoms, the dose temporarily stopped for a few doses till symptoms subside, and then resumed with slower upwards dose adjustment;
It is common cause that sexual and erectile function never mind reproduction are progressively impaired by increasing obesity and thus insulin- glucose intolerance, and glycation.
And even in diabetics let alone prediabetes, metformin with sensible use has zero adverse effects that are not easily avoided/ reversed by dose reduction- as shown in both giant metformin trials in type 2 diabetics that were completed a decade ago: the almost 20 year long UKPDS (Holman ea) – about 12000 patient years; and the year -long landmark American COSMIC trial (Cryer ea at Bristol-Myers-Squibb BMS 2005 ) some 9000 patient years- mean age 58yrs.
When we asked, BMS refused to explain why the results of the COSMIC trial – done on USA volunteers- were scandalously not published for some 7years. While the numbers were too small to reach statistical significance, the table of adverse events in their trial showed that especially in the 2/3 over 65yrs, gastrointestinal, infection, neoplastic and vascular adverse effects were 25% to 66% more common in the control group than on metformin. The only paper apparently ever published on the COSMIC trial did not mention the changes in blood sugar / other markers achieved; but did show the remarkable superiority of metformin: “By study end, 90% of the metformin group and 77% of the usual care group were still receiving their initial study treatment, while 5.4 and 19%, respectively, had switched to the alternative treatment arm. Apart from adverse events, the most common reason for switching from initial treatment (<1% of patients) was lack of efficacy (1.5 % vs 4% respectively in the metformin and usual care groups).
In fact, when we asked for the paper, BMS and their parent metformin patent-holder Merck actually denied knowledge of this biggest-ever planned metformin ab initio trial in diabetics (mandated by the FDA and started in 1996 as a condition of registration in USA) even in 2005 after the results had first been presented at a diabetic congress.
This inexusable delay in publication may or may not be due to the fact than these metformin-partner companies first wanted to see the successful launch of their new patent combination Glucovance (metformin plus a sulphonylurea- either glyburide or glibenclamide), on which the first human RCTs were published only in 2002 -and which have been increasingly discredited except as last-ditch therapy due to the serious risks of sulphonylureas. “One already-marketed combination diabetes pill, Glucovance, a combination of metformin and glyburide, generated sales of $330 million in 2001″. “Glucophage (metformin), which had more than $1.3 billion in sales in 1999 (presumably in USA), loses patent protection in September (presumably in USA, in 2000). The economics of antidiabetic drugs are staggering: ”Diaßeta glyburide in the U.S. and Canada; glibenclamide in most of the rest ….. World-wide sales of oral diabetes medications reached $7.8 billion in 2003″.
So antidiabetic drugs alone generate sales of around $10billion a year?
The $multibillion smoking-alcohol industry aside, overweight is the main natural gateway to diabetes, hypertension, lipidemia, ischemic and hypertensive heart –brain- kidney and peripheral vascular disease, dementia, arthritis, cancer and thus decades- premature disablity and death. So the global market for high technology created by the epidemic of overweight plus smoking (including cosmetic and cardiovascular procedures) must already have passed $trillions a year.
And a cheap safe plant derivative like metformin or galega, combined with other panaceas like vitamins, minerals and plant and animal biologicals can reduce this epidemic by up to 90%.
No wonder Merck, BMS, Pfizer, Bayer and their fellow Big Pharma and research and political connections including Regulators and Governments do everything in their power to cover up, suppress, regulate non-patentable supplements (including galega) that can eliminate the profitability (and most jobs) of the disease industry, and largely do away with research for new remedies for the chronic major degenerative diseases.
A Medscape review now reminds us in ”Diabetes and Cardiovascular Disease Among Older Adults: An Update on the Evidence” that “Treatment should be individualized with consideration given to patient preference and quality of life.” But this is not licence for regulators, doctors and medical schemes to disparage and delay preventative metformin use, or people to continue reckless obesogenic diet and lifestyle, which takes decades off life and, worse, off healthspan; and the sooner makes them (or their dependents) unnecessarily needing the support of others.
Metformin is the only chronic preventative drug that in tolerated (and low cost) dose – alone but especially combined with appropriate other supplements (vitamins, minerals and biologicals including fish oil and hormone replacement- reduces ALL risks of the major chronic degenerative diseases from conception to death. Contrary to the vested interests that promote disease and newer synthetic drugs, there is never an absolute contraindication to metformin – merely appropriate dose adjustment.
Thus metformin is the necessary obligatory first drug to prescribe permanently for all with overweight/ excess body fat; let alone those with tobacco/alcohol use, suspected polycystic ovary syndrome; (pre)hypertension; lipidemia; vascular disease; and prediabetes/ diabetes.
Until metformin is made available without prescription, it is freely available as the parent herb galega officinalis – even if retailers have to be forced to order the standardized herb extract to US/UK/Japanese pharmacopoea standard on request. Like metfomin and antihypertensive and most other drugs, the dose of galega is simply cautiously built up to tolerance and effectiveness – in this case appetite reduction and gradual weight loss.