Metformin, The Anti-Aging Miracle Drug by Jeffrey Dach MD
Diabetes Drugs Take A BAD RAP
You probably think of Diabetes Drugs as all lumped together as “Bad
Drugs”. For many years , I certainly did. Perhaps it was the Avandia
story that gave Diabetes Drugs a Bad Rap and made us think poorly of ALL Diabetes Drugs.
Upper Left Image: Photo of French Lilac Plant , the plant origin of Metformin, courtesy of Wikimedia Commons.
Avandia, the “BAD Drug” for Diabetes
Take the case of Avandia, approved in 1999, it quickly became the
world’s best selling diabetes drug. However, 8 years later, the New
England Journal reported that Avandia causes increased heart attack rates, and sales were suspended in Europe.(1A)
In November 2011, GlaxoSmithKline admitted they withheld safety data
on Avandia and agreed to pay the US government 3 billion in civil and
criminal penalties related to illegal marketing. The Avandia case gave
all diabetes drugs a “Bad Rap”. The reality is that there is one
diabetes drug that has stood the test of time, and is in fact a “Good
Drug”. This is Metformin. Perhaps the plant origin of the drug makes
it a “good drug”.
Metformin, the “Good Drug” Is There Anyone Who Should not Take It ?
At the May 2012 Orlando A4M Meeting, Terry Grossman, M.D. from Golden Colorado gave
an excellent presentation on Metformin. Credit and thanks goes to
Terry Grossman MD for sharing his talk at the meeting with all of us.
Much of this article comes from Grossman’s PowerPoint slides. Dr Terry
Grossman is co-author of the Ray Kurzweil book, Fantastic Voyage.
Upper Left Image : Photo of Terry Grossman MD, courtesy of Terry Grossman MD.
Metformin by Terry Grossman MD- Metformin Discovery and Approval
Discovered in the 1920′s, Metformin is currently the most widely
prescribed anti-diabetic drug in the world, approved for Type Two
Diabetes in 1958 for the United Kingdom (UK), in 1972 for Canada, and in
1995 by the FDA in the United States,
Metformin Origin From the Plant World, Guanidine Compounds:
Metformin comes from the plant world. The French Lilac plant (called
Galega officinalis) was used for centuries as a folk medicine for the
treatment of Diabetes. The active ingredient in the French Lilac
plant, called guanidine compounds, were discovered and isolated in the
Metformin - Mechanism of Action
Master Switch which Up-Regulates AMP Kinase
At the risk of boring you with overly technical matters, here is the
exact mechanism of how Metformin works its magical benefits. The
actions of metformin are intimately related to AMPK, these letters stand
for Adenosine Mono- Phosphate Kinase (AMP Kinase), which has been
called a metabolic “master switch“ involved with energy status of cells, hormone expression and protein synthesis.
Metformin Up-Regulates AMP Kinase Expression.
AMPK Affects Cellular Energy/Biochemistry
If AMPK is turned OFF: (This is BAD)
ATP is consumed
Glucose is burned for energy.
Fatty acids and cholesterol are synthesized.
This is similar to effects of HIGH insulin levels.
If AMPK is Turned ON: (This is GOOD)
ATP is created.
Fatty acids are predominantly consumed for energy.
This is similar to the effects of Caloric Restriction and LOW insulin levels.
AMPK Effects on Key Organ Systems
Pancreas: Decreases insulin secretion.
Liver: Decreases fatty acid and cholesterol synthesis.
Adipose (Storage Fat Tissue): Decreases fatty acid synthesis, increase lipolysis.
Skeletal muscle: Increases fatty acid oxidation, glucose uptake, and glycolysis
Heart muscle: Increases fatty acid oxidation, and glucose uptake
Metformin – Mechanisms of Action
1) Decreases glucose absorption from GI tract. (2)
2) Inhibits hepatic gluconeogenesis (production of sugar by the liver).
3) Increases sensitivity and number of insulin receptors.
4) Increases peripheral glucose uptake
5) Increases fatty acid oxidation.
Metformin Decreases Glucose Absorption From GI Tract
In studies using lab mice, metformin (in dosage of 250 mg/kg) given
for five days decreased Glucose absorption by the GI tract by more than
half. (2) These results indicate that metformin had a significant
inhibitory effect on the absorption of sugar (glucose) by the
Metformin Inhibits Hepatic Gluco-Neogensis (Sugar Production)
Primary Action of Metformin
People with Type Two Diabetes have a Three-Fold increase in
gluconeogenesis (sugar production by the liver). Metformin decreases
gluconeogenesis by 36% as a result of AMPK upregulation. (3)
Metformin Increases Sensitivity and Number of Insulin Receptors
Insulin Resistance can be seen in Metabolic Syndrome, in Type two Diabetes (T2DM) and in the Aging Process.
With Insulin Resistance, higher levels of insulin are needed by the
body to move glucose into the cells. Metformin is beneficial here
because metformin increases both insulin sensitivity and number of
insulin receptors. With Metformin use, insulin levels fall and patients
often lose weight, ameliorating metabolic syndrome. (4)
Metformin Increases Fatty Acid Oxidation
When blood insulin levels are high, as in Type Two Diabetes, glucose
is preferentially burned rather than fatty acids. When insulin levels
decrease, fatty acids are may then be utilized (oxidized, burned,
metabolized) for energy production rather than sugar (glucose).
Metformin increases utilization of FAT Stores as energy for muscle
(fatty acids oxidation by muscle cells). (5)
Uses of Metformin
FDA approved Use: Metformin is FDA approved for use in Type 2 Diabetes.
Off-Label Uses of Metformin
1) Polycystic ovary syndrome (PCOS)
2) Drug-induced weight gain
3) Cancer Prevention
4) Caloric restriction (CR)-mimetic
Metformin , the Diabetes Drug – 48 Million Prescriptions
Metformin is first line drug treatment for Type Two Diabetes.
Forty Eight million prescriptions for metformin were written in United States in 2010.
Metformin is the Ninth most commonly prescribed drug.
Metformin is the only anti-diabetic drug proven to prevent the Cardiovascular Complications of Type Two Diabetes.
Metformin Lowers LDL-C and Triglycerides.
Metformin does not cause weight gain, and does not cause hypoglycemia.
Metformin is Safer and Fewer Adverse Effects Compared to Other (6)
Metformin vs. Sulfonureas
Any DM Endpoint 9% 21%
Heart Attacks 15% 33%
All Cause Mortality 13% 27%
This is data is from : Ten-year follow-up of intensive glucose
control in type 2 diabetes. by Holman RR, N Engl J Med. 2008 Oct 9.(6)
Metformin- Has Added Beneficial Effects
Here is a Meta-Analysis of 31 Metformin drug trials with 4,570 participants.(7)
Metformin reduced BMI (Body Mass Index) – 5.3%
Reduced Fasting Sugar – (Glucose) – 4.5%
Reduced Fasting insulin -14.4%
Reduced Triglycerides – 5.3%
Reduced LDL-C – 5.6%
Reduced New-onset diabetes – 40%
Increased HDL-C + 5%
Metformin reduces new onset Diabetes by 40% (7)
Statin Drugs or Metformin ?
For people with elevated total and LDL cholesterol, mainstream
cardiologists and primary care physicians commonly prescribe statin
drugs. Many of these patients may actually benefit from Metformin
Metformin is useful for the patient with the “High Normal” fasting
blood sugar (85-99) and elevated triglycerides. Rather than use a
statin drug to alter LDL cholesterol, why not use Metformin ?
Metformin is more beneficial with fewer adverse effects than statin
drugs. Statin primary prevention studies are disappointing with no
reduction in all cause mortality in healthy men. On the other hand, Metformin
reduces cardiovascular mortality by 40% (13) when fasting blood sugar
is reduced to below 86 mg/ml, with fewer adverse effects. In addition
Metformin is cancer preventive, and prolongs survival as a
Definitions of Diabetes and Pre-Diabetes
Diabetes is defined as Fasting Glucose greater than 125 mg/ml.
and a 2 hr Post prandial glucose (after a meal) greater than 200 mg/ml.
and a Hemoglobin A1C (Hb A1c) greater than 6.5 mg/ml
Pre-diabetes is defined as a Fasting Glucose 100-124 mg/ml.
and a 2 hr Post prandial serum glucose 140-199 mg/ml.
amd a Hb A1c in the 5.7 – 6.4 range.
Type II Diabetes is NOW at Epidemic Levels (8)
There has been a 10-fold increase in Type Two Diabetes worldwide over
the past 27 years. The number of Type Two Diabetics has increased from
30 million in 1985, to 300 million in 2012.
1.9 million people were diagnosed with Type Two Diabetes (T2 DM) in
2010. This is one person every 16 seconds.(8) Currently in the United
States, 26 million Americans are Diabetic. Almost a third of the
over-65 population is diabetic.
Lifetime Risk of Diabetes is Substantial
The estimated lifetime risk of developing diabetes for individuals
born in 2000 is about thirty per cent (32.8% for males and 38.5% for
Increased All-Cause Mortality With Diabetes- Two and a Half Times
Diabetes increases all-cause mortality up to 2.5-fold (10)
Morbidity Risk Reduction With Metformin (11)
Metformin use producing each one per cent reduction in Hemoglobin
A(1c) was associated with risk reductions of the following (11)
One Per Cent Hgb A1C Reduction Associated With Reduction of (11)
21% for any end point related to diabetes.
21% for deaths related to diabetes.
14% for myocardial infarction.
37% for microvascular complications.
Metabolic Syndrome Increases All-Cause and CardioVascular Mortality
Meta-analysis of 87 studies involving 951,083 patients (12)
Metabolic syndrome increased Relative Risk (12)
2.35 for CardioVascular disease,
2.02 for CardioVascular disease mortality,
1.58 for total mortality
2.99 for Myocardial Infarction (heart attack)
2.27 for stroke
Increased Risk of CV Death Even with “Normal” Blood Sugar (13)
This study followed 2,000 men ages 40 to 60 years old followed over
22 years (from 1975 to 1997)(13). They found that for men with a
Fasting Blood Sugar greater than 85 mg/ml, the Relative Risk of
cardiovascular death increased 40%.(13) So we now have a new category
called “high normal , with FBS 85 – 100 mg/ml= “high normal”
Epidemic of High Normal Fasting Blood Sugar (above 85)(14)
85% of adults have high normal blood glucose or above.
In 1976, only 25% had FBS greater than 85 mg/ml
By 2009, this number had increased to 85% (14)
Only One in Eight People Have Optimal Fasting Blood Sugar (FBS)
Fasting Blood Sugar Percent of Population
FBS > 125 Diabetes 11%
FBS 100 –124 Prediabetes 35%
FBS 86 – 99 High normal 39%
FBS 70 – 85 Optimal 13%
FBS < 69 Hypoglycemia 2%
Executive Health Patients Grossman Wellness Center
FBS Desciption Longevity ClinicPts Average
>125 T2 DM +300% risk of MI 3% 11%
100-124 Prediabetes 12% 35%
85-99 High Normal (+40% risk of MI) 60% 39%
70-84 Optimal 24% 13%
<69 Hypoglycemia 2% 2%
Off-Label Uses of Metformin
Although Metformin is FDA approved for use in Type Two Diabetes,
other uses which have not been submitted is called “off-label use”. For
many drugs used in the practice of medicine, off-Label use is quite
Off-Label Uses of Metformin
1) PCOS (PolyCystic Ovary Syndrome)
2) Prevents Drug-induced weight gain
3) Anti-cancer Effects
4) Caloric Restriction (CR)-mimetic
PCOS PolyCystic Ovary Syndrome
1) PCOS affects 9 per cent of young, premenopausal women. This is an epidemic.
2) PCOS is characterized by insulin resistance and hyper-insulinemia.
3) PCOS women have increased risk of Diabetes (T2DM) and Cardiovascular Disease
See my two part article on PCOS:
PCOS part one
PCOS part two
Benefits of Metformin in PCOS (15-17)
For the PCOS patient, Metformin lowers glucose, lowers insulin and
testosterone levels. Metformin reduces the androgenic symptoms of acne
and hirsutism, abdominal obesity, amenorrhea and other symptoms of PCOS.
Metformin for Drug Induced Weight Gain From Newer Psychiatric Drugs
Weight gain is common with newer generation antipsychotics such as
Clozapine (Clozaril), olanzapine (Zyprexa), Risperidone (Risperdol),
quetiapine (Seroquel) and Aripiprozole (Abilify) Patients on Zyprexa
gain 20 pounds of weight over three months of treatment.(18) A number
of studies have shown Metformin useful in preventing this type of weight
gain from anti-psychotic drugs. (19-20)
Diabetics Gain Weight From Insulin Use
When insulin or other agents are used is used for Type Two Diabetes,
it is common to see weight gain of 4 kilograms (10 pounds) for each 1
per cent drop in Hemoglobin A1C. (21)
Metformin and Cancer Prevention
Virtually all cancers eats only one food, and that is Glucose, also called sugar.
Cancer cells have many times the normal number of insulin receptors on
their outer cell membranes which makes the cancer cell “Gobble Up” sugar
when it is available. Cancer cells are very sensitive to Insulin, and
high insulin levels massively increase sugar uptake by cancer cells.
AMPK Activation by Metformin and Effect on Cancer
Metformin upregulates AMPK which blocks expression of cancer-promoting genes (22)
and activates the tumor suppressor p53 gene. (22) Metformin inhibits
aromatase expression in breast tissue which decreases estrogenic
Increased Cancer in Diabetes
Diabetics have increased risk of numerous types of cancers , such as
primary liver cancer, pancreatic cancer, colorectal cancer, endometrial cancer, breast cancer, and renal cancers. (24)
Metformin Use Reduced Cancer almost in HALF
In a Dutch study, 85,000 Type Two Diabetics (T2DM) on metformin or
sulfonylurea were followed over ten years. The risk of a cancer
diagnosis was reduced by 10% for metformin users compared to diabetics
on sulfonylurea agents. Metformin users had lower risks for cancers of
the esophagus, stomach, colon, liver, pancreas, lung, breast, and
In another study of 4,085 metformin users compared to controls,
cancer was reduced by 46% for the metformin users compared to non-users.
(26) An Italian study from Florence showed Metformin use reduced
cancer incidence. (27) A study from MD Anderson Cancer center showed
Metformin use reduce pancreatic cancer incidence by 62 per cent. (28)
Another MD Anderson study shows Metformin to be beneficial to the breast
cancer patient while undergoing treatment.(29)
Metformin as a CR Mimetic – Caloric Restriction
What is Caloric Restriction ?
In the race to find some type of intervention that would decelerate
the aging process in animals (and humans) and prevent the onset of
age-related degenerative disease, one intervention stands out as the
most successful, restricting the food supply to the laboratory mouse.
This is called caloric restriction. “Caloric restriction (CR) is the
most robust environmental method known for decelerating aging and the
development of age-related diseases.”(32)
Antiaging Potential of Metformin
In the early 1970s, Dr. Vladimir Dilman
hypothesized that Metformin Compounds, the biguanides may have use as
“geroprotectors” and anticancer effects (“metabolic rehabilitation”).
In the early 1990s, Dr. Dilman and Ward Dean hypothesized that metformin
should be considered as an “antiaging” therapy.(30)
The Metformin/AMPK Connection – CR
Metformin/AMPK use prevents cell damage, triggers cell repair, and
switches our cells into “survival mode” which increases and energy (ATP)
production. The cellular long term needs for protein, lipid and starch
Metformin use very closely mimics cell repair processes associated
with Caloric Restriction (CR), creating a Genetic Profile (mRNA) in
mice very similar to the changes in gene profile seen with Caloric Restriction (CR)(31)
Using gene chip technology, studies show Metformin affects 63 genes
involved in energy production, protein synthesis, and cell growth
(31-33). Metformin induced gene modifications closely mimic caloric
restriction, and dramatically extends lifespan of mice by almost 40 per
Metformin – Precautions and Adverse effects
The major adverse effects of Metformin relate to gastrointestinal
symptoms, and may affect up to half of users. Gastrointestinal side
effects such as diarrhea may be reduced by beginning metformin slowly,
starting with a lower dose, or using a time release formulation -
Diarrhea may be reported up to 53.2% (11.7% placebo)
Nausea/vomiting – up to 25.5% (8.3% placebo)
Gas – up to 12.1%
Weakness – up to 9.2%
Indigestion – up to 7.1%
GI discomfort – up to 6.4%
Headache – up to 5,7%
From: Drug Facts and Comparisons 2005. St. Louis, Mo:
Facts and Comparisons; 2004.
Metformin: How To Avoid Side Effects
Begin Metformin at a low dose and increase gradually. Use 250 mg
Metformin Twice a Day with meals for 7 to 14 days, then increase to 500
mg twice a day with meals. Adverse effects tend to be less with
metformin ER (extended release), and Diarrhea is 80% less likely.
Metformin – Metabolism and Excretion
Metformin is not bound to plasma protein or metabolized.
Most of the Metformin dose (75-90%) is excreted by kidneys within in 12 hrs.
There are no clinically relevant drug interactions, because Metformin it
is not metabolized and does not interfere with the metabolism of other
Other Adverse Effects – B12 malabsorption
Metformin may cause Vitamin B12 malabsorption and B12 deficiency,
with increased homocysteine levels, make sure each patient supplements
with B12 while taking metformin. (35-36)
Metformin Contra-indications and Safety – Less Adverse Events – Lactic Acidosis
Metformin is safer than its predecessor drug, phenformin, with a 20
fold lower incidence of fatal lactic acidosis, causing only 3 cases/per
100,000 patient years of fatal lactic acidosis, compared to Phenformin
which has 64 cases. Virtually all occurring in renal failure patients.
Because of this, renal failure is a contraindication to use of
Renal Failure – Lactic acidosis
Lactate serves as a Krebs cycle substrate . Metformin impedes
hepatic lactate uptake as part of its action in interfering with
gluconeogenesis . The slight increase in metformin-induced lactic acid
is cleared by the kidneys. Therefore, renal failure is a
contraindication to the use of Metformin.(37)
Other relative contraindications: Congestive Heart Failure (CHF), alcoholism, severe COPD Chronic Obstructive Lung Disease.
Clinical Considerations in using Metformin in healthy non-diabetics
1) Informed consent for off-label use
2) Check HbA1c, fasting glucose, liver and renal functuion/kidney tests
3) If FBS > 85 or Hb A1c >5.3, consider metformin
Begin with ¼ – ½ of 500 mg tablet once a day with meals x 7-14 days;
then increase to twice a day x 7-14 days If tolerated, stay at 250 or
increase to 500 mg twice a day
Check HbA1c, fasting glucose, liver & kidney function tests every 6 months
Generic Metformin is Very Affordable
Cost is 7 cents per 500 mg tablet, or $4.20/ month for 500 mg tablet twice a day.
Side effects are less with time-release formulation. Name brand
metformin XR costs $1.10 per500 mg tablet, or $66 per month for 500 mg
tablet twice a day.
Metformin- is there anyone who shouldnt take it?
Type II diabetes 11% YES
Prediabetes 35% YES
High normal 39% YES
Optimal 13% ??
Hypoglycemia 2% NO
Links and References
Crofford OB (August 1995). Metformin. N. Engl. J. Med. 333 (9): 588–9
Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death
from Cardiovascular Causes. Steven E. Nissen, M.D., and Kathy Wolski,
N Engl J Med 2007; 356:2457-2471June 14, 2007
Ikeda T, Iwata K, Murakami H. Biochem Pharmacol. 2000 Apr 1;59(7):887-90. Biochem Pharmacol. 2000 Apr 1;59(7):887-90.
Inhibitory effect of metformin on intestinal glucose absorption in
the perfused rat intestine. Ikeda T, Iwata K, Murakami H. Source The
Department of Medical Technology, Tottori University College of Medical
Care Technology, Yonago, Japan.
In rats orally administered metformin (250 mg/kg) for 5 days, glucose
absorption by the perfused intestine (375.0+/-164.3 micromol/30 min)
was significantly (P<0.001) lower than that in control rats
(811.0+/-83.1 micromol/30 min).
3) www.ncbi.nlm.nih.gov/pmc/articles/PMC2995498/?tool=pubmed www.ncbi.nlm.nih.gov/pubmed/11118008
Hundal R, Krssak M et al.
Diabetes. 2000;49(12):2063–9. Diabetes. 2000 Dec;49(12):2063-9.
Mechanism by which metformin reduces glucose production in type 2
diabetes. Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V,
Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR,
Source Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Abstract To examine the mechanism by which metformin lowers
endogenous glucose production in type 2 diabetic patients, we studied
seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3
mmol/l), before and after 3 months of metformin treatment.
Seven healthy subjects, matched for sex, age, and BMI, served as
control subjects. Rates of net hepatic glycogenolysis, estimated by 13C
nuclear magnetic resonance spectroscopy, were combined with estimates of
contributions to glucose production of gluconeogenesis and
glycogenolysis, measured by labeling of blood glucose by 2H from
ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose.
The rate of glucose production was twice as high in the diabetic
subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x
m(-2) min(-1), P < 0.0001).
Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x
min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to
10.8 +/- 0.9 mmol/l, P = 0.0002).
The rate of gluconeogenesis was three times higher in the diabetic
subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03
mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/-
0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a
twofold increase in rates of gluconeogenesis in diabetic subjects (0.42
+/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin
treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was
no glycogen cycling in the control subjects, but in the diabetic
subjects, glycogen cycling contributed to 25% of glucose production and
explains the differences between the two methods used.
In conclusion, patients with poorly controlled type 2 diabetes have
increased rates of endogenous glucose production, which can be
attributed to increased rates of gluconeogenesis. Metformin lowered the
rate of glucose production in these patients through a reduction in
Fontbonne A, Charles MA et al. 1996,
Diabetes Care 19:920-92614. Diabetes Care. 1996 Sep;19(9):920-6.
The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group.
Fontbonne A, Charles MA, Juhan-Vague I, Bard JM, André P, Isnard F,
Cohen JM, Grandmottet P, Vague P, Safar ME, Eschwège E. Source National
Institute of Health and Medical Research, INSERM U21, Villejuif, France.
Abstract OBJECTIVE: The constellation of anomalies associated with
insulin resistance is a plausible additional cause of ischemic
cardiovascular disease and of NIDDM. To test this hypothesis in a
primary prevention trial, the effects of metformin as a potential
candidate for intervention in the insulin resistance syndrome (IRS) were
evaluated in 324 middle-aged subjects with upper-body obesity.
RESEARCH DESIGN AND METHODS: Trial patients were selected on the basis
of a high waist-to-hip ratio. They were randomly allocated to receive
either metformin or placebo, following a double-blind procedure. After 1
year of treatment, the main clinical and biological parameters of the
IRS were assessed and their evolution compared between treatment groups.
RESULTS: Compared with placebo, metformin induced a significant
weight loss, a better maintenance of fasting blood glucose, total and
LDL cholesterol levels, and a greater decrease of fasting plasma insulin
concentration. Moreover, tissue-type plasminogen activator antigen, a
marker of fibrinolytic impairment, showed a significant decrease under
metformin. By contrast, metformin treatment had no significant effect on
blood pressure or serum triglyceride and HDL cholesterol
concentrations. The main side effect of metformin was diarrhea.
CONCLUSIONS: The BIGuanides and Prevention of Risks in Obesity
(BIGPRO1) results suggest that metformin would be a suitable candidate
for long-term intervention for the prevention of diabetes but that its
use in a trial of primary prevention of cardiovascular diseases requires
either a reevaluation of its properties toward the most potentially
atherogenic anomalies of the IRS or a better definition of the target
5) Fatty acid oxidation relative to storage in soleus and epitrochlearis muscle during 0–30 min of incubation
Collier C A et al. Am J Physiol Endocrinol Metab 2006;291:E182-E189
Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E182-9. Epub 2006 Feb 14.
Metformin counters the insulin-induced suppression of fatty acid
oxidation and stimulation of triacylglycerol storage in rodent skeletal
Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck DJ.
Source Dept. of Human Health and Nutritional Sciences, Univ. of Guelph, Guelph, ON, Canada.
Abstract The present study examined the acute effects of metformin on
fatty acid (FA) metabolism in oxidative soleus (SOL) and glycolytic
epitrochlearis (EPT) rodent muscle. SOL and EPT were incubated for
either 30 or 180 min in the absence or presence of 2 mM metformin and
with or without insulin (10 mU/ml). Metformin did not alter basal FA
metabolism but countered the effects of insulin on FA oxidation and
incorporation into triacylglyerol (TAG). Specifically, metformin
prevented the insulin-induced suppression of FA oxidation in SOL but did
not alter FA incorporation into lipid pools. In contrast, in EPT
metformin blunted the incorporation of FA into TAG when insulin was
present but did not alter FA oxidation. In SOL, metformin resulted in a
50% increase in AMP-activated protein kinase alpha2 activity and
prevented the insulin-induced increase in malonyl-CoA content. In both
fiber types, basal and insulin-stimulated glucose oxidation were not
significantly altered by metformin. All effects were similar regardless
of whether they were measured after 30 or 180 min. Because increased
muscle lipid storage and impaired FA oxidation have been associated with
insulin resistance in this tissue, the ability of metformin to reverse
these abnormalities in muscle FA metabolism may be a part of the
mechanism by which metformin improves glucose clearance and insulin
sensitivity. The present data also suggest that increased glucose
clearance is not due to its enhanced subsequent oxidation. Additional
studies are warranted to determine whether chronic metformin treatment
has similar effects on muscle FA metabolism.
N Engl J Med. 2008 Oct 9;359(15):1577-89.
10-year follow-up of intensive glucose control in type 2 diabetes.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. Diabetes Trials
Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism,
Churchill Hospital, Headington, Oxford OX3 7LJ,
During the United Kingdom Prospective Diabetes Study (UKPDS),
patients with type 2 diabetes mellitus who received intensive glucose
therapy had a lower risk of microvascular complications than did those
receiving conventional dietary therapy. We conducted post-trial
monitoring to determine whether this improved glucose control persisted
and whether such therapy had a long-term effect on macrovascular
outcomes. METHODS:Of 5102 patients with newly diagnosed type 2 diabetes,
4209 were randomly assigned to receive either conventional therapy
(dietary restriction) or intensive therapy (either sulfonylurea or
insulin or, in overweight patients, metformin) for glucose control. In
post-trial monitoring, 3277 patients were asked to attend annual UKPDS
clinics for 5 years, but no attempts were made to maintain their
previously assigned therapies. Annual questionnaires were used to follow
patients who were unable to attend the clinics, and all patients in
years 6 to 10 were assessed through questionnaires. We examined seven
prespecified aggregate clinical outcomes from the UKPDS on an
intention-to-treat basis, according to previous randomization
RESULTS:Between-group differences in glycated hemoglobin levels were
lost after the first year. In the sulfonylurea-insulin group, relative
reductions in risk persisted at 10 years for any diabetes-related end
point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk
reductions for myocardial infarction (15%, P=0.01) and death from any
cause (13%, P=0.007) emerged over time, as more events occurred. In the
metformin group, significant risk reductions persisted for any
diabetes-related end point (21%, P=0.01), myocardial infarction (33%,
P=0.005), and death from any cause (27%, P=0.002).
CONCLUSIONS : despite an early loss of glycemic differences, a
continued reduction in microvascular risk and emergent risk reductions
for myocardial infarction and death from any cause were observed during
10 years of post-trial follow-up. A continued benefit after metformin
therapy was evident among overweight patients.
Salpeter SR, Buckley NS, Kahn JA, Salpeter EE.
Am J Med. 2008 Feb; 121(2):149-157. Santa Clara Valley Medical Center, San Jose, CA 95128, USA.
We performed a meta-analysis of randomized controlled trials to
assess the effect of metformin on metabolic parameters and the incidence
of new-onset diabetes in persons at risk for diabetes.
METHODS:We performed comprehensive English- and non-English-language
searches of EMBASE, MEDLINE, and CINAHL databases from 1966 to November
of 2006 and scanned selected references. We included randomized trials
of at least 8 weeks duration that compared metformin with placebo or no
treatment in persons without diabetes and evaluated body mass index,
fasting glucose, fasting insulin, calculated insulin resistance,
high-density lipoprotein cholesterol, low-density lipoprotein
cholesterol, triglycerides, and the incidence of new-onset diabetes.
RESULTS: pooled results of 31 trials with 4570 participants followed for 8267 patient-years showed that metformin reduced
body mass index (-5.3%, 95% confidence interval [CI], -6.7–4.0),
fasting glucose (-4.5%, CI, -6.0–3.0),
fasting insulin (-14.4%, CI, -19.9–8.9),
calculated insulin resistance (-22.6%, CI, -27.3–18.0),
triglycerides (-5.3%, CI, -10.5–0.03), and
low-density lipoprotein cholesterol (-5.6%, CI, -8.3–3.0%), and
increased high-density lipoprotein cholesterol (5.0%, CI, 1.6-8.3) compared with placebo or no treatment.
The incidence of new-onset diabetes was reduced by 40% (odds ratio
0.6; CI, 0.5-0.8), with an absolute risk reduction of 6% (CI, 4-8)
during a mean trial duration of 1.8 years.
CONCLUSION:Metformin treatment in persons at risk for diabetes
improves weight, lipid profiles, and insulin resistance, and reduces
new-onset diabetes by 40%. The long-term effect on morbidity and
mortality should be assessed in future trials.
CDC, Jan 26, 2011. Press Release Number of Americans with Diabetes Rises to Nearly 26
Million More than a third of adults estimated to have prediabetes
Nearly 26 million Americans have diabetes, according to new estimates
from the Centers for Disease Control and Prevention (CDC). In addition,
an estimated 79 million U.S. adults have prediabetes, a condition in
which blood sugar levels are higher than normal, but not high enough to
be diagnosed as diabetes. Prediabetes raises a person’s risk of type 2
diabetes, heart disease and stroke. Diabetes affects 8.3 percent of
Americans of all ages, and 11.3 percent of adults aged 20 and older,
according to the National Diabetes Fact Sheet for 2011. About 27 percent
of those with diabetes—7 million Americans—do not know they have the
disease. Prediabetes affects 35 percent of adults aged 20 and older. In
2008, CDC estimated that 23.6 million Americans, or 7.8 percent of the
population, had diabetes and another 57 million adults had prediabetes.
The 2011 estimates have increased for several reasons: More people are
developing diabetes. Many people are living longer with diabetes, which
raises the total number of those with the disease. Better management of
the disease is improving cardiovascular disease risk factors and
reducing complications such as kidney failure and amputations.
Hemoglobin A1c is now used as a diagnostic test, and was therefore
incorporated into calculations of national prevalence for the first
time. The test, also called glycated hemoglobin, measures levels of
blood glucose (sugar) over a period of two to three months. Because of
this change, estimates of populations with diabetes and prediabetes in
the 2011 fact sheet are not directly comparable to estimates in previous
fact sheets. In a study published last year, CDC projected that as many
as 1 in 3 U.S. adults could have diabetes by 2050 if current trends
continue. Type 2 diabetes, in which the body gradually loses its ability
to use and produce insulin, accounts for 90 percent to 95 percent of
diabetes cases. Risk factors for type 2 diabetes include older age,
obesity, family history, having diabetes while pregnant (gestational
diabetes), a sedentary lifestyle, and race/ethnicity. Groups at higher
risk for the disease are African-Americans, Hispanics, American
Indians/Alaska Natives, and some Asian-Americans and Pacific Islanders.
9) jama.jamanetwork.com/article.aspx?volume=290&page=1884 www.ncbi.nlm.nih.gov/pubmed/14532317
JAMA. 2003 Oct 8;290(14):1884-90.
Lifetime risk for diabetes mellitus in the United States. Narayan KM,
Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Centers for Disease
Control and Prevention, National Center for Chronic Disease Prevention
and Health Promotion, Division of Diabetes Translation, Atlanta, Ga,
USA. email@example.com Although diabetes mellitus is one of the most
prevalent and costly chronic diseases in the United States, no estimates
have been published of individuals’ average lifetime risk of developing
OBJECTIVE:To estimate age-, sex-, and race/ethnicity-specific
lifetime risk of diabetes in the cohort born in 2000 in the United
DESIGN, SETTING, AND PARTICIPANTS: Data from the National Health
Interview Survey (1984-2000) were used to estimate age-, sex-, and
race/ethnicity-specific prevalence and incidence in 2000. US Census
Bureau data and data from a previous study of diabetes as a cause of
death were used to estimate age-, sex-, and race/ethnicity-specific
mortality rates for diabetic and nondiabetic populations.
MAIN OUTCOME MEASURES:Residual (remaining) lifetime risk of diabetes
(from birth to 80 years in 1-year intervals), duration with diabetes,
and life-years and quality-adjusted life-years lost from diabetes.
RESULTS:The estimated lifetime risk of developing diabetes for
individuals born in 2000 is 32.8% for males and 38.5% for females.
Females have higher residual lifetime risks at all ages. The highest
estimated lifetime risk for diabetes is among Hispanics (males, 45.4%
and females, 52.5%). Individuals diagnosed as having diabetes have large
reductions in life expectancy. For example, we estimate that if an
individual is diagnosed at age 40 years, men will lose 11.6 life-years
and 18.6 quality-adjusted life-years and women will lose 14.3 life-years
and 22.0 quality-adjusted life-years.
CONCLUSIONS:For individuals born in the United States in 2000, the
lifetime probability of being diagnosed with diabetes mellitus is
substantial. Primary prevention of diabetes and its complications are
important public health priorities.
16-year excess all-cause mortality of newly diagnosed type 2 diabetic
patients: a cohort study by Lars J Hansen*†, Niels de Fine Olivarius†
and Volkert Siersma†
The Research Unit for General Practice and Section of General Practice,
Department of Public Health, University of Copenhagen, Copenhagen,
BMC Public Health 2009, 9:400
11) www.ncbi.nlm.nih.gov/pmc/articles/PMC27454/?tool=pubmed www.ncbi.nlm.nih.gov/pubmed/10938048
BMJ. 2000 Aug 12;321(7258):405-12.
Association of glycaemia with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 35): prospective observational
Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden
D, Turner RC, Holman RR. Diabetes Trials Unit, Oxford Centre for
Diabetes, Endocrinology and Metabolism, University of Oxford, Radcliffe
Infirmary, Oxford OX2 6HE.
OBJECTIVE:To determine the relation between exposure to glycaemia
over time and the risk of macrovascular or microvascular complications
in patients with type 2 diabetes. DESIGN: Prospective observational
Setting: 23 hospital based clinics in England, Scotland, and Northern
Ireland. Participants: 4585 white, Asian Indian, and Afro-Caribbean
UKPDS patients, whether randomised or not to treatment, were included in
analyses of incidence; of these, 3642 were included in analyses of
OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any
end point or deaths related to diabetes and all cause mortality.
Secondary aggregate outcomes: myocardial infarction, stroke, amputation
(including death from peripheral vascular disease), and microvascular
disease (predominantly retinal photo-coagulation). Single end points:
non-fatal heart failure and cataract extraction. Risk reduction
associated with a 1% reduction in updated mean HbA(1c) adjusted for
possible confounders at diagnosis of diabetes.
RESULTS:The incidence of clinical complications was significantly associated with glycaemia.
Each 1% reduction in updated mean HbA(1c) was associated with reductions in risk of
21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001),
21% for deaths related to diabetes (15% to 27%, P<0.0001),
14% for myocardial infarction (8% to 21%, P<0.0001), and
37% for microvascular complications (33% to 41%, P<0.0001).
No threshold of risk was observed for any end point.
CONCLUSIONS:In patients with type 2 diabetes the risk of diabetic
complications was strongly associated with previous hyperglycaemia. Any
reduction in HbA(1c) is likely to reduce the risk of complications, with
the lowest risk being in those with HbA(1c) values in the normal range
J Am Coll Cardiol. 2010 Sep 28;56(14):1113-32.
The metabolic syndrome and cardiovascular risk a systematic review and
meta-analysis. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L,
Poirier P, Rinfret S, Schiffrin EL, Eisenberg MJ. Jewish General
Hospital/McGill University, Montreal, Quebec, Canada.
OBJECTIVES:We sought to conduct a systematic review and meta-analysis
of the cardiovascular risk associated with the metabolic syndrome as
defined by the 2001 National Cholesterol Education Program (NCEP) and
2004 revised National Cholesterol Education Program (rNCEP) definitions.
BACKGROUND:Numerous studies have investigated the cardiovascular risk
associated with the NCEP and rNCEP definitions of the metabolic
syndrome. There is debate regarding the prognostic significance of the
metabolic syndrome for cardiovascular outcomes. METHODS:We searched the
Cochrane Library, EMBASE, and Medline databases through June 2009 for
prospective observational studies investigating the cardiovascular
effects of the metabolic syndrome. Two reviewers extracted data, which
were aggregated using random-effects models.
RESULTS:We identified 87 studies, which included 951,083 patients
(NCEP: 63 studies, 497,651 patients; rNCEP: 33 studies, 453,432
patients). There was little variation between the cardiovascular risk
associated with NCEP and rNCEP definitions. When both definitions were
pooled, the metabolic syndrome was associated with an increased risk of
cardiovascular disease (CVD) (relative risk [RR]: 2.35; 95% confidence
interval [CI]: 2.02 to 2.73), CVD mortality (RR: 2.40; 95% CI: 1.87 to
3.08), all-cause mortality (RR: 1.58; 95% CI: 1.39 to 1.78), myocardial
infarction (RR: 1.99; 95% CI: 1.61 to 2.46), and stroke (RR: 2.27; 95%
CI: 1.80 to 2.85). Patients with the metabolic syndrome, but without
diabetes, maintained a high cardiovascular risk.
CONCLUSIONS:The metabolic syndrome is associated with a 2-fold
increase in cardiovascular outcomes and a 1.5-fold increase in all-cause
mortality. Studies are needed to investigate whether or not the
prognostic significance of the metabolic syndrome exceeds the risk
associated with the sum of its individual components. Furthermore,
studies are needed to elucidate the mechanisms by which the metabolic
syndrome increases cardiovascular risk.
Diabetes Care. 1999 Jan;22(1):45-9.
Fasting blood glucose: an underestimated risk factor for
cardiovascular death. Results from a 22-year follow-up of healthy
nondiabetic men. Bjørnholt JV, Erikssen G, Aaser E, Sandvik L,
Nitter-Hauge S, Jervell J, Erikssen J, Thaulow E. Medical Department,
Rikshospitalet, Oslo, Norway.
OBJECTIVE:Because of the available conflicting epidemiological data,
we investigated the possible impact of fasting blood glucose as a risk
factor for cardiovascular death in nondiabetic men. This study reports
the results from a 22-year prospective study on fasting blood glucose as
a predictor of cardiovascular death.
RESEARCH DESIGN AND METHODS:Of the 1,998 apparently healthy
nondiabetic men (aged 40-59 years), a total of 1,973 with fasting blood
glucose < 110 mg/dl were included in the study in which also a number
of conventional risk factors were measured at baseline.
RESULTS:After 22 years of follow-up, 483 men had died, 53% from
cardiovascular diseases. After dividing men into quartiles of fasting
blood glucose level, it was found that men in the highest glucose
quartile (fasting blood glucose > 85 mg/dl) had a significantly
higher mortality rate from cardiovascular diseases compared with those
in the three lowest quartiles. Even after adjusting for age, smoking
habits, serum lipids, blood pressure, forced expiratory volume in 1 s,
and physical fitness (Cox model), the relative risk of cardiovascular
death for men with fasting blood glucose > 85 mg/dl remained 1.4 (95%
CI 1.04-1.8). Noncardiovascular deaths were unrelated to fasting blood
CONCLUSIONS:Fasting blood glucose values in the upper normal range
appears to be an important independent predictor of cardiovascular death
in nondiabetic apparently healthy middle-aged men.
J Atheroscler Thromb. 2009;16(6):857-61.
Fasting plasma glucose and incidence of diabetes — implication for
the threshold for impaired fasting glucose: results from the
population-based Omiya MA cohort study. Kato M, Noda M, Suga H,
Matsumoto M, Kanazawa Y. Japan Foundation for the Promotion of
International Medical Research Cooperation, Tokyo, Japan.
In 2003, the American Diabetes Association recommended that the
threshold for diagnosing impaired fasting glucose (IFG) should be
lowered from 6.1 mmol/L (110 mg/dL) to 5.6 mmol/L (100 mg/dL). To
discuss the diagnostic threshold for IFG, the association between
fasting plasma glucose (FPG) and the risk of future diabetes must be
known; however, data regarding this relation in the Japanese population
are scarce. The aim of this study was to determine the relation between
FPG and the risk of future diabetes in the Japanese general population.
METHODS:A retrospective cohort study was conducted using data from
annual health check-ups performed in Omiya city. A total of 11,369
subjects between the ages of 40-79 years who were not diabetic at
baseline were followed for seven years. Diabetes was defined as FPG >
or =126 mg/dL or self-report.
RESULTS:The incidence of diabetes increased as the baseline FPG level
increased and a similar pattern was observed irrespective of sex or
age. The hazard ratios compared with subjects with FPG <85 mg/ dL
adjusted for possible confounding factors were
3.83 for 85-100
2.41- 6.08 for subjects with 100 to 104 mg/dL FPG and
7.87 ( for subjects with 105 to 109 mg/dL FPG.
CONCLUSIONS:Subjects with 100-109 mg/dL FPG have an appreciable risk
of diabetes that cannot be considered as “normal” and should be notified
of their potential risk of developing diabetes.
15) www.nejm.org/doi/full/10.1056/NEJM199608293350902 www.ncbi.nlm.nih.gov/pubmed/8687515
N Engl J Med. 1996 Aug 29;335(9):617-23.
Decreases in ovarian cytochrome P450c17 alpha activity and serum free
testosterone after reduction of insulin secretion in polycystic ovary
Nestler JE, Jakubowicz DJ. Department of Internal Medicine, Medical
College of Virginia, Virginia Commonwealth University, Richmond, VA
BACKGROUND:Insulin resistance and increased ovarian cytochrome
P450c17 alpha activity are both features of the polycystic ovary
syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has
both 17 alpha-hydroxylase and 17,20-lyase activities. Increased
activity of this enzyme results in exaggerated conversion of
progesterone to 17 alpha-hydroxyprogesterone in response to stimulation
by gonadotrophin. We hypothesized that hyperinsulinemia stimulates
ovarian P450c17 alpha activity.
METHODS:We measured fasting serum steroid concentrations and the
response of serum 17 alpha-hydroxyprogesterone to leuprolide, a
gonadotrophin-releasing hormone agonist, and performed oral
glucose-tolerance tests before and after oral administration of either
metformin (500 mg three times daily) or placebo for four to eight weeks
in 24 obese women with the polycystic ovary syndrome.
RESULTS:In the 11 women given metformin, the mean (+/- SE) area under
the serum insulin curve after oral glucose administration decreased
from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56
+/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease
was associated with a reduction in the basal serum 17
alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng
per deciliter (4.1 +/- 0.6 to 2.0 +/- 0.2 nmol per liter) (P = 0.01) and
a reduction in the leuprolide-stimulated peak serum 17
alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng
per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01).
The serum 17 alpha-hydroxyprogesterone values increased slightly in the
placebo group. In the metformin group, the basal serum luteinizing
hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per
milliliter (P = 0.01), the serum free testosterone concentration
decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3
to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex
hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3
+/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter)
(P < 0.001). None of these values changed significantly in the
CONCLUSIONS:In obese women with the polycystic ovary syndrome,
decreasing serum insulin concentrations with metformin reduces ovarian
cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.
Prevents or delays onset of DM
16) www.ncbi.nlm.nih.gov/pmc/articles/PMC1370926/?tool=pubmed www.ncbi.nlm.nih.gov/pubmed/11832527
N Engl J Med. 2002 Feb 7;346(6):393-403.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker
EA, Nathan DM; Diabetes Prevention Program Research Group. Diabetes
Prevention Program Coordinating Center, Biostatistics Center, George
Washington University, 6110 Executive Blvd., Suite 750, Rockville, MD
BACKGROUND:Type 2 diabetes affects approximately 8 percent of adults
in the United States. Some risk factors–elevated plasma glucose
concentrations in the fasting state and after an oral glucose load,
overweight, and a sedentary lifestyle–are potentially reversible. We
hypothesized that modifying these factors with a lifestyle-intervention
program or the administration of metformin would prevent or delay the
development of diabetes.
METHODS:We randomly assigned 3234 nondiabetic persons with elevated
fasting and post-load plasma glucose concentrations to placebo,
metformin (850 mg twice daily), or a lifestyle-modification program with
the goals of at least a 7 percent weight loss and at least 150 minutes
of physical activity per week. The mean age of the participants was 51
years, and the mean body-mass index (the weight in kilograms divided by
the square of the height in meters) was 34.0; 68 percent were women, and
45 percent were members of minority groups.
RESULTS:The average follow-up was 2.8 years. The incidence of
diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the
placebo, metformin, and lifestyle groups, respectively. The lifestyle
intervention reduced the incidence by 58 percent (95 percent confidence
interval, 48 to 66 percent) and metformin by 31 percent (95 percent
confidence interval, 17 to 43 percent), as compared with placebo; the
lifestyle intervention was significantly more effective than metformin.
To prevent one case of diabetes during a period of three years, 6.9
persons would have to participate in the lifestyle-intervention program,
and 13.9 would have to receive metformin.
CONCLUSIONS:Lifestyle changes and treatment with metformin both
reduced the incidence of diabetes in persons at high risk. The lifestyle
intervention was more effective than metformin. Restores ovulation,
Fertil Steril. 2002 Apr;77(4):669-73.
Pregnancies following use of metformin for ovulation induction in
patients with polycystic ovary syndrome. Heard MJ, Pierce A, Carson SA,
Buster JE. Department of Obstetrics and Gynecology, Division of
Reproductive Endocrinology and Infertility, Baylor College of Medicine,
Houston, Texas 77030, USA.
OBJECTIVE:To assess pregnancy outcome in anovulatory infertility
patients diagnosed with polycystic ovary syndrome (PCOS) who were
treated with metformin. DESIGN:Case series.
PATIENT(S):Anovulatory patients (n = 48) with a diagnosis of PCOS based
on clinical, diagnostic, and laboratory evaluations were enrolled in the
study over a 15-month period.
INTERVENTION(S):Metformin was started at 500 mg b.i.d. for 6 weeks and
then increased to 500 mg t.i.d. if no ovulation occurred. Clomiphene
citrate (CC; 50 mg) was added if no ovulatory response occurred after 6
MAIN OUTCOME MEASURE(S):Resumption of menses, presumptive ovulation, and pregnancy.
RESULT(S):Nineteen of 48 (40%) patients resumed spontaneous menses
following treatment and showed presumptive evidence of ovulation with
metformin alone; 15/48 (31%) required CC (50 mg) in conjunction with
metformin therapy, and 10 of these 15 (67%) had evidence of ovulation;
20/48 (42%) conceived with a median time to conception of 3 months, and 7
of these 20 (35%) had spontaneous abortions (SA; 19/48 (40%) had
gastrointestinal-related side effects, and 5 of 48 patients (10%) had to
decrease the dosage of metformin. Only 1 patient discontinued therapy.
CONCLUSION(S):Metformin alone in patients with PCOS results in a
substantial number of pregnancies, with 69% (20/29) of those who
ovulated conceiving in less than 6 months.
Eur Psychiatry. 2007 Oct;22(7):453-4. Epub 2007 Aug 30.
Orally disintegrating olanzapine induces less weight gain in adolescents than standard oral tablets.
Crocq MA, Guillon MS, Bailey PE, Provost D. Centre Hospitalier, Service
de Psychiatrie de l’Adolescent, BP29, 68250 Rouffach, France.
We compared the changes in weight (kg) and body mass index (BMI)
(kg/m(2)) in 52 hospitalized adolescents between baseline and after 12
weeks of monotherapy with either (i) olanzapine (OLZ) orally
disintegrating tablets (ODT) (N=16; 16.6 mg/day+/-4.4 [SD]), or (ii) OLZ
standard oral tablets (SOT) (N=10; 18.0 mg/day+/-4.2), or (iii)
risperidone (N=26; 2.8 mg/day+/-1.2). Significantly greater increases in
mean weight and BMI were observed in the patients treated with OLZ SOT
(8.9+/-5.1 [SD] kg; 1.9+/-0.6 kg/m(2), respectively) than in those with
ODT (3.0+/-2.1 kg; 1.1+/-0.8 kg/m(2)). Similarly, OLZ ODT treatment was
associated with significantly greater increases in weight and BMI than
risperidone (1.0+/-1.8 kg; 0.4+/-0.7 kg/m(2)). These findings suggest
that adolescents gain less weight with OLZ ODT than OLZ SOT, possibly
because the former formulation shortens the time of interaction with
digestive serotonin receptors mediating satiety.
Morrison JA et al. Am J Psychiatry. 2002 Apr;159(4):655-7. 39 children
10 – 17 y/o on 2nd gen antipsychotics & 10+% weight gain Half
placebo, half given 500 – 850 mg metformin bid Placebo gained 4 kg;
metformin no weight gain
Am J Psychiatry. 2006 Dec;163(12):2072-9.
A randomized, double-blind, placebo-controlled trial of metformin
treatment of weight gain associated with initiation of atypical
antipsychotic therapy in children and adolescents.
Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. Division
of Endocrinology, Cincinnati Children’s Hospital Medical Center, ML
7012, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
OBJECTIVE:Second-generation, or atypical, antipsychotics effectively
treat psychiatric illness in children and adolescents. However, weight
gain and abnormalities in insulin sensitivity, including diabetes,
complicate this therapy. METHOD:A 16-week double-blind,
placebo-controlled trial was conducted to evaluate the effectiveness of
metformin in managing weight gain in 39 subjects, ages 10-17, whose
weight had increased by more than 10% during less than 1 year of
olanzapine, risperidone, or quetiapine therapy. Body weight, body mass
index (kilograms per square meter of height), and waist circumference
were measured regularly, as were fasting insulin and glucose levels.
RESULTS:Weight was stabilized in subjects receiving metformin, while
those receiving placebo continued to gain weight (0.31 kg/week). Because
the study was conducted with growing children, metformin treatment
resulted in reduction in z scores for both weight and body mass index.
The homeostasis model assessment, a surrogate indicator of insulin
sensitivity, decreased in treated subjects. Overt diabetes was diagnosed
in two subjects before treatment (elevated baseline fasting glucose and
insulin values) and in two placebo-treated subjects (one at week 12 and
the other after study completion). One subject taking placebo developed
impaired fasting glucose. Placebo treatment was associated with the
need to perform oral glucose tolerance testing upon study completion, by
which three additional subjects were identified with impaired glucose
tolerance. No serious adverse events resulted from metformin treatment.
CONCLUSIONS:Metformin therapy is safe and effective in abrogating
weight gain, decreased insulin sensitivity, and abnormal glucose
metabolism resulting from treatment of children and adolescents with
UKPDS Study Group. Lancet. 1998;352:837-853. Lancet. 1998 Sep 12;352(9131):837-53.
Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study
(UKPDS) Group. Thiazolidinediones (TZDs) such as rosiglitazone (Avandia)
associated wit ave +2.8 kg
Future Oncol. 2010 March; 6(3): 457–470.
AMPK as a metabolic tumor suppressor: control of metabolism and cell growth
Zhijun Luo Department of Biochemistry, Boston University School of Medicine
Breast Cancer Res Treat. 2010 Sep;123(2):591-6.
Metformin inhibits aromatase expression in human breast adipose stromal
cells via stimulation of AMP-activated protein kinase. Brown KA, Hunger
NI, Docanto M, Simpson ER. Source Prince Henry’s Institute of Medical
Research, P.O. Box 5152, Clayton, VIC, 3168, Australia.
Abstract AMP-activated protein kinase (AMPK) is recognized as a
master regulator of energy homeostasis. In concert with the AMPK-kinase
LKB1, it has been shown to provide a molecular link between obesity and
postmenopausal breast cancer via its actions to inhibit aromatase
expression, hence estrogen production, within the breast.
The anti-diabetic drug metformin is known to increase the activity of
AMPK and was therefore hypothesized to inhibit aromatase expression in
primary human breast adipose stromal cells.
Results demonstrate that metformin significantly decreases the
forskolin/phorbol ester (FSK/PMA)-induced expression of aromatase at
concentrations of 10 and 50 muM. Consistent with the hypothesized
actions of metformin to increase AMPK activity, treatment with 50 muM
metformin results in a significant increase in phosphorylation of AMPK
at Thr172. Interestingly, metformin also causes a significant increase
in LKB1 protein expression and promoter activity, thereby providing for
the first time an additional mechanism by which metformin activates
AMPK. Furthermore, metformin inhibits the nuclear translocation of
CRTC2, a CREB-coactivator known to increase aromatase expression which
is also a direct downstream target of AMPK.
Overall, these results suggest that metformin would reduce the local
production of estrogens within the breast thereby providing a new key
therapeutic tool that could be used in the neoadjuvant and adjuvant
settings and conceivably also as a preventative measure in obese women.
Eur J Intern Med. 2000 Oct;11(5):245-252. Diabetes mellitus and cancer.
Czyzyk A, Szczepanik Z. Department of Gastroenterology and Metabolic
Diseases, Central Clinical Hospital, University Medical School of
Warsaw, ul. Banacha 1A, PL-02-097, Warsaw, Poland
Although an association between diabetes and cancer was found over
100 years ago, the issue underwent different interpretations over the
subsequent decades, and only modern, prospective, epidemiological cohort
and case-control studies conducted in several countries have provided
reliable evidence of an increased cancer risk in diabetic patients,
mainly in those with type 2 diabetes. This risk varies according to the
tumor site: it is the greatest for primary liver cancer, moderately
elevated for pancreatic cancer, and relatively low for colorectal,
endometrial, breast, and renal cancers. The cause of the association is
not clear and remains the subject of different hypotheses. The most
frequently cited reason is the potential effect of insulin. Found in
high concentrations, due to insulin resistance in most patients with
type 2 diabetes, this hormone is believed to express a mitogenic effect.
This hypothesis needs to be confirmed in appropriately programmed
prospective studies, but it may already be helpful in choosing an
adequate treatment for type 2 diabetes to achieve optimal metabolic
control with a simultaneous reduction in hyperinsulinemia, such as diet,
physical exercise, metformin, and acarbose.
Ruiter R et al. Diabetes Care 2012 Jan; 35:119
Diabetes Care January 2012 vol. 35 no. 1 119-124
Lower Risk of Cancer in Patients on Metformin in Comparison With Those
on Sulfonylurea Derivatives Results from a large population-based
follow-up study by Rikje Ruiter, MD Department of Epidemiology, Erasmus
MC, Rotterdam, the Netherlands
OBJECTIVE Numerous studies have suggested a decreased risk of cancer
in patients with diabetes on metformin. Because different comparison
groups were used, the effect magnitude is difficult to estimate.
Therefore, the objective of this study was to further analyze whether,
and to what extent, use of metformin is associated with a decreased risk
of cancer in a cohort of incident users of metformin compared with
users of sulfonylurea derivatives.
RESEARCH DESIGN AND METHODS Data for this study were obtained from
dispensing records from community pharmacies individually linked to
hospital discharge records from 2.5 million individuals in the
Netherlands. The association between the risk of cancer in those using
metformin compared with those using sulfonylurea derivatives was
analyzed using Cox proportional hazard models with cumulative duration
of drug use as a time-varying determinant.
RESULTS Use of metformin was associated with a lower risk of cancer
in general (hazard ratio 0.90 [95% CI 0.88–0.91]) compared with use of
sulfonylurea derivatives. When specific cancers were used as end points,
similar estimates were found. Dosage-response relations were identified
for users of metformin but not for users of sulfonylurea derivatives.
CONCLUSIONS In our study, cumulative exposure to metformin was
associated with a lower risk of specific cancers and cancer in general,
compared with cumulative exposure to sulfonylurea derivatives. However,
whether this should indeed be seen as a decreased risk of cancer for the
use of metformin or as an increased risk of cancer for the use
sulfonylurea derivatives remains to be elucidated.
Diabetes Care. 2009 Sep;32(9):1620-5. Epub 2009 Jun 29.
New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes.
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM.
Division of Clinical and Population Sciences and Education, University of Dundee, Dundee, UK.
The antidiabetic properties of metformin are mediated through its
ability to activate the AMP-activated protein kinase (AMPK). Activation
of AMPK can suppress tumor formation and inhibit cell growth in addition
to lowering blood glucose levels. We tested the hypothesis that
metformin reduces the risk of cancer in people with type 2 diabetes.
RESEARCH DESIGN AND METHODS:In an observational cohort study using
record-linkage databases and based in Tayside, Scotland, U.K., we
identified people with type 2 diabetes who were new users of metformin
in 1994-2003. We also identified a set of diabetic comparators,
individually matched to the metformin users by year of diabetes
diagnosis, who had never used metformin. In a survival analysis we
calculated hazard ratios for diagnosis of cancer, adjusted for baseline
characteristics of the two groups using Cox regression.
RESULTS:Cancer was diagnosed among 7.3% of 4,085 metformin users
compared with 11.6% of 4,085 comparators, with median times to cancer of
3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard
ratio (95% CI) for cancer was 0.46 (0.40-0.53). After adjusting for sex,
age, BMI, A1C, deprivation, smoking, and other drug use, there was
still a significantly reduced risk of cancer associated with metformin:
CONCLUSIONS:These results suggest that metformin use may be associated
with a reduced risk of cancer. A randomized trial is needed to assess
whether metformin is protective in a population at high risk for cancer.
Acta Diabetol. 2009 Dec;46(4):279-84. Epub 2008 Dec 10. Sulphonylureas
and cancer: a case-control study. Monami M, Lamanna C, Balzi D,
Marchionni N, Mannucci E. Department of Critical Care Medicine and
Surgery, Unit of Gerontology and Geriatrics, University of Florence and
Azienda Ospedaliero-Universitaria Careggi, Via delle Oblate 4, 50134,
This study was aimed at the assessment of incidence of malignancies
in type 2 diabetic patients treated with different sulphonylureas.
A matched case-control study was performed. Cases were 195 diabetic
patients aged 69.0 +/- 9.2 years who had an incident malignancy.
Controls were 195 diabetic patients, unaffected by cancer, who were
matched with the corresponding case for age, sex, duration of diabetes,
BMI, HbA1(c), comorbidity, smoking and alcohol abuse.
Exposure to hypoglycaemic drugs during the 10 years preceding the
event (or matching index date) was assessed. After adjusting for
concomitant therapies, exposure to metformin and gliclazide for more
than 36 months was associated with a significant reduction in the risk
of cancer (adj. ORs with 95% CI: 0.28 (0.13-0.57), p < 0.001, and
0.40 (0.21-0.57), p = 0.004, respectively). Conversely, use of
glibenclamide for at least 36 months was associated with increased
incidence of malignancies (adj. OR 2.62 (1.26-5.42); p = 0.009).
Treatment with insulin, thiazolidinediones, or acarbose, was not
associated with significant differences in the incidence of cancer.
Long-term treatments with individual sulphonylureas could have
differential effects on the risk of cancer. In particular, the possible
protective effect of gliclazide, as well as the risk associated with
glibenclamide, deserves further investigation.
28) www.ncbi.nlm.nih.gov/pmc/articles/PMC2735093/?tool=pubmed www.ncbi.nlm.nih.gov/pubmed/19375425
Gastroenterology. 2009 Aug;137(2):482-8.
Antidiabetic therapies affect risk of pancreatic cancer. Li D, Yeung SC,
Hassan MM, Konopleva M, Abbruzzese JL. Department of Gastrointestinal
Medical Oncology, The University of Texas MD Anderson Cancer Center,
Houston, Texas 77030, USA.
Antidiabetic drugs have been found to have various effects on cancer
in experimental systems and in epidemiologic studies, although the
association between these therapeutics and the risk of human pancreatic
cancer has not been explored. We investigated the effect of antidiabetic
therapies on the risk of pancreatic cancer. METHODS:A hospital-based
case-control study was conducted at M. D. Anderson Cancer Center from
2004 to 2008 involving 973 patients with pancreatic adenocarcinoma
(including 259 diabetic patients) and 863 controls (including 109
diabetic patients). Information on diabetes history and other risk
factors was collected by personal interview. The frequencies of use of
insulin, insulin secretagogues, metformin, and other antidiabetic
medications among diabetic patients were compared between cases and
controls. The risk of pancreatic cancer was estimated using
unconditional logistic regression analysis.
RESULTS- Diabetic patients who had taken metformin had a
significantly lower risk of pancreatic cancer compared with those who
had not taken metformin (odds ratio, 0.38; 95% confidence interval,
0.22-0.69; P = .001), with adjustments for potential confounders. This
difference remained statistically significant when the analysis was
restricted to patients with a duration of diabetes >2 years or those
who never used insulin. In contrast, diabetic patients who had taken
insulin or insulin secretagogues had a significantly higher risk of
pancreatic cancer compared with diabetic patients who had not taken
CONCLUSIONS:Metformin use was associated with reduced risk, and
insulin or insulin secretagogue use was associated with increased risk
of pancreatic cancer in diabetic patients.
29) www.ncbi.nlm.nih.gov/pmc/articles/PMC2736070/?tool=pubmed www.ncbi.nlm.nih.gov/pubmed/19487376
J Clin Oncol. 2009 Jul 10;27(20):3297-302. Epub 2009 Jun 1.
Metformin and pathologic complete responses to neoadjuvant
chemotherapy in diabetic patients with breast cancer. Jiralerspong S,
Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L,
Hung MC, Hortobagyi GN, Gonzalez-Angulo AM. Department of Breast Medical
Oncology, The University of Texas M. D. Anderson Cancer Center,
Houston, 77030-4009, USA. Population studies have suggested that
metformin use in diabetic patients decreases cancer incidence and
mortality. Metformin inhibits the growth of cancer cells in vitro and
tumors in vivo. However, there is little clinical data to support this.
Our purpose was to determine whether metformin use was associated with a
change in pathologic complete response (pCR) rates in diabetic patients
with breast cancer receiving neoadjuvant chemotherapy.
PATIENTS AND METHODS:We identified 2,529 patients who received
neoadjuvant chemotherapy for early-stage breast cancer between 1990 and
2007. Patients were compared by groups: 68 diabetic patients taking
metformin, 87 diabetic patients not taking metformin, and 2,374
nondiabetic patients. pCR rates were compared between the three groups
using chi(2) tests of independence and compared pair- wise using a
binomial test of proportions. Factors predictive of pCR were assessed
using a multivariate logistic regression model.
RESULTS:The rate of pCR was 24% in the metformin group, 8.0% in the
nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise
comparisons between the metformin and nonmetformin groups (P = .007)
and the nonmetformin and nondiabetic groups (P = .04) were significant.
Comparison of the pCR rates between the metformin and nondiabetic groups
trended toward but did not meet significance (P = .10). Metformin use
was independently predictive of pCR (odds ratio, 2.95; P = .04) after
adjustment for diabetes, body mass index, age, stage, grade, receptor
status, and neoadjuvant taxane use.
Diabetic patients with breast cancer receiving metformin and neoadjuvant
chemotherapy have a higher pCR rate than do diabetics not receiving
metformin. Additional studies to evaluate the potential of metformin as
an antitumor agent are warranted.
Dilman, Vladimir, and Dean, Ward.
The Neuroendocrine Theory of Aging, The Center for Bio-Gerontology, Pensacola, Florida, 1992
31) physiolgenomics.physiology.org/content/23/3/343.long physiolgenomics.physiology.org/content/23/3/343.full.pdf
Physiol Genomics. 2005 Nov 17;23(3):343-50.
Identification of potential caloric restriction mimetics by microarray profiling.
Dhahbi JM, Mote PL, Fahy GM, Spindler SR. Department of Biochemistry, University of California, Riverside, California
To facilitate the development of assays for the discovery of
pharmaceuticals capable of mimicking the effects of caloric restriction
(CR) on life- and healthspan (CR mimetics), we evaluated the
effectiveness of glucoregulatory and putative cancer chemopreventatives
in reproducing the hepatic gene expression profile produced by long-term
CR (LTCR), using Affymetrix microarrays. We have shown that CR
initiated late in life begins to extend lifespan, reduce cancer as a
cause of death, and reproduce approximately three-quarters of the
genomic effects of LTCR in 8 wk (CR8). Eight weeks of metformin
treatment was superior to CR8 at reproducing LTCR-like gene expression
changes, maintaining a superior number of such changes over a broad
range of statistical stringencies, and producing more Gene Ontology
terms overlapping those produced by LTCR. Consistent with these results,
metformin has been shown to reduce cancer incidence in mice and humans.
Phenformin, a chemical cousin of metformin, extends lifespan and
reduces tumor incidence in mice. Taken together, these results indicate
that gene expression biomarkers can be used to identify promising
candidate CR mimetics.
32) sens.org/node/1821 Spindler SR et al.
Rapid identification of candidate CR mimetics using microarray.
Biogerontology 2003 4(Suppl 1):
Rapid identification of candidate CR mimetics using microarrays
S.R. Spindler, J.D. Dhahbi, P.L. Mote, H.J. Kim, T. Tsuchiya University
of California, Riverside, Department of Biochemistry, 5478 Boyce Hall,
Riverside, CA 92521, U.S.A.
Quantitative changes in the activity of genes can control the rate of
aging and the development of age-related diseases in invertebrates and
mammals. Caloric restriction (CR) is the most robust environmental
method known for decelerating aging and the development of age-related
diseases. CR is widely viewed as acting slowly and incrementally to
prevent the accumulation of deleterious age-related physiological
changes. CR is also widely thought to be less effective in older
animals. Using survival and high-density microarray studies we
demonstrate that CR acts rapidly and reversibly to establish a pattern
of gene expression temporally associated with enhanced life span and
reduced tumor incidence in mice. CR was fully effective at extending
life span and reducing tumor incidence when begun in old animals. The
results indicate that therapies mimicking the gene expression effects of
CR may be rapidly effective, even in old animals. To investigate this
possibility, we screened three glucoregulatory pharmaceuticals and a soy
isoflavone extract (a putative chemopreventative) for their ability to
mimic the effects of long-term CR on gene expression using hepatic RNA,
since most of these mice die of liver tumors. The glucoregulatory
pharmaceuticals and the combination of two of these pharmaceuticals
produced a significant number of changes in hepatic gene expression
identical to those produced by long-term and/or short-term CR. The most
extensive overlap with CR was obtained from metformin. The gene
expression changes common to metformin and CR were associated with
xenobiotic metabolism, cellular stress, energy metabolism, biosynthesis,
signal transduction, and the cytoskeleton. The changes are consistent
with enhanced apoptosis and protein turnover, and reduced tumor
incidence and cellular stress. These results suggest that metformin is
potential CR-mimetic. Others have shown that phenformin, a
glucoregulatory pharmaceutical structurally and functionally similar to
metformin, extends the lifespan of mice by 23%, and reduces cancer as a
cause of death from 80% to 20% (1). Others recently have presented
preliminary evidence that metformin extends the lifespan of rats (2).
Therefore, agents that reproduce the long-term CR signature in
microarray assays are candidate CR mimetics. 89
Cell Cycle. 2008 Sep 1;7(17):2769-73. Epub 2008 Sep 11.
Metformin slows down aging and extends life span of female SHR mice.
Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG,
Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE,
Semenchenko AV. N.N.Petrov Research Institute of Oncology, St.
Studies in mammals have led to the suggestion that hyperglycemia and
hyperinsulinemia are important factors both in aging and in the
development of cancer. It is possible that the life-prolonging effects
of calorie restriction are due to decreasing IGF-1 levels. A search of
pharmacological modulators of insulin/IGF-1 signaling pathway (which
resemble effects of life span extending mutations or calorie
restriction) could be a perspective direction in regulation of
Antidiabetic biguanides are most promising among them.
Here we show the chronic treatment of female outbred SHR mice with
metformin (100 mg/kg in drinking water) slightly modified the food
consumption but decreased the body weight after the age of 20 months,
slowed down the age-related switch-off of estrous function, increased
mean life span by 37.8%, mean life span of last 10% survivors by 20.8%,
and maximum life span by 2.8 months (+10.3%) in comparison with control
mice. On the other side, treatment with metformin failed influence blood
estradiol concentration and spontaneous tumor incidence in female SHR
mice. Thus, antidiabetic biguanide metformin dramatically extends life
span, even without cancer prevention in this model.
Arch Intern Med. 2002 Feb 25;162(4):484-5.
Metformin and vitamin B12 deficiency.Gilligan MA.
Metformin is a drug increasingly used as a first-line treatment for
type 2 diabetes mellitus. In this country, there is less experience with
the drug than in England and Europe, where it has been used for
decades. The drug is well tolerated in most patients. The primary
adverse effect discussed in the North American literature is lactic
acidosis, which is seen in patients with renal insufficiency and those
undergoing radiologic procedures using contrast dye. Another
well-documented but little-discussed adverse effect, notably omitted
from an article in the ARCHIVES on laboratory diagnosis of B12
deficiency,1 is biguanide-associated decreased levels of vitamin B12.
The following case highlights this problem.
Letters to the Editor
Use of Metformin Is a Cause of Vitamin B12 Deficiency Am Fam Physician. 2004 Jan 15;69(2):264-266.
Salpeter S, Greyber E, et al. Arch Int Med. 2003;163(21):2594–602 Arch Intern Med. 2003 Nov 24;163(21):2594-602.
Risk of fatal and nonfatal lactic acidosis with metformin use in type
2 diabetes mellitus: systematic review and meta-analysis. Salpeter SR,
Greyber E, Pasternak GA, Salpeter EE. Source Department of Medicine,
Stanford University School of Medicine, Stanford, CA, USA.
Metformin therapy for type 2 diabetes mellitus has been shown to
reduce total mortality rates compared with other antihyperglycemic
treatments but is thought to increase the risk of lactic acidosis. The
true incidence of fatal and nonfatal lactic acidosis associated with
metformin use is not known.
METHODS:A comprehensive search was performed to identify all
comparative trials or observational cohort studies published between
January 1, 1959, and March 31, 2002, that evaluated metformin therapy,
alone or in combination with other treatments, for at least 1 month. The
incidence of fatal and nonfatal lactic acidosis was recorded as cases
per patient-years for metformin treatment and for placebo or other
treatments. In a second analysis, lactate levels were measured as a net
change from baseline or as mean treatment values for metformin and
Pooled data from 194 studies revealed no cases of fatal or nonfatal
lactic acidosis in 36 893 patient-years in the metformin group or in 30
109 patients-years in the nonmetformin group. Using Poisson statistics
with 95% confidence intervals, the probable upper limit for the true
incidence of lactic acidosis in the metformin and nonmetformin groups
was 8.1 and 9.9 cases per 100 000 patient-years, respectively. There was
no difference in lactate levels for metformin compared with placebo or
other nonbiguanide therapies.
CONCLUSION:There is no evidence to date that metformin therapy is
associated with an increased risk of lactic acidosis or with increased
levels of lactate compared with other antihyperglycemic treatments if
the drugs are prescribed under study conditions, taking into account
Aging (Albany NY). 2011 Apr;3(4):348-62.
Gerosuppressant Metformin: less is more
Javier A. Menendez,1,2 Sílvia Cufí,1,2 Cristina Oliveras-Ferraros,1,2
Luciano Vellon,3 Jorge Joven,4 and Alejandro Vazquez-Martin1,2 1 Catalan
Institute of Oncology, Girona (Catalonia, Spain) 2 Girona Biomedical
Research Institute, Girona (Catalonia, Spain) 3 Fundación INBIOMED, Cell
Reprogramming Unit, San Sebastián (Basque Country, Spain) 4 Centre de
Recerca Biomèdica, Hospital Universitari Sant Joan de Reus, Institut
d’Investigaciò Sanitària Pere Virgili, Universitat Rovira i Virgili,
Reus (Catalonia, Spain)
Jeffrey Dach MD
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