Metformin

Metformin's potential to aid in weight loss is thought to come from several mechanisms related to its effects on metabolism, insulin sensitivity, and appetite regulation:

Improved Insulin Sensitivity: Metformin works by increasing insulin sensitivity, meaning your body becomes more efficient at using insulin to control blood sugar. In people with insulin resistance (often seen in obesity and type 2 diabetes), this can help reduce fat storage and potentially lead to weight loss. Improved insulin sensitivity can make it easier for the body to access stored fat and use it for energy.

Reduction in Appetite: Some studies suggest that metformin may help reduce appetite. It’s thought that metformin may alter the way the body processes glucose and hormones like ghrelin (the "hunger hormone"), leading to reduced hunger and, in turn, fewer calories consumed. However, the appetite-suppressing effects are generally modest and not seen in all individuals.

Effect on Gut Microbiome: There is some emerging evidence that metformin may alter the gut microbiome, which could influence metabolism and weight. Some research suggests that the drug might promote the growth of beneficial gut bacteria that help with energy metabolism and fat regulation. However, the exact relationship between metformin and the microbiome is still being explored.

Lowering Liver Glucose Production: Metformin decreases hepatic glucose production (the liver's release of glucose into the bloodstream), which can help lower blood sugar levels. This can prevent excessive insulin spikes that would otherwise lead to fat storage, especially in abdominal fat.

Effect on Fat Stores: Some studies suggest that metformin may help reduce visceral fat (fat around internal organs), which is particularly harmful and associated with higher risks of cardiovascular disease and diabetes.

Metformin’s possible anti-aging effects are thought to stem from its ability to modulate several biological processes related to aging, including:

• AMPK Activation: Metformin activates AMP-activated protein kinase (AMPK), which is often described as a "cellular energy sensor." When energy levels are low, AMPK gets activated and promotes metabolic processes that increase energy production and improve cellular function. This activation has been linked to improved mitochondrial function and a decrease in age-related cellular damage.
• Reduction of Insulin Resistance and Inflammation: As we age, insulin resistance and low-grade inflammation (often called "inflammaging") can contribute to various age-related diseases like cardiovascular disease, Alzheimer's, and diabetes. Metformin helps improve insulin sensitivity and can reduce systemic inflammation, which might, in turn, reduce the risk of these age-related conditions.
• Inhibition of mTOR Pathway: Metformin has been shown to inhibit them TOR (mechanistic target of rapamycin)pathway, which plays a key role in regulating cell growth, protein synthesis, and aging. Overactivation of the mTOR pathway is associated with accelerated aging and age-related diseases. By inhibiting mTOR, metformin may help delay some of the biological processes of aging.
• Autophagy: Autophagy is the process by which cells clean out damaged components, which is crucial for maintaining cellular health. Metformin has been shown to induce autophagy, a mechanism that may protect cells from the accumulation of damaged proteins and organelles, which is thought to contribute to aging and age-related diseases.

The weight loss effects of metformin vary, but research generally suggests that most people experience modest weight loss over time. Some of the key studies have reported:

• 3 to 5 kg (6.6 to 11 pounds) over 6 to 12 months.
• 5-10% reduction in body weight for some individuals, particularly in those with insulin resistance or type 2 diabetes.

Metformin is generally well-tolerated, but it can have side effects, particularly when starting treatment. Common side effects include:

• Gastrointestinal issues: Nausea, diarrhea, and stomach upset are common, especially at the beginning of treatment. These side effects often subside over time.
• Lactic acidosis (rare): This is a very rare but serious side effect, especially in people with kidney issues. Metformin is typically avoided in people with kidney disease.
• Vitamin B12 deficiency: Long-term use of metformin has been associated with lower levels of vitamin B12 in some people, which could require supplementation.

Lactic Acidosis (Rare but Serious)

• What it is: Lactic acidosis is a rare but serious condition where lactic acid builds up in the bloodstream. It can be life-threatening and requires immediate medical attention.
• Risk factors: People with certain conditions are at higher risk for lactic acidosis, including:

1. Kidney problems (especially reduced kidney function)
2. Liver disease
3. Severe dehydration
4. Excessive alcohol consumption
5. Heart failure or other conditions that can reduce blood flow to organs

• Symptoms: The symptoms of lactic acidosis include:

1. Unusual tiredness or weakness
2. Muscle pain or cramping
3. Difficulty breathing
4. Abdominal discomfort, nausea, or vomiting
5. Slow or irregular heartbeat
6. Cold or blue skin

• What to do: If you experience any of these symptoms, seek medical help immediately.

Kidney Function

• Monitoring kidney function: Metformin is primarily excreted through the kidneys, so individuals with kidney disease (particularly moderate to severe impairment) are at a higher risk of experiencing metformin-related complications, including lactic acidosis.

1. Before starting treatment: Kidney function should be evaluated through blood tests (e.g., serum creatinine, eGFR) to ensure the kidneys are functioning properly.
2. During treatment: Kidney function should be monitored regularly, especially if you have risk factors such as advanced age, dehydration, or other medications that may affect kidney health.
3. When not to use metformin: Metformin is typically avoided or discontinued if kidney function is significantly impaired (e.g., eGFR < 30 mL/min/1.73m²).

Use in People with Liver Disease

• Risk of lactic acidosis: People with liver disease may be at an increased risk of lactic acidosis, especially if the liver's ability to process and clear lactic acid is impaired.
• Precaution: If you have liver disease, your healthcare provider may adjust the dosage or avoid prescribing metformin altogether.

Alcohol Use

• Impact on lactic acidosis risk: Excessive alcohol consumption increases the risk of lactic acidosis, particularly when combined with metformin.
• Advice: Limit alcohol intake, especially in large quantities. If you consume alcohol regularly or binge drink, speak with your doctor about the safety of metformin for you.

Gastrointestinal Side Effects

• Common side effects: The most common side effects of metformin are gastrointestinal (GI) in nature:

1. Nausea
2. Diarrhea
3. Stomach upset
4. Bloating and gas

• Managing GI issues:

1. Start with a low dose and gradually increase to reduce the likelihood of GI side effects.
2. Taking metformin with food may help reduce nausea and stomach upset.
3. If side effects persist or become bothersome, speak with your doctor about adjusting the dose or considering an extended-release formulation of metformin, which may be gentler on the stomach.

Vitamin B12 Deficiency

• Long-term use: Prolonged use of metformin (over several years) has been associated with a decrease in vitamin B12 levels, potentially leading to deficiency.

1. Symptoms of deficiency: Fatigue, weakness, numbness or tingling in the hands and feet, difficulty walking, and memory problems.
2. Monitoring: If you take metformin for a long time, your doctor may monitor your vitamin B12 levels periodically and recommend supplements if necessary.

Hypoglycemia (Low Blood Sugar)

• Risk of hypoglycemia: Metformin alone does not typically cause low blood sugar (hypoglycemia), but when combined with other medications (e.g., insulin or sulfonylureas), the risk increases.

1. Symptoms of hypoglycemia: Sweating, shakiness, dizziness, confusion, headache, and weakness.
2. What to do: If you experience symptoms of hypoglycemia, consume a quick source of glucose (e.g., a glucose tablet, juice, or candy) and monitor your blood sugar. Contact your healthcare provider for further guidance if necessary.

Discontinuation before Surgery or Contrast Imaging

• Before surgery or medical procedures: Metformin may need to be temporarily discontinued before certain surgeries or imaging procedures, particularly those involving contrast agents (e.g., CT scans with iodinated contrast).

1. Reason: Contrast agents can affect kidney function, which increases the risk of lactic acidosis when combined with metformin.
2. Timing: Typically, metformin is stopped 48 hours before the procedure and resumed after kidney function is checked and found to be stable.

Pregnancy and Breastfeeding

• Pregnancy: Metformin is classified as a Category B medication for pregnancy, meaning it is generally considered safe but should only be used if clearly needed. If you are pregnant or planning to become pregnant, talk to your doctor about alternative treatments.

1. Gestational diabetes: Metformin is sometimes used in gestational diabetes when lifestyle changes alone are insufficient, but insulin is typically the first-line treatment during pregnancy.

• Breastfeeding: Metformin passes into breast milk in small amounts. The American Academy of Pediatrics considers it generally safe for breastfeeding, but you should consult with your healthcare provider to make an informed decision.

Interactions with Other Medications

Metformin can interact with various medications, potentially affecting its effectiveness or increasing the risk of side effects:

• Diuretics (water pills): May increase the risk of dehydration and kidney issues.
• Corticosteroids: May raise blood sugar levels, potentially affecting the effectiveness of metformin.
• Certain blood pressure medications (ACE inhibitors, ARBs): May affect kidney function when combined with metformin.
• Other diabetes medications: Careful monitoring is needed if you are taking other medications that affect blood sugar levels.