WHY PREVENT OBESITY? “Obesity alone may be the best predictor of undiagnosed diabetes in subjects aged 45 to 75 years according to new results of the Netherlands DiabScreen Study (Woolthuis, Univ Nijmegen). Among diagnostic models using various risk factors, the best predictor of undiagnosed diabetes was obesity alone (OR, 3.2).
There are currently 435 trials, reviews and metanalyses on Pubmed under ‘metformin and prevention before diabetes’. BIGPRO 1991 seems to be the first analysis on Pubmed about metformin prevention of diabetes; followed by the 1999 USA Diabetes Prevention Program planning paper. But since the 3year Chinese Diabetes Prevention Trial (Yang Wenying ea) was published already in June 2001 (the English translation) , it must have started a full year or more before the USA DPP.
Unlike preselected highly motivated volunteers in trials like the 2002 USA DPP Diabetes Prevention Program testing lifestype-diet and exercise, in real life few at risk patients let alone the obese are capable of preventing never mind reversing obesity by diet and exercise. Yet in RSA neither State clinics nor medical schemes will provide metformin for early and permanent prevention of obesity. Why this prejudice against metformin, when the evidence since the UKPDS trial – the longest and biggest rigorous drug trial ever- a generation ago – is overwhelming?
PREVENTING DIABETES? Recently Lilly & Godwin (Newfoundland) reviewed “Treating prediabetes with metformin; showing that metformin decreases the rate of conversion from prediabetes to diabetes both at higher (1700mg daily) and lower dosage (500-750mg daily); in people of varied ethnicity; and even when a sensitivity analysis was applied to the data. The number needed to treat was between 7 and 14 for treatment over a 3-year period.
PREVENTION IN CHILDREN:
There is only one paper on metformin for weight loss in boys, from Morrison ea in Maryland in 2002, which showed that it is as valuable in boys as it is in girls and adults with obesity- insulin resistance caused by psychotropes. There is one paper – Freemark ea 2001 North Carolina – similarly showing the uniform benefit of metformin in boys as in girls with prediabetes. Experience with metformin in adults shows no significant difference in response between the sexes- provided there is reasonable compliance with both sensible diet, lifestyle and metformin titration to tolerance.
Ibanez ea at Univ Barcelona have done landmark controlled trials of metformin in the past decade: in 2000 they showed the dramatic effect of metformin in even nonobese ~17year old girls with PCOS, restoring normal menses within months- with relapse as soon as metformin was stopped. in 2002 the “additive effects of insulin-sensitizing and anti-androgen (flutamide) treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. Between 2004 and the present they have published a series of trials showing that “Insulin sensitization early after menarche prevents progression from precocious pubarche to polycystic ovary syndrome. Girls with low birth weight (LBW) and with a history of precocious pubarche (pubic hair before the age of +-8years) in childhood (PP) are at high risk of polycystic ovary syndrome (PCOS) in adolescence. In untreated LBW-PP girls, insulin sensitivity, serum androgens, lipids, total and truncal fat mass, and lean body mass significantly diverged further from normal over 12 months. In metformin-treated girls, all these abnormalities significantly reversed within 6 months, and body composition continued to improve at 12 months. “They found the first evidence that 1) prepubertal metformin therapy has normalizing effects on PCOS features in high risk girls with a combined history of LBW and PP; and 2) in adolescence, metformin’s normalizing effects are reversed as soon as metformin therapy is discontinued. And in 2006: “Metformin therapy during early-normal onset puberty (for 36 months -mean age at start, 9.0 yr- all girls remained untreated between 36 and 42 months) delays menarche, prolongs pubertal growth, and augments adult height.. Now in 2009 : “Puberty is part of a critical window in which adiposity and its correlates can be fine-tuned toward reproduction, which implies that puberty provides an opportunity to reprogram a misprogramming that occurred in early life. LBW girls with PP ( mean age 8 years, BMI Z-score 1.3) were randomized to remain untreated or to receive metformin across puberty (425 mg/d for 2 years, then 850 mg/d for 2 years); subsequently, all girls were monitored without intervention. The benefits of metformin were mostly maintained during the posttreatment year so that, after 5 years, unlike the untreated girls, metformin therapy was associated with: 2cm taller height; 9% higher lean mass; with 5kg less total fat, 50% less visceral and liver fat; BMI Z score 1.4sd lower; much better lipids; with much lower circulating levels of androgens and leptin; and with elevated levels of high-molecular-weight adiponectin and undercarboxylated osteocalcin.
THE PRIORITY: PREVENTION OF OBESITY AND IT’S COMPLICATIONS – DIABETES, VASCULAR-RENAL, CANCER, DEMENTIA, BLINDNESS: Haffner & Cassells San Antonio 2003 discuss “Hyperglycemia as a cardiovascular risk factor. Patients with type 2 diabetes mellitus have a 2- to 4-fold increased risk of coronary heart disease (CHD) and a 4-fold increase in mortality from CHD; and an increased risk of cardiovascular mortality before the onset of type 2 diabetes. The presence of CHD before the onset of clinical diabetes provides strong evidence for a strategy of diabetes prevention in at-risk patients. Data indicate that the atherogenic pattern of changes in the prediabetic state is seen primarily in insulin-resistant patients rather than in those with abnormally low insulin secretion. Therefore, strategies to prevent or treat type 2 diabetes should focus on improving insulin sensitivity. Clinical trials have demonstrated that lifestyle changes (e.g., diet and exercise) as well as use of metformin, acarbose, or glitazone reduce the incidence of type 2 diabetes. Prevention of type 2 diabetes may be an important strategy to delay or prevent cardiovascular disease in many individuals.
Scheen AJ. 2007 Liege, Belgium discusses “prevention or early treatment of type 2 diabetes? Besides lifestyle, various pharmacological treatments have proven their efficacy to reduce the incidence of type 2 diabetes in high-risk individuals, especially in those with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG). Owing to the pathophysiology of the disease, the only way to block the progression of type 2 diabetes is probably to avoid the progressive loss of beta-cell function and/or mass. Data obtained in large clinical trials bring further argument to support early treatment even at a prediabetic state, in order to stop the vicious circle leading to an inevitable deterioration of glycaemia in predisposed subjects.
But the low cost of the 80year old metformin aside, the heavily marketed antiobesity and antidiabetic drugs are precluded from routine preventative use in obesity and in diabetes– acarbose and orlistat by formidable side-effect (steatorrhoea/,diarrhoea), others by major risks- sibutramine (cardiovascular) and glitazones (heart failure, weight gain) .
Metformin on the other hand used in appropriate dose to tolerance has been shown over more than 50 years of use, in the longest drug trial ever (UKPDS – 30year followup), and in 4 major prevention trials lasting a mean of over 3 years on 4 continents (China then USA then India then Greece) in over 4000 prediabetics to have no significant risks but lower new diabetes and other common chronic degenerative diseases and all deaths by around half. No other patent and prescription drug does this – only natural supplements like metformin; fish oil; combined vitamin-mineral-biologicals; and appropriate sex-hormone replacement have this irrefutable evidence base.
THE VESTED INTERESTS AGAINST METFORMIN PREVENTION:
EVIDENCE-BASED OR VESTED-INTEREST MANDATE? But practicing medicine in South Africa [governed by the Marxist/Communist-run ANC which like most governments allows it’s cadres to corruptly accumulate massive wealth at the expense and to the detriment of taxpayers and the poor] – is unique: doctors and other health professionals, (like teachers), are proclaimed to be the only professions who are expected to carry out life-or-death work and yet are stridently told they are not entitled to commensurate due rights and income (as other professionals or businessmen or politicians) for the “privilege” of lifelong high risk dedication to healing, teaching and the necessary constant study these entail.
And we are under threat of penalty if we do not perform constant updating – but are threatened with prosecution if we dare to follow the best evidence-based medicine and not guidelines laid down by bureaucratic institutions whose members are mostly either non-practicing health professionals, or who are linked to Big Pharma – the $billion Disease technology industry.
Hence we are criticised if not threatened if we prescribe the evidence-based gold standards- metformin, vitamins- minerals, biologicals and appropriate sexhormone replacement, reserpine and lowdose amiloretic – for crucial prevention of all major common degenerative diseases, but do not prescribe the heavily marketed but inferior snakeoil modern drugs like statins, other antidiabetics, antihypertensives, bisphosphonates and some vaccines (now including those still-unproven safe necessary and effective against HPV -cervix cancer, and swine flu) that are dictated by manufacturer-driven ‘guidelines’. .
As this column has previously discussed, the problem with metformin and the dozens of other natural supplements is that (unlike much-marketed still-patented drugs) they are virtually the only medicines that address the cause of common disease, and are so successful at actually ~halving these diseases and allcause mortality.
Since Only Disease Pays Big Business (and the governments, bureaucrats, p0liticians, regulators and lobbyists- including researchers- that Big Business buys), vested interests – certainly in USA, UK, Europe and RSA- relentlessly suppress the cheap and old remedies that work, compete too well against modern prescription drugs.
DEDICATION: to metformin the best-established panacea/ pleomorphic drug, and the pioneers: it’s discoverers Werner & Bell 1922; Francis Lovell’s studies on insulin resistance in the 1940s; Turner & Holman of the UKPDS from the 1970s; Per Bjorntorp’s 50years of obesity and lipidemia research; LS Hermann’s Recent Review of Metformin Pharmacology 1996 (in Handbook of Exp Pharmacology 1996:119:263-407), JD Lalau’s 20year clarification of it’s protective effect in severe illness eg lactic acidosis; Gerald Reaven for advancing the concept of Metabolic Syndrome; and Lourdes Ibanez, Charles Glueck and the 4 major DPP trialists (China, USA, India and Greece) for irrevocably establishing metformin as mandatory prevention against PCOS, gestational diabetes and it’s morbidity, metabolic syndrome, obesity and diabetes.