Adjusted simply and slowly up to the tolerated dose, metformin use in type 2 diabetics for 30 years- without any major adverse effects longterm – lowers myocardial infarctions and deaths by 30%; over about 5 years it halves mortality, and reverses weight gain to maintain overweight about 6% lower than at baseline; and in prevention trials it halves incidence of new diabetes. .
Search under “disease time bomb” on Google brings up many lurid reports on heart, lung, liver, kidney, obesity, infection threats etc;
eg last week: : “In a new report published in the Lancet Scientists say we need an Integrated approach to tackle the chronic disease ‘time-bomb’. Salt and tobacco control, cheap combination drugs for cardiovascular disease as well as simple, easily-applied mental health interventions are all recommended to tackle the disease. The report claims a combination course of therapy involving several drugs for people at high risk of cardiovascular disease could cost as little as $1.10 per person, avert millions of deaths over the next ten years. Management of chronic diseases in primary health care was fundamentally different from that for acute care. Primary health care was probably more effective when complemented by effective public policies to tackle the major risk factors, such as tobacco use, obesity, and excessive salt consumption.
This month, as the Paralympics enthral the world, six new studies – gold medals- reaffirm the primacy of galega officinalis- the origin of galegine and thus metformin (Werner and Bell 1922) – as the parent panacea herb ahead of all comers including statins:
1. A major trial in St Petersburg Russia (Anisimov ea) shows that feeding female rats metformin slowed down the switchoff of oestrus function and increased mean lifespan by 38% and maximum life span by 2.8months- despite failing to influence spontaneous tumour incidence.
2. A Swiss analysis (Bodmer) of 50 000 United Kingdom type 2 diabetics (mean age 61yrs at enrolment) in general practice in the decade to 2005 – ie mostly after the 20year UKPDS trial to 1997 – reassuringly confirms the safety of metformin as shown in the uniquely long UKPDS. .
3. The 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes (Holman UKPDS 80) shows that after up to 30years of use in 3277 diabetics, metformin in still attending enrolees continues to sustain about 30% reduction in myocardial infarction and all-cause mortality – double the reductions by insulin-sulphonylureas- even though there was no longer difference in the HBA1c level achieved. .This confirms that metformin has unique major benefits beyond lowering raised blood glucose.
4. in Diabetes Vascular Disease Research, the diabetes editor Prof Cliff Bailey from Birmingham UK writes about Metformin: A multitasking medication.
5. In a Veterans Affairs study (Gosmanova U Tennissee) of 2200 diabetics patients over a mean of 5 years, after multivariate adjustment, metformin users had significantly 23% decreased all-cause mortality compared with non-metformin users (P < 0.01).
6. The ALLHAT study (Rahman USA ) confirmed that In hypertensive patients with moderate dyslipidemia and impaired kidneys, pravastatin was not superior to usual care in preventing clinical renal outcomes.
Safe reduction by 50 to 70% of progression of overweight and the progressively irreparable damage and risk that goes with type 2 diabetes (eg AGES- advanced glycation endproducts) is obviously the mandatory duty of health workers, using promotion of healthy diet and lifestyle as well as pre-obesity prediabetic prescription of harmless (antioxidant-anticancer – antivascular disease pro-nitric oxide) insulin sensitizers like fish oil, metformin, vitamin C, carnitine, CoQ10, arginine and appropriate human sex hormones .
Already in 2000 Bell & Ovale from Alabama calculated that “when monotherapy fails to control diabetes, combination therapy with a sulfonylurea and metformin is potentially effective in maintaining glycemic control and avoiding the addition of insulin or a thiazolidinedione for a mean duration of 7.9 years“. Thirty years of UKPDS followup has amply confirmed this- even in 1998 the UKPDS 24 concluded that “obese patients allocated to metformin gained the least weight and had the fewest hypoglycemic attacks. For all therapies, control achieved at 6 years was worse in the primary diet failure group than in the diet-controlled group. Because initial insulin therapy induced more hypoglycemic reactions and weight gain without necessarily providing better control, it may be reasonable to start with oral agents and change to insulin if goals for glycemic levels are not achieved”
THE EFFECTIVE ANTIHYPERTENSIVE PARADIGM:
By contrast UKPDS 81 published simultaneously with UKPDS 80 last week showed that in the hypertension study of the UKPDS, after another 10 years of followup of hypertensive diabetics, the original (cardiovascular) benefit of tighter hypertension control was lost along with the loss of tighter bloodpressure control.
Thus in contrast to the pluripotential benefits of metformin beyond it’s glucose-regulating benefit, even the multiple antihypertensives used in UKPDS patients (betablockers, ACEI, furosemide, nifedipine, methyldopa or prazosin) had no extra heart- or all-disease protection beyond that of tighter hypertension control (just as statins have no benefit other than via improving CVD through lowering lipidemia; and bisphosphonates no benefit beyond lowering fractures via better bone density).
This is in stark contrast to the gold standard triple best-ever treatment of mild-to-moderate hypertension – lowdose reserpine about 0.05 (to 0,1)mg daily plus lowdose 6,25 (to12.5)mg hydrochlorthiazide plus 0.6 (to 1.25)mg amiloride (ie amiloretic) daily- as shown in numerous trials and studies from the 1970s Veterans to the 1990s German Reserpine Group and USA SHEP trials, and the more recent ALL-HAT trial; and the Cache County study .
But because these agents are too effective and cheap- costing <US6/year – they leave little market need for newer patented designer antihypertensive (and stress-blocking and calcium-magnesium- potassium sparing) drugs that simply do not work as well – and mostly have major potential adverse effects. So Regulators, academics and Hypertension “Authorities” -certainly in Europe, UK and South Africa – who depend on the new drug industry for their living – have simply and infamously dropped them – see the UK -European and RSA State Formularies.
Even Wikipedia subtly mocks eg the UK- Europe cynical disaster capitalism for dropping reserpine:
“Reserpine has been discontinued in the UK for some years due to its vast interactions and side effects. (but..) is one of the few antihypertensive medications that have been shown in trials to reduce mortality: the HDFP, the VA Study Group in Anti-hypertensive Agents, and SHEP. Reserpine is listed as a second line choice by the JNC 7. . It is an excellent second agent for patients who are uncontrolled on a diuretic. It is also used to treat symptoms of dyskinesia in patients suffering from Huntington’s disease. In some countries reserpine is still available as part of combination drugs for the treatment of hypertension, in most cases they contain also a diuretic.. These combinations are currently regarded as second choice drugs. The daily dose of reserpine in antihypertensive treatment is as low as 0.1mg… At doses of less than 0.2 mg/day, it has few side effects, most common is nasal congestion.There has been much concern about it causing depression leading to suicide.. however this was reported in uncontrolled studies using doses averaging 0.5 mg per day”.
In SHEP the Systolic Hypertension in the Elderly Program trial in 4700 subjects from 1988 for a mean of 5 years, even an ordinary thiazide diuretic significantly lowered CV D mortality by 15%, with improved longterm outcomes. but more important, reduced stroke by 36% and mortality by 40%.. And reserpine 0.05 to 0.1mg/d as add-on in resistant cases approximately halved risks of stroke, CVD or mortality.
ALLHAT The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial from 1994 to 2002 with >42, 000 patients was the largest antihypertensive trial. It confirmed that a diuretic is still overall the baseline best therapy of essential hypertension compared to calcium channel (or beta-) blocker or ACEI, even for metabolic risk factors ; and that adding a statin for mild to moderate lipidemia did not improve mortality or reduce renal decline ; and as in SHEP, reserpine as backup add-on was unsurpassed. (Barzilay 2007: Getting to goal blood pressure: why reserpine deserves a second look ; J Clin Hypertension: 2007:9:591-4)
Reserpine is criticised for many adverse effects in overdose. But what foods and therapies do not have adverse effects in overdose? As authorities here and elsewhere have to admit, reserpine and amiloretic have been sidelined simply because they are so powerful, low cost and safe in well below “traditional” dose – and they do not attract research funds because they put modern wannabe baseline substitute drugs down to 4th-line add-ons.
This does not contradict the paradigm of good nutrition, that both drug prevention and micronutrient therapy should also be broadly based, multiagent for early and maximum control to prevent progression and irreversible damage, as in eg hypertension, AIDS, vascular disease, tuberculosis, osteoporosis, arthritis, memory loss, osteoporosis etc. .
Bodmer’s 2008 Swiss UK study also confirms what other studies showed – the three continents’ Diabetes Prevention Program DPP trials (Wenying 2001 Chinese J Endoc Metab, Knowler 2002 USA, Ramachandran 2006 India); the massive one-year COSMIC trial in USA in new diabetics (Cryer 2005); the Saskatchewan retrospective metformin study (Johnson 2002-2006), the ACCORD trial 2008, and now the Veterans’ Study 2008 –
that apart from giving significantly better outcomes and thus survival in both diabetics and pre-diabetics (halving the incidence of new diabetes), metformin to tolerance is also uniquely safer than all other antidiabetic drugs in if anything protecting against co-incidental lactic acidosis (common in older diabetics; Lalau & Race 2000), and with sensible use not producing the hypoglyemia that plagues use of all other (ie hypoglycemic) antidiabetic drugs..
METFORMIN AGAINST CANCER:
The panacea role of metformin is further strengthened by the June 2008 report (Gonzalez-Angulo) from the MD Anderson Cancer Centre Texas that ” diabetic women who developed breast cancer on metformin had treble the pathologic breast cancer complete response rates ie up from 8% to 24% compared to women not on metformin“. This is further evidence for starting metformin early and permanently in anyone who cannot maintain ideal body fat with diet and exercise alone.
a McGill University study (Gotlieb ea 2008) shows that metformin significantly inhibits the growth of ovarian cancer cell lines and potentiates cisplatin .
METFORMIN AND FRACTURES:
the latest study, from Monami Italy 2008 again shows a trend to metformin reducing osteoporosis fractures.
METFORMIN AND LONGEVITY:
It has been known for at least 70 years (McKay 1935) if not millennia that dietary caloric restriction (CR) is the only intervention conclusively shown to slow aging and prolong health and vitality in mammals and all species down to yeasts. Ingram, Roth ea at the NIH have confirmed this (2001) “in primates with 2 deoxyglucose, and proposed it also with metformin (2005). Furthermore, it is not known whether CR extends longevity in long-lived species or in the already lean. There is evidence that CR in obese and lean subjects alike improves insulin sensitivity“.
Whether it applies equally or more so to good quality CR diet remains to be seen, since historically those subjected involuntarily to CR have been on poor quality food.
But very few free-living species willingly undergo permanent calorie restriction.
Mikhail Blagosklonny (a medical scientist and basic science journal editor at the Ordway Research Centre at Albany Medical College who has authored over 140 publications especially in cancer) comments last week (Cell Cycle. 2008 Sep;7:2615-8). “Cancer and aging: more puzzles, more promises? “Anisimov shows that metformin activates AMP-activated protein kinase, prolongs both mean and maximal life span and prevents reproductive aging of female mice. Unexpectedly, metformin did not decrease the incidence of cancer in this mice strain. Here, we discuss the relationship between aging and cancer, the mechanism of metformin action, and the prospects of using this compound for life span extension in humans. .
Last year Blagosklonny wrote (An anti-aging drug today: from genes to anti-aging pill. Drug Discov Today. 2007): ”Numerous mutations increase lifespan in diverse organisms from worms to mammals. Most genes that affect longevity encode components of the target of rapamycin (TOR) pathway, thus revealing potential targets for pharmacological intervention. I propose that one target, TOR itself, stands out simply because its inhibitor (rapamycin) is a non-toxic, well-tolerated drug that is suitable for everyday oral administration. Preclinical and clinical data indicate that rapamycin is a promising drug for age-related diseases and seems to have anti-tumor, bone-sparing and calorie-restriction-mimicking ‘side-effects’. I also discuss other potential anti-aging agents (calorie restriction, metformin, resveratrol and sirtuins silent information regulator 2 proteins) and their targets, interference with the TOR pathway and combination with antioxidants.” But unfortunately rapamycin while it is antifungal and pluripotential, does not have insulin-sensitizing weight-reducing benefits, is very costly (eg Sirolimus 100mg US$199), and does not have the warranty of centuries of safe use as does galega/metformin.
His and Anisimov’s work proposes that such antiaging regimes delay both senescence and cancer, so that when cancer does break through, the “longevity” regime no longer inhibits it. This concurs with the landmark supermouse studies of Lemon and Rollo at McGill who showed by 2005 that in genetically obese and shortlived mice, a lifelong 31-ingredient multimicronutrient supplement from infancy to death (including the evidence-based vitamins, minerals, biologicals and herbs like flaxseed and DHEA – but not metformin nor fish oil), improved learning, and longevity by 28%, but many of the males developed lymphoma.
These pioneer rodent studies seem to work on the dosing principle that the metabolism of rodents is 10 times faster than that of humans; so the 100mg/kg/day metformin that Anisimov’s group used equates to a modest 10mg/kg/day in humans, or 750 -1500mg/day in the overweight. It remains to be seen whether this modest dose will be effective in global anti-aging prevention for the average overweight person; as opposed to double that dose ie around 2650mg/day achieved and tolerated and needed by average overweight diabetics on metformin.
Using metformin for secondary prevention (ie for the still-well of any age who cannot sustain weight below a threshold of say BMI 25 or 27kg/sqm)- long before the development of diabetes, obesity and PCOS polycystic ovary syndrome – remains the minefield for most health workers. Many health professionals – who should know better- still propound the naive dogma that patients can and must change their personalities and permanently stop smoking and start dieting and exercising strenuously enough to diminish obesity. Yet do even 10% of patients achieve and maintain even 5% weight loss with such urging, let alone get anywhere near optimal body composition?.
This dilemma of human inability to comply is nicely summed up by Shelley Wood’s Medscape report on the Lifestyle, Not Drugs, for Preventing Type 2 Diabetes “Gladiatorial” Debate at the EASD meeting last week. “Dr Zimmet argued that “glucose-lowering drugs importantly prevent progression to diabetes… environmental, cultural, economic, and sociopolitical forces work against lifestyle changes in developed countries, many of which are amplified in other parts of the world. Preventing onset of type 2 diabetes is to reduce the risk of CVD, the clock starts ticking long before the line we actually call diabetes. And whether lifestyle changes alone will be enough to alter long-term effects remains unproven. Lifestyle interventions can work, but maybe only where you put people in prison and then rigorously control their exercise and diet regimen,” he said.
Whereas continued metformin use for 30years in the UKPDS associated with 30% fewer myocardial infarctions and deaths.
CONCLUSION: Metformin is the only agent that has been shown (after about 80 years, and centuries as the parent herb galega) to safely and permanently assist voluntary effort to restrict calorie intake so as to reduce weight gain and extend health – and has been strikingly successful in achieving and maintaining about 6 to 8% average weight loss in the obese (eg Glueck 2006), while halving the incidence of new diabetes and halving the deathrate in diabetics, adding maybe at least a decade to health and life.
No designer ie patented multi-tasking drug for chronic use since metformin (- except possibly the too-cheap discarded combination of lowdose reserpine plus lowdose diuretic) remotely matches the unique record of metformin plus fish oil, plus a multimucronutrient combination, plus appropriate HRT in men and women, for reducing all major chronic degenerative diseases and mortality.