February 25, 2020
Doctor Stacy Dana D. San Diego, M.D.
For the typical Filipino household, the dinner table during Christmas time can get so festive as if the excise tax on sugar was never implemented. Times and trends may be changing but our culture towards food doesnot seem to be adapting to these changes creating an increase intype 2 diabetes mellitus (DM) and obesity cases. Luckily, an anti-diabetic drug seems to be making these adjustments for us.
Metformin is a common drug known to diabetics and to anyone who lives with a diabetic. It is also prescribed to patients who are pre-diabetic or people at great risk of diabetes. Metformin,a biguanide derivative, is better understood as an “insulin sensitizer” and works by helping to restore the body's response to insulin.It does not depend on the pancreas to release insulin. Metformin has been shown to reduce diabetes mortality and complications by 30% compared to insulin, glibenclamide, and chlorpropamide.
Aside from its antidiabetic properties, metformin has been found to have antineoplastic, anti-aging, renoprotective, and cognitive-enhancing abilities. It has been used for polycystic ovary syndrome and has potential role against pancreatic cancer and nephrotoxic agents. Moreover, metformin has been proposed to decrease mortality by decreasing the risks of cardiovascular disease. Its anti-aging property is currently being investigated in two large trials.
Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is frequently associated with resistance to insulin. Metformin has been proposed as treatment for PCOS especially for those with a body mass index (BMI) above 25.
A systematic review using comparative trials of clomiphene and metformin found equal results for infertility. Moreover, metformin also has positive effects on insulin resistance, hirsutism, anovulation and obesity, which are often associated with PCOS. On the other hand, a large review using 27 clinical trials found that metformin was not associated with any increase in the number of live births. However, improved ovulation rateswere observed especially when metformin was used in combination with clomiphene.
The use of metformin throughout pregnancy in women with PCOS decreases the rates of early pregnancy loss and preterm labor, hence protecting against fetal growth restriction. There have been no demonstrable teratogenic effects, intrauterine deaths, or developmental delays with the use of metformin.
Pregnancy and Gestational Diabetes
Metformin appears to be effective and safe for the treatment of gestational diabetes mellitus (GDM), particularly for overweight or obese women. However, as metformin crosses the placenta, its use during pregnancy raises concerns regarding potential adverse effects on the mother and fetus.
Due to lack of clinical guidelines, it is suggested that metformin therapy be used for glycemic control only for those women with GDM who do not have satisfactory glycemic control despite medical nutrition therapy and those who refuse or cannot use insulin or glyburide in the first trimester.
Several epidemiologic studies have shown that metformin use is associated with reduced cancer incidence and mortality. One study showed that overall cancer incidence was reduced by 31% and cancer mortality by 34%.
Metformin as a cancer protector of patients against pancreatic cancer was suggested in a study. The metformin group had 62% lower chance of developing pancreatic cancer than the placebo group. The participants receiving sulfonylureas or insulin were found to have a 2.5 and 5-times higher risk of developing pancreatic cancer, respectively, in comparison to the placebo group.
Metformin has shown strong antiproliferative effects on colon, pancreatic, breast, ovarian, prostate and lung cancer cells. A proposed role on its antitumorigenic activity is currently being studied.
Other anti-diabetic drugs have not shown the same anticancer activities; hence, the anticancer effect of metformin should not be related to the anti-diabetic activity of this drug. Althougha trialhasyet to determine reported effects of chronic treatment with metformin oncancer prevention, studies in early-stage cancer or pre-malignancy suggest this may be fruitful.
Protection Against Nephrotoxicity
One of the dreaded complications of diabetes is diabetic nephropathy. Diabetes is the most common cause of end stage renal disease (ESRD) worldwide. Diabetics on hemodialysis have a higher mortality risk and a worse quality of life compared to non-diabetics on hemodialysis.
Studies have shown that metformin may have therapeutic or renoprotective effects against nephrotoxic agents evidenced by a significant reduction of albuminuria in patients with DM. Various studies have reported that metformin is capable of decreasing intracellular reactive oxygen species (ROS).It restores the biochemical alterations within the kidneys.
Several studies have also shown that ROS overproduction might be the key that causes development of complications of diabetes. ROS generation by oxidative stress causes cell death. Cell death (apoptosis) is implicated in the pathogenesis of diabetic nephropathy. ROS is an inducer of apoptosis in various cell types.
With all the proposed benefits of metformin, several trials were initiated to further understand its role as an anti-aging wonder drug. Metformin modulates the biology of aging and is believed to prolong life span.
Metformin use leads to decreased insulin levels, decreased insulin -like growth factor 1 (IGF-1) signaling, inhibition of mammalian target of rapamycin (mTOR), inhibition of mitochondrial complex 1 in the electron transport chain,reduction of endogenous production of reactive oxygen species (ROS), activation of AMP-activated kinase (AMPK), and reduction in DNA damage.
All abovementioned processes affect inflammation, cellular survival, stress defense, autophagy, senescent cell removal and protein synthesis, which are major biological outcomes associated with aging/longevity. If metformin can target and delay aging, its administration should be associated with fewer age-related diseases in general, rather than merely the decreased incidence of a single disease.
Data from several randomized clinical trials and multiple observational studies provided evidence for such an effect, which would not be expected from glucose lowering alone.
Association with Better Cognitive Function
Memory loss is common among the elderly. Emerging evidence suggests that metformin may preserve cognitive function. Therefore, this drug may improve not just our physical bodies but also our mental health.
In a Singaporean study, metformin use was associated with a 51% reduced risk of developing cognitive impairment. Further, the lowest risk was seen in those with longer-term (> 6 years) metformin use. In a study of type 2 DM patients with depression, the metformin group showed improved cognition and reduced depressive symptoms, with improved glycemic control.
Association with Decreased Mortality
Metformin-treated diabetic patients had survival rates similar to their matched non-diabetic control group, despite the fact that the diabetic patients had greater BMI and had more co-morbidities at baseline. Further, metformin treatment was associated with improvement in cardiovascular disease (CVD) risk factors and subclinical atherosclerosis (coronary artery calcium) in males.
Metformin is not a drug without side effects. It may cause a serious condition called lactic acidosis. Lactic acidosis usually occurs due to drug overdose and presence of certain medical conditions. It is a rare but serious and fatal side effect.
Gastric intolerance is common with metformin use. Incidence of myocardial infarction is also an important event but seen less in metformin compared with sulfonylurea agents.
Metformin has been around since the 1950s and it was around that time that it was recommended as a treatment for diabetes. Due to advancements in medicine, several beneficial properties of metformin are now being discovered. Its lengthy history will also require lengthy studies which may entirely change the use of metformin and improve the quality of people’s lives.