What is Type 2 Diabetes Mellitus and What Causes It?
Type 2 diabetes mellitus is a common endocrine disorder that affects approximately 35,000,000 people in the United States.
This disease commonly affects adults over the age of 45.
However, we are increasingly seeing children, teenagers, and younger adults developing Type 2 Diabetes.
Glucose is a source of energy that all plants and animals need.
Without it, all the biological processes necessary for sustaining life cease to exist.
The glucose needs to be shuttled inside the body’s cells for energy to be generated.
The hormone responsible for moving the glucose molecule into the cell is insulin, produced by the beta cells in your pancreas.
In people with Type 2 Diabetes, the cells’ sensitivity to insulin decreases, resulting in insulin resistance.
This resistance prevents the glucose from entering the cells, causing high glucose levels to remain in and circulate in the blood.
Uncontrolled and sustained blood glucose elevations result in a myriad of health complications, including kidney damage (end-stage-renal disease), increased risk of heart failure, cardiovascular (heart attack) and cerebrovascular (stroke) accidents, and nerve damage throughout the body, including the eyes (diabetic retinopathy).
What is metformin used for?
Labeled Indication: Treatment of type 2 diabetes in adults and older adults, in combination with lifestyle changes (exercise and healthy diet)
Metformin, approved by the FDA in 1994, is a type of diabetes medication taken by mouth.
It is the “gold standard” diabetes treatment, the preferred first-line glucose-lowering medication endorsed by the American Diabetes Association, the Endocrine Society, and other official healthcare organizations for Type 2 diabetes. Some refer to it as the “wonder drug” for preventing and treating the disease.
Metformin comes in both immediate-release and extended-release formulations.
It is available as a standalone prescription medication or in combination with other antidiabetic drugs empagliflozin and metformin, brand name Synjardy, and several others).
Metformin has decades of research and clinical evidence supporting its beneficial effects and ability to lower blood sugar levels in individuals with Type 2 Diabetes.
The ground-breaking landmark clinical trial, the UK Prospective Diabetes Study (UKPDS), showed overwhelming evidence of the long-term cardiovascular benefits of metformin.
Off-Label Indications:
- Prevention of type 2 diabetes: Metformin has been shown to reduce the incidence of diabetes in people without diabetes but at high risk for developing the disease.
- Antipsychotic-associated weight gain: When behavioral interventions have failed, metformin can be used to promote modest weight loss and prevent weight gain induced by the use of second-generation antipsychotics, such as quetiapine (Seroquel), clozapine (Clozaril), olanzapine (Zyprexa), etc.
- Treatment of Gestational Diabetes: Short-term data suggests that metformin may be used to treat gestational diabetes. Long-term data is unavailable.
- Treatment of oligomenorrhea (infrequent menstrual periods) due to polycystic ovary syndrome (PCOS): Data suggests that metformin may improve menstrual patterns in patients with PCOS. However, it should be noted that metformin is not as effective as combination oral contraceptives in regulating the ovulation rate.
- Prevention of ovarian hyperstimulation syndrome in PCOS: Metformin significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS who are receiving gonadotropin during in vitro fertilization or intracytoplasmic sperm injection.
How does metformin work?
Metformin works in several different ways to reduce blood glucose:
- Inhibits hepatic gluconeogenesis: Decreases the amount of glucose production by the liver by inhibiting the enzyme that is responsible for releasing sugar into the bloodstream
- Inhibits glycogenolysis: Reduces the conversion of glycogen (a form of stored glucose in the muscles) into glucose
- Improves insulin sensitivity: Metformin enhances insulin-stimulated glucose uptake into skeletal muscles
Metformin also helps control blood sugar levels after meals by decreasing intestinal glucose absorption.
Pharmacokinetics of Metformin (How the drug moves within the body)
- Onset of Action (how quickly it starts working): Within days, maximum effects can take up to 2 weeks
- Metabolism: Not broken down by the liver, so there are no interactions with other drugs in the liver
- Bioavailability (amount of drug that enters the circulation to exert therapeutic effect): Absolute (with food); 50% to 60% (fasting)
- Half-life elimination (time taken for the concentration of drug to reduce by half in the body): Plasma (yellow liquid portion of blood): 4-9 hrs; Blood: ~17.6 hrs
- Time to peak: Immediate release: 2-3 hrs; Extended-release tabs: About 7 hrs
- Excretion: Primarily via urine (90%) – Drug concentration remains elevated in people with impaired kidney function, leading to adverse effects, which is why it needs to be dosed according to renal function
What does A1c mean?
Hemoglobin A1c, or HbA1c, is a simple blood test your healthcare provider will order to determine your blood sugar control.
The test measures your average blood glucose levels over the past three months.
When glucose builds up in your blood, it binds to the hemoglobin in your red blood cells.
The A1c test measures the amount of sugar bound to your red blood cells.
Since the average life span of red blood cells is approximately three months, this test gives a pretty good estimate of your overall glucose control.
If you have been keeping track of your daily blood glucose levels and would like to know your estimated A1c level, there is a quick mathematical equation you can use to figure it out yourself.
It is called the ADAG formula, derived from the A1C-derived average glucose Study Group Report published in 2008.
The formula is this: [28.7 x your A1c] – 46.7 = estimated average blood glucose.
So, let’s say your average daily blood glucose is around 250. The equation will look like this:
[28.7 x A1c] – 46.7 = 250.We want to know what your A1c is, so we are going to say that it is “x,” and we are going to solve the equation as follows:
28.7x -46.7 = 250
28.7x = 250 + 46.7 (bringing the -46.7 over the equal sign turns it positive)
28.7x = 296.7
Solving for x, we bring the 28.7 over to the other side of the equation (the multiplication becomes a division): x = 296.7 divided by 28.7, which yields an approximate answer of about 10.34 (your estimated A1c).
This calculation is surprisingly quite accurate. I use it all the time in my clinical practice to determine my patients’ average blood sugar levels from their A1c levels in their medical charts.
If this calculation is too cumbersome for you, then no worries! You can simply enter your numbers in the online calculator on this website, which will calculate your A1c or estimated average blood glucose levels!
Based on the results of their study, the authors of the ADAG report were able to create a table of corresponding A1c and estimated average glucose levels. I have provided the table below:
Estimated Average Glucose (eAG) Compared to Measured Hemoglobin A1c Levels
| A1c | estimated Average Glucose (eAG) | |
|---|---|---|
| % | mg/dL (US) | mmol/L (Europe, other countries) |
| 6 | 126 | 7.0 |
| 6.5 | 140 | 7.8 |
| 7 | 154 | 8.6 |
| 7.5 | 169 | 9.4 |
| 8 | 183 | 10.1 |
| 8.5 | 197 | 10.9 |
| 9 | 212 | 11.8 |
| 9.5 | 226 | 12.6 |
| 10 | 240 | 13.4 |
The great thing about this table is that the values are very close to the numbers you would get if you used the ADAG formula to calculate them.
Drug Administration: How is metformin dosed?
Metformin is dosed from 500 mg to 2000 mg daily, usually with meals. Common dosage tablets include 500 mg, 850 mg, and 1000mg.
The most common side effects that people experience when starting metformin are GI issues, specifically nausea and diarrhea.
To minimize or avoid these stomach issues, I tell my patients to start their medication regimen as follows (for people who do not have kidney issues):
- Week 1: 500 mg low dose with dinner or at bedtime with a few crackers
- Week 2: If my patient tolerates it well, they can increase the dose to 500 mg twice daily with meals
- Week 3: If tolerated, maintain the morning dose at 500 mg, increase the evening dose to 1000 mg
- Week 4: If they still tolerate it well, increase to the final therapeutic dose of 1000 mg twice daily with meals. This dose yields the best A1c reduction, as metformin’s pharmacological effect is dose-dependent. In other words, the higher the dose, the lower the A1c is.
How much does metformin lower A1c?
People can expect an A1c reduction between 1-1.5% at maximum dose- a remarkably beneficial effect!
By itself, metformin does not cause hypoglycemia or low blood sugar (blood glucose level less than 70 mg/dL).
However, people must exercise caution when they are combining this medication with other diabetes drugs or insulin.
The combined effect of metformin and these medications can increase the risk of hypoglycemia if dosed inappropriately or if glucose levels are not being monitored as instructed by their physicians.
Hypoglycemia (Low Blood Sugar) in Older Adults
In younger people, symptoms of hypoglycemia are:
- Pale-looking skin (especially the face)
- Shakiness
- Sweating
- Fast heart rate
- Tiredness
- Anxiety or Irritability
- Headache
- Nausea
- Hunger
However, the identification of hypoglycemia in older adults is more challenging.
This is because the elderly show atypical symptoms that can be misdiagnosed, or the hypoglycemic episode is missed completely.
This can be especially dangerous to our elderly loved ones. I drill this statement into my medical and pharmacy students’ brains:
“It takes only ONE hypoglycemic event to kill an older adult.”
So, how do older people present with hypoglycemia?
The usual autonomic responses such as increased heart rate, sweating, and shakiness may not be present.
It is not uncommon to see many older patients sitting in their bed comfortably watching television, and the glucometer returns a value of 25 or 30 when a glucose check is done!
This number is almost not conducive to life, and if the hypoglycemia is not reversed immediately, the older adult can fall into a coma and not awaken.
Now, imagine that this person is a widow, lives by herself, and is only checked on occasionally by relatives or friends. You can imagine the horrible result that can happen.
Older adults with hypoglycemia will also present with confusion, appear delirious, or become agitated. These symptoms can easily be misdiagnosed as those of dementia, and the underlying hypoglycemia remains uncorrected.
Additionally, individuals with dementia may be unable to communicate their symptoms to their loved ones or caregivers.
If you suspect that your loved one is suffering from hypoglycemia and they are unresponsive, seek IMMEDIATE medical help. Your quick thinking and response could save the life of your loved one.
Metformin dosing adjustments for kidney function
Metformin must be dosed according to your kidney function.
Before starting you on metformin, your doctor will order a simple blood test to determine how well your kidneys are working.
From the blood test, your age, body, type, race, and gender, your estimated Glomerular Filtration Rate (eGFR), the conventional clinical metric used to determine kidney function, is determined.
The table below lists all dosing recommendations based on kidney function:
Metformin Dosing Based on Kidney Function
| Kidney Function (eGFR) | Dosing | Monitoring |
|---|---|---|
| ≥60 (mild kidney disease to normal) | No dosage adjustment needed | Monitor kidney function at least annually |
| >45 to <60 (Stage 3A moderate kidney disease) | No dosage adjustment needed | Increase monitoring of kidney function (every 3 to 6 months) |
| 30 to 45 (Stage 3B moderate kidney disease) | Initiation of therapy: Use generally not recommended; but can start with 500 mg with dinner, increase to 500 mg twice daily as tolerated Continuation of existing therapy: May continue at a reduced dose up to a maximum of 500 mg twice daily | Close monitoring of kidney function - Discuss with Doctor about frequency of testing |
| <30 (Severe to end-stage kidney disease) | Use is contraindicated | N/A |
What are common side effects of metformin?
The manufacturer’s product labeling lists the following side effects of metformin:
- Diarrhea (53% with the immediate-release metformin tablets; 10% with extended-release formulation)
- Nausea and Vomiting (Immediate-release – 26%; Extended-release – 7%)
- Constipation
- Abdominal distension (bloating)
- Abdominal pain
- Flatulence (Gas)
- Indigestion or upset stomach (dyspepsia)
- Unpleasant metallic taste in the mouth
- Heartburn
- Headache
- Skin flushing
- Muscle pain (myalgia)
What are some serious side effects of taking metformin?
US Boxed Warning
There have been a few reports of an increased risk of lactic acidosis associated with metformin use.
Usually, this is due to the patient’s declining health, existing kidney disease, liver disease, co-existing chronic and acute medical problems, and overall compromise in functional ability.
When you get a buildup of lactic acid in your body, you may experience very subtle changes to your health. Signs of lactic acidosis are not typical, meaning you may miss recognizing them.
Some symptoms of lactic acidosis are fatigue or malaise, muscle pains, respiratory distress (difficulty breathing, shortness of breath), sleepiness, and stomach pain.
Metformin has also been associated with vitamin B12 deficiency. This is because long-term use of metformin interferes with the gut’s ability to absorb dietary vitamin B12.
However, this problem is easily prevented and managed by regularly monitoring your Vitamin b12 levels and appropriate supplementation if your b12 drops to an unsafe level.
Is metformin safe for the elderly?
When dosed appropriately and monitored, metformin is very safe for use in older adults.
The benefits of taking this medication far outweigh any modest risks associated with its use.
Refer to the kidney function-associated dosing table above for guidance on appropriate dosing for your elderly loved one.
Intensive blood glucose control is encouraged in younger patients to prevent long-term cardiovascular, cerebrovascular, and nerve damage.
However, all evidence suggests that tight glucose control can increase the risk of death, hypoglycemic events with severe consequences, and weight gain in older adults.
The American Geriatrics Society and the American Diabetes Association recommend the following goals for blood glucose control in older adults. Blood pressure and cholesterol goals are also included in this table:
Treatment Goals for Blood Glucose, Blood Pressure, and Dyslipidemia In Older Adults with Diabetes
| Patient characteristics/ health status | Rationale | Reasonable A1C goal | Fasting or pre-meal glucose | Bedtime glucose | Blood pressure | Lipids |
|---|---|---|---|---|---|---|
| Healthy (few coexisting chronic illnesses, intact cognitive and functional status) | Longer remaining life expectancy | <7.0–7.5% (53–58 mmol/mol) | 80–130 mg/dL (4.4–7.2 mmol/L) | 80–180 mg/dL (4.4–10.0 mmol/L) | <140/90 mmHg | Statin unless contraindicated or not tolerated |
| Complex/ intermediate (multiple coexisting chronic illnesses or 2+ instrumental ADL impairments or mild-to-moderate cognitive impairment) | Intermediate remaining life expectancy, high treatment burden, hypoglycemia vulnerability, fall risk | <8.0% (64 mmol/mol) | 90–150 mg/dL (5.0–8.3 mmol/L) | 100–180 mg/dL (5.6–10.0 mmol/L) | <140/90 mmHg | Statin unless contraindicated or not tolerated |
| Very complex/poor health (LTC or endstage chronic illnesses or moderate-to-severe cognitive impairment or 2+ ADL impairments) | Limited remaining life expectancy makes benefit uncertain | Avoid reliance on A1C; glucose control decisions should be based on avoiding hypoglycemia and symptomatic hyperglycemia | 100–180 mg/dL (5.6–10.0 mmol/L) | 110–200 mg/dL (6.1–11.1 mmol/L) | <150/90 mmHg | Consider likelihood of benefit with statin |
Source: American Diabetes Association Professional Practice Committee. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan 1;45(Suppl 1):S17-S38. doi: 10.2337/dc22-S002. PMID: 34964875.
The table mentions Activities of Daily Living (ADLs) and Instrumental Activities of Daily Living (IADLs). You can read more about them here.
Does metformin cause weight loss?
The relationship between metformin use and weight loss (or the prevention of weight gain from one’s current weight) is unclear and inconclusive.
Several theoretical explanations and clinical trials claim that there is an association, but these claims about metformin as a weight loss drug are called into question upon further scrutiny.
In an often cited Diabetes Prevention Program study, investigators concluded that there was a statistically significant weight loss trend noted in individuals who were taking metformin.
The study authors go on to claim that the weight loss is sustained for ten years.
Let’s look at the specifics of the study:
Over 3,000 participants were enrolled in this study between 1996 and 1999 from 27 clinics in the United States.
About half of them were assigned to metformin treatment (intervention group), while the other half (control group) took a placebo pill. The average age of the participants was 25, and the average body mass index (BMI) was greater than or equal to 24kg/m2. (Normal weight: BMI is 18.5 to 24.9)
All study participants were provided standard lifestyle recommendations and written information on healthy eating, reduced food intake, healthy weight, and physical activity annually.
As I carefully dissected the results and the conclusions of this study, I determined that there were no significant changes and the average weight loss only amounted to a little under 5 pounds for the participants and some minor reduction in waist circumference.
In my opinion, this is a modest body weight loss and does not account for the fact that the metformin group and the placebo group also engaged in healthy eating, exercise, and lifestyle choices.
The weight change seen could be due to these other factors and not solely due to metformin use.
Other studies I reviewed did not yield a clear, conclusive relationship between metformin and practically relevant weight loss.
Here’s the bottom line and my conclusion as a clinician: Metformin is an AMAZING drug for managing Type 2 Diabetes Mellitus. BUT, it is not a reliable option as a weight-reducing agent.
Summary
- Metformin has decades of clinical and real-world evidence supporting its ability to decrease the risk of cardiovascular disease, kidney problems, and cerebrovascular disease in people with Type 2 Diabetes
- Metformin can be safely used in older adults with Type 2 Diabetes with appropriate monitoring and renal dosing
- Metformin can be used in combination with other antidiabetes medications, but monitoring for hypoglycemia must be part of the care plan
- There is inconclusive evidence that metformin is associated with weight loss
