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ANALYSIS: Victor M Montori, William L Isley, and Gordon H Guyatt Waking up from the DREAM of preventing diabetes with drugs BMJ 2007; 334: 882-884 [Full text]

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Metformin is the only safe and proven life-saving weightloss drug

Neil D Burman   (30 April 2007)

Glitazone woes and ethics

Neil D Burman   (15 June 2007)

Pharmacological versus lifestyle interventions

Clare L Gillies, Keith R. Abrams and Paul C. Lambert   (29 June 2007)

Metformin is the only safe and proven life-saving weightloss drug 30 April 2007
Neil D Burman, Metabolic Internist HealthSpan Life Research Foundation, Claremont, Cape Town 7708 Send response to journal: Re: Metformin is the only safe and proven life-saving weightloss drug	The BBC 26 April email headline on the excellent Mayo-McMaster analysis of the DREAM trial (BMJ 28 April) typifies how news-bites can miss the point: as Montori et al made in their 2nd paragraph: “ the evidence .. for drugs to prevent diabetes is poor EXCEPT FOR METFORMIN”. Metformin is 85years old(1), a synthetic form of the natural guanide in galega officinalis used to treat diabetes for centuries. Metformin was sidelined for 50 years because of the simultaneous birth of insulin, and then profitable new patents - sulphonylureas - whose lack of long term benefit on all-cause morbidity and mortality was first shown in the UGDP 1971 trial, and confirmed in the UKPDS 1998. On one hand, both the (BBC and Montori) brief reports overlook stark human reality. In the DPP (USA 2002) highly motivated well overweight people volunteered for a spartan trial. But in practice (pre)diabetic patients- the overweight public - are not motivated willing well volunteers – so in no medium-term trials in the overweight, let alone the obese, do more than perhaps 4% sustainably maintain weight loss of much more than 4% through effective exercise and diet. There are no long term trials whatsoever to assess sustained weight loss on willpower alone - participants simply give up without pharmacologic help. The studies by Lustman 2000 and Rasgon 2002 give a glimpse into what is obvious in practice, the powerful effect metformin may have on reversing the vicious cycle of low mood, maladaptive behaviour, overweight, fatigue, metabolic syndrome- insulin resistance- hypertension- lipidemia, diabetes, and all-cause mortality (whereas statins and glitazones have neutral or adverse overall effect).. In contrast with diet-exercise advice alone, in the USA (DPP- Knowler 2002) and China (Wenying 2001) 3 to 4yr trials, metformin alone combined with usual advice halved the incidence of new diabetes in the fattening diabetes-prone in sustained effective tolerated dose (~5 – to 40mg/kg/day. In the only major long term diabetic studies (UKPDS 2002; Canada- Johnson ea 2002-6), metformin halves all-cause mortality ie halves all major common fatal degenerative diseases. Metformin has sustained a mean weight loss of 8% over 4 years (Glueck 2006) irrespective of severity of overweight; Dr Glueck reported personally that those who did not drop out because of the desired pregnancy, or move away for family reasons, the majority retained ~8% weight loss from baseline year after year. In the only long term drug trial ever (the 20year UKPDS to 1998 - compared to both placebo and sulphonylurea) - metformin for a mean of 13.6 years reduced all-cause mortality ie cardiovascular and cancer disease by about 36% - with the lowest weight gain. The 17-nation ADOPT trial (Kahn 2006) gave the major adverse effect of metformin as gastro-intestinal - which is indeed the goal of slow upwards metformin titration to tolerance, to limit calorie intake & absorption by titrating the dose to just below abdominal discomfort. But in ADOPT, compared to a glitazone (let alone sulphonylurea), metformin was associated with fall in weight, and much lower LDL cholesterol and much less vascular disease & edema. Metformin in appropriate dose is anti-oxidant (Bellin 2006); anti- arrhythmic (Najeed 2005); anti-cancer (UKPDS 1998; Evans 2005; Johnson 2006) antihrombotic (Grant 2003); anti-lipidemic (Carlsen 1996); anti- hypertensive(Giugliano 1993); anti-heart failure (Johnson 2006); anti- anginal (Jadhav ea 2006); anti-fatty hepatitis (Uygun 2004); anti- infertility and pro-pregnancy (Glueck ); performs equally well in both obese and non-overweight diabetics(Ong ea 2006), and in the presence of sepsis (Gras & Lalau 2006). No modern antidiabetic/ weight reducing drug does all this, and safely –without a single significant risk in the 20yr UKPDS. By contrast, the 21- nation DREAM trial (Gerstein 2006) showed that while glitazone reduced the incidence of new diabetes by 60%, it had no significant benefit on mortality or cardiovascular endpoints, in fact increased the incidence of heart-failure five fold.; while rampiril failed to reduce the incidence of new diabetes. The European ProActive glitazone study (Dormandy 2005) in diabetics for a mean of three years failed to prove glitazone superiority to placebo in its primary endpoint, but glitazone caused far more oedema, weight gain and heart failure If the above information –for metformin and against glitazones - is not crucial evidence, then what is? (1) Werner & Bell: J Chem Soc 1922:121:1790-95 Other references are on Pubmed. Competing interests: None declared
Glitazone woes and ethics 15 June 2007
Neil D Burman, Metabolic Internist neil.burman@healthspanlife.com, Claremont, Cape Town 7708 Send response to journal: Re: Glitazone woes and ethics	Why the current media glitazone hype (NEJM, Lancet, newspapers) rehashing the troglitazone tragedy within 8 years? Glitazones were successively discredited by their RCTs: DPP 1998; then PROActive 2005, DREAM 2006 and ADOPT 2006. The first hoped-for $billion Glaxo rain-check crashed by 1999 with liver (and weight gain and heart) problems (troglitazone-story.net) – followed within a few years by cerivastatin(Bayer), glitazars, and now torcetrapib (Pfizer) - under similar circumstances of corporate denial. No metabolic corrective- statin, glitazone, glitazar, gliptin or rimonabant - has given any reason to expect anywhere as good or safe long term as the 85year old gold standard metformin.. Useful weight loss in obese diabetics with metformin (dimethylbiguanide -1922 –Germany: Werner & Bell) was already reported by Pedersen 1965. But out-of-patent metformin was sidelined for 50 years by corporate greed - the simultaneous birth of insulin; and then sulphonylureas (1955) - whose lack of long term benefit on all-cause morbidity and mortality was first shown in the UGDP 1971 trial, confirmed in the UKPDS 1998, but which continues to be glibly ignored by manufacturers and most prescribing physicians. The estimated world diabetes prevalence is >200 million, and overweight >1billion. That’s some market. "The global diabetes market was worth $18.6bn in 2005 -of which the US had half".(piribo.com; The Diabetes Market Outlook to 2011: price $2990. May 2006). Why else would a billion overweight(including some 200million diabetic) patients not be on the only proven safe prevention metformin? Reversal of insulin resistance, prevention – approximate halving -of new diabetes by metformin was already addressed in BIGPRO (Fontbonne 1991), confirmed in the 3 to 4yr China (Wenying 2001) and USA (DPP- Knowler 2002) trials in sustained effective tolerated dose (up to ~40mg/kg/day). By contrast, the prediabetic DREAM trial (Gerstein 2006) showed that while glitazone also halved incidence of new diabetes, it had no significant benefit on mortality or cardiovascular endpoints, in fact increased the incidence of heart-failure five fold.. No other synthetic designer drug ever for chronic preventative use does all that metformin does, and safely –without a single significant risk in the 20yr UKPDS or in RCTs eg COSMIC (Cryer 2006 –which BMS delayed publishing for almost 8 years, presumably because the results so strongly favoured solo metformin). No synthetic designer drug for chronic preventative use has ever been (or will be) tested in a proper long term RCT (like UKPDS) for half as long as metformin and sulphonylureas were. Apart from metformin, the only other regime that achieves such reduction is the evidence-based combination of safe preventative vitamins, minerals, human biologicals, herbs; fish oil; and appropriate balanced sex hormone replacement for proven deficiency/imbalance (eg Salpeter 2005; Heikinen 2006). Now in interim analysis at 3.75years (Home et al NEJM 5 June 2007) of the unblinded RECORD trial in Europe and Australasia in 4447 mostly obese hypertensive advanced diabetics ie uncontrolled on either maximum sulphonylurea or metformin (2.55g/d), addition of rosiglitazone (compared to those on sulphonylurea and metformin) resulted in 11% more primary endpoints (vascular disease with death or admission to hospital). This was not yet significant, but bears out the same trend as in the earlier glitazone trials - lack of global benefit. Thus it may well be asked: for the major causes of premature degenerative aging-related mortality (overweight- metabolic syndrome- diabetes, vascular, osteoporosis) - why are patients allowed to become obese with diabetes before metformin and proven safe preventative supplements are added? and why are physicians world wide not disciplined by Regulators for failing to first prescribe appropriate long-proven combination (of multisystem protectants - metformin, vitamins, minerals, human biologicals and appropriate physiological balanced human sex hormone replacement) BEFORE prescribing in the remaining resistant cases inferior newer therapy with known serious risks and costs- sulphonylureas, statins, glitazones, glitazars, gliptins, anti-obesity drugs, biphosphonates, rimonabants, and surgery? The reason is presumably the dominant twin modern human deities ie the convenient quick fix (offered by profit-driven medicine) rather than responsible living, and maximum profit for the Disease industry. Competing interests: None declared
Pharmacological versus lifestyle interventions 29 June 2007
Clare L Gillies, Medical Statistician University of Leicester, LE1 7RH, Keith R. Abrams and Paul C. Lambert Send response to journal: Re: Pharmacological versus lifestyle interventions	We were very interested to read the article by Montori et al (1). discussing the potential problems of using pharmacological therapies to prevent diabetes. The use of medication to treat what is essentially a lifestyle problem raises important issues and we agree with much of what was said in the article. In our recent systematic review in the BMJ (2) we meta-analysed all relevant trials and found both pharmacological and lifestyle interventions resulted in a reduced risk of diabetes, hazard ratios 0.70 (95% confidence interval 0.62 to 0.79) and 0.51 (95% confidence interval 0.44 to 0.60) respectively. As it appeared that lifestyle interventions may in fact be superior to pharmacological interventions, since the publication of our review we have used mixed treatment comparison methodology (3) to directly compare the two forms of intervention. No statistically significant difference between the two was found, hazard ratio of 1.06 (95% credible interval: 0.70 to 1.46) and probability of lifestyle interventions being superior to pharmacological only 62%. As lifestyle interventions therefore are at least as effective as pharmacological interventions, the choice of which is used to prevent diabetes in those at high risk is open to discussion. Both have their advantages and disadvantages, with compliance and cost probably being the barriers for the long-term success of lifestyle interventions, whilst pharmacological interventions may have side-effects and although they treat symptoms of obesity and low physical activity, they do not treat the cause. Given that interventions are for a long term chronic condition, long term evaluation of both harms and benefits are required. (1) Montori VM, Isley WL, and Guyatt GH (2007). Waking up from the DREAM of preventing diabetes with drugs, BMJ, 334: 882 – 884 (2) Gillies CL, Abrams KR, Lambert PC, Cooper NJ, Sutton AJ, Hsu RT, Khunti K (2007). Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ, 334: 299 (3) Caldwell DM, Ades AE, Higgins JPT (2006). Simultaneous comparison of multiple treatments: combining direct and indirect evidence, BMJ, 331, 897-900 Competing interests: None declared