What do you think is the most common endocrine disorder in the world?

You guessed it right! Diabetes!

Every one in 11 individuals is suffering from diabetes. The past two decades have seen a global rampage in health sector with no fewer than 90% new cases emerging in the US alone.

Diabetes, as we speak, has become a pandemic. In 2015, the diabetic population was 415 millions. It is expect to escalate to 642 millions by 2040.

The prevalence of diabetes is highest among the Chinese adults. Not less than 12 percent (about 113.9 million people) of the Chinese youth is racked with diabetes.

Globally, 12% of the health expenses is splashed out on diabetes.

Diabetes, as we know, is categorized into two types;

Type 1 Diabetes Mellitus (T1DM) 

It is also called juvenile diabetes. It has a genetic predisposition and accounts only for 5% of newly diagnosed diabetes cases.

Type 2 Diabetes (T2DM) 

This type most affects adults, particularly those who are have a family history or are obese and have a sedentary lifestyle. It accounts for 95% of newly diagnosed diabetes cases.

Although, the history of diabetes dates back to 4000 years back, it was not until the 20th century that the present pharmacologic therapies for diabetes treatment came into being.

The first one to be discovered was obviously the insulin –the mainstay therapy for type 1 diabetes.

However, among oral anti-hyperglycemic agents, metformin (Glucophage), still holds the key position as a first-line treatment for diabetes.

Besides managing diabetes, metformin is effective in a number of conditions. Let us look at some detail.

1.Metformin Is Still The Best Treatment For Diabetes (T2DM)

Numerous studies have been carried out and a plethora of scholarly articles have been penned down about metformin, and its potential beneficial effects in controlling the glycemic levels in diabetics.

Metformin primarily acts as an insulin–sensitizer; it enhances and stimulates the effect of insulin in the target cells and promotes the uptake and metabolism of glucose by the cells. It also lowers the production of glucose (gluconeogenesis) in the liver.

Metformin belongs to the class of drugs called biguanides. It is the only agent of the class that has clinical application in curtailing the glycemic levels in diabetes.

Metformin, commonly known by the brand name Glucophage, holds a focal position among all anti-hyperglycemic agents since it is very much favorable in controlling the glycemic levels.

High blood glucose levels, or hyperglycemia, is a major risk factor in progression of diabetes and can lead to multiple microvascular and macrovascular complications such as cardiovascular disease, renal disease, and eye disease (retinopathy).

Both, American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) collectively recommend that metformin be instituted in diabetic patients following inadequate control of glycemic levels by life-style intervention and diet.

Recently, The American College of Physicians (ACP) has updated its 2012 recommendations and has reiterated that that metformin should be the first-line treatment in patients with type 2 diabetes.

If metformin fails to control hyperglycemia, the ACP recommends adding another oral hypoglycemic to the regimen, such as thiazolidinedione, sulfonylurea, SGLT-2 inhibitors or DPP-4 inhibitors.

Metformin’s effectiveness can be greatly enhanced if healthy lifestyle is maintained which includes:

  • Minimizing Consumption of fatty and sugary meals
  • Physical activity

A study, published in The New England Journal of Medicine (NEJM) by “Diabetes Prevention Program Research Group” carried out a research engaging 3,234 non-diabetic subjects with exalted fasting plasma glucose levels and post-meal elevated glucose levels.

The participants were arbitrarily consigned to either a placebo, metformin or lifestyle intervention which involved 150 minutes of physical activity per week and seven percent of weight reduction.

The study was pursued for a period of 2.8 years and the results were surprising, demonstrating that the incidence of diabetes reduced by 58 percent in the lifestyle intervention group whereas the diabetes rate declined by 31 percent in metformin group when both were compared to the placebo.

The study concluded that life style intervention alone is the best approach in pre-diabetes group in order to keep the disease at bay and the combined therapy is an excellent option for the actual diabetics.

Similar results were again obtained from a second long-term study that was followed up for 15 years and yet again executed by the “Diabetes Prevention Program Research Group”. The second study additionally observed the pace of emergence of microvascular complications that develop as a consequence of chronic diabetes.

The study findings reported that the incidence of diabetes declined by 27% in the treatment group that managed diabetic condition with lifestyle intervention and 18% in the treatment group that received metformin therapy. These findings inferred that besides being treated by the mainstay metformin therapy as managed care, lifestyle modification is compulsive in order to delay the progression of diabetes and microvascular complications.

The normal HbA1c levels in non–diabetic is 4%- 5.6%, levels exceeding this range indicate extreme risk of catching up diabetes and values exceeding 6.5% of HbA1c levels signify diabetes has actually precipitated in a patient.

Studies carried out on metformin effectiveness in reducing the blood sugar level indicate that metformin reduces HbA1c levels by 1.1% in comparison to a placebo whereas a comparison between high (2000 mg/day) and low doses (1000 mg/day) indicated that high dose metformin was 0.3% more effective in reducing HbA1c.

Addition of metformin to insulin was also beneficial and reduced the HbA1c levels by 0.8% as compared to insulin mono-therapy.

2.Metformin Prevents Neonatal Complications In Obese But Non-Diabetic Mothers

Metformin efficacy has also been assessed among obese but non-diabetic pregnant females.

A very influential and major-league study, EMPOWAR, published in The Lancet-Diabetes and Endocrinology, was conducted for a period of four years, from 2011 to 2014, to find truth regarding the hypothesis that metformin is effective in reducing high birth weight in off springs of obese but non–diabetic females since high birth weight is a future risk factor for obesity and diabetes in such off springs.

The study was carried out in prenatal clinics of 15 NHS hospitals in UK. It was a multicenter, randomized, placebo-controlled trial that engaged 449 obese, non-diabetic, pregnant females.

The trial was conducted at 12 to 16 weeks of gestation. The metformin dosage assigned to the metformin treatment group was 500 mg oral metformin to be given 5 times per day making a total of 2500 mg per day in 2 to 3 divided doses.

The findings reported that though metformin was not effective in reducing the high birth weight in offspring of obese-non diabetic females, it was however, beneficial in reducing the inflammatory markers – C-reactive protein (CRP) and Interleukin-6, which are found in  obese women as compared to normal females and linked to detrimental consequences such as preterm birth and pre-eclampsia – a condition in pregnant females that is associated with high blood pressure along with edema and high protein amounts in urine (proteinuria).

Additionally, the fasting plasma glucose, insulin levels and two-hour glucose levels were also found to be low in the metformin treatment group at 28 weeks of gestation in comparison to placebo group. The side-effects endured by the participants were vomiting and diarrhea.

3.Glucophage Has a Role To Play In Female Endocrinological Disorders

Although, beneficial effects of metformin in pregnant females still need further exploration, the effectiveness of the drug is well-established in conditions related to female endocrine disorders such as polycystic ovaries (PCOS).

Numerous studies have reported effectiveness of glucophage in such patient population. PCOS is a condition that causes menstrual irregularities, anovulation and infertility in females.

Studies on the pathogenesis of PCOS have found that apart from menstrual irregularities as a root cause, obesity is also a surrogate factor for this condition. Obesity is associated with glucose intolerance and insulin resistance and metformin acts as an insulin–sensitizer in this condition, by stimulating and promoting the action of insulin in glucose uptake.

Studies have reported that besides improving insulin activity in such females, metformin was found to be beneficial in regulating the menstrual cycle, weight loss and in decreasing the high androgen levels that arise due to imbalance in female hormones; mainly the estrogen and progesterone.

The studies also reported that metformin was highly favorable in inducing ovulation, counteracting anovulation, the primary symptom of PCOS, and increasing the pregnancy rates.

4.Patients With Renal Disease Can Also Benefit From Metformin With Monitoring

Generally, metformin is regarded as well-tolerable anti-diabetic drug with minimal adversities, such as nausea, flatulence and vomiting  which cannot be rendered as detrimental side effects, it is however, responsible for inducing lactic acidosis – a significant adverse effect in patients with chronic kidney impairment that cannot be overlooked.

For this reason, metformin is not recommended in patients with chronic kidney disease.

The findings of a population-based cohort study, employing 223,968 diabetic patients, stated that metformin was found to be responsible for increasing lactate levels in really compromised patients and can further worsen the metabolic condition by aggravating lactic acidosis.

Renal function should be periodically monitored, especially if renal function drops to 60 ml/minute or below. This is because metformin is primarily excreted by the kidneys and chronic kidney disease results in gradual loss or shrinkage of excretory function.

Another retrospective cohort study engaged 813 subjects with type 2 diabetes and advanced chronic kidney disease, to investigate the mortality rate among the respective patient population. The study findings revealed that metformin users with creatinine levels exceeding 530 umol/L and T2DM had extremely high risk of all-cause mortality and that metformin use should not be advocated in such patients.

However, the FDA has revised its warnings against metformin use among patients with reduced renal function showing leniency by expanding the confines of patients among which metformin might be used.

The FDA states that metformin should be used cautiously among patients with mild to moderate decline in renal activity and that the renal function of the patient should be assessed using estimated glomerular filtration rate (e GFR).

Earlier, the restrictions were more stringent and patients with serum creatinine at or greater than 1.5 mg/dL were contraindicated for using metformin. This obviously resulted in depriving a large patient population from remarkable benefits of metformin. However, the FDA still advises health care professionals to follow the latest guidelines regarding metformin use or medications that contain metformin as an additional ingredient in the respective patient population.

5.Metformin Is Compatible With Other Oral Hypoglycemics

Metformin has also been investigated regarding its dosage regimens. Metformin is more effective when combined with sulfonylureas (SU) in reducing both HbA1c levels and low density lipoproteins – the bad lipids.

However, the combination is not confined to sulfonylureas alone but other classes of anti-diabetic agents such as insulin , GLP-1 agonists, thiazolidinediones (TZDs),  and dipeptidyl peptidase-4 (DPP-4) inhibitors can be added to metformin therapy.

Despite, being the mainstay therapy for diabetes for decades, health professionals have now switched from Sulfonylureas to the aforementioned new anti-hyperglycemics. This is because combination therapy with SU and metformin reduces HbA1c levels by only 1% as compared to monotherapy with either of the agent and recent studies have suggested that after 6 months of combination therapy with SU and metformin, the glycemic levels actually worsen.

Among DPP-4 inhibitors, saxagliptin and sitagliptin have been found to reduce HbA1c levels in the range of 0.8-1.0 % when added to metformin.

Among GLP-1 agonists, liraglutide had been found to lower the HbA1c levels by 0.3% when added to metformin therapy. As regards to thiazolidinediones (pioglitazone and rosiglitazone), these were added as a third agent to metformin and SU combination therapy- a sort of  trio-therapy, and all were found to possess equal proficiency in  lowering the HbA1c levels by 1.0%.

6.Is Metformin Effective Against Breast Cancer?

Metformin can doubtless be regarded as a magic bullet for diabetes management and is still being investigated by the researchers for its potential benefits in other ailments.

Latest medical news regarding metformin proclaims that metformin may have a beneficial role in breast cancer, although timing is very important in such patients as regards the initiation of metformin.

According to the research conducted by the University of Pennsylvania School of Medicine, use of metformin in breast cancer patients had received skepticism and remained controversial for a long time but recent research findings report that metformin use after the diagnosis of breast cancer has resulted in 50% more survival rate as compared to the patients who did not take metformin following diagnosis of breast cancer.

However, patients who were already taking metformin before being diagnosed for breast cancer were twice more likely to die as compared to non-users or their cancer became more aggressive in nature.

Therefore, metformin role still needs to be further investigated and affirmed regarding its use in oncologic malignancies.

7.Is Metformin An Anti-Aging Drug?

Glumetza (metformin) is also being evaluated for its anti-aging properties.

Research has shown that metformin delays the aging process by reducing the oxidative stress, inflammation, and apoptosis – the programmed cell death and other biological processes that aid the aging process.

Metformin is believed to somehow intervene the normal course of aging. Since, aging is considered as a risk factor for multiple diseases that come with age such as Alzheimer’s, heart disease and cancer, researchers are hopeful that metformin might be favorable in delaying the aging process though it might not be an absolute anti-aging agent.

Dr. Nir Barzilai, MD, director of the Institute for Aging Research at Albert Einstein College of Medicine, the Bronx and his team has already conducted a study – the MILES study, on metformin to analyze its effect on longevity in which he administered 1700 mg of metformin daily to the participants.

The team is assessing the effect of metformin on genetic expression of aging in elderly with impaired glucose tolerance and Dr.Nir Barzilai has planned to study the impact of metformin as a peculiar anti-aging agent to evaluate whether metformin can increase the “health span” of an individual.

Despite researches being carried out on metformin for exploring its potential perks in multiple diseased conditions, metformin has benefitted its patient population over a span of 60 years, being steadfast in this manner and continues to hold a leading edge on novice formulations.

Co Author: Dr Affaf Salman