METFORMIN vs INSULIN — COMPLETE ZERO-OMISSION MASTER TABLE

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• Metformin = insulin sensitizer, oral, low hypoglycemia, crosses placenta, acceptable in GDM.
• Insulin = anabolic hormone, injectable, high hypoglycemia risk, does NOT cross placenta, drug of choice in pregnancy.

METFORMIN

Drug class

• Biguanide oral antihyperglycemic

Mechanisms of Action

Main effects occur without increasing insulin secretion (so low risk of hypoglycemia):

1. ↓ Hepatic gluconeogenesis

– suppresses liver glucose production

2. ↑ Peripheral insulin sensitivity

– especially in skeletal muscle

3. ↓ Intestinal glucose absorption
4. Activates AMPK (AMP-activated protein kinase)

– key metabolic sensor → switches off anabolic pathways, promotes glucose uptake

Clinical Uses

• First-line for type 2 diabetes
• Insulin-resistant states
• Metabolic syndrome
• Polycystic ovary syndrome (PCOS) → improves ovulation

In pregnancy

• Used for:
• GDM when target sugars not achieved with lifestyle
• PCOS pre-conception or early pregnancy in some cases (controversial)

Benefits

• No weight gain (often slight weight loss)
• Very low hypoglycemia risk
• Improves lipid profile (↓ TG, ↓ LDL)

Major Adverse Effects

• GI upset

diarrhea, nausea, abdominal discomfort (most common)

• Lactic acidosis (rare, life-threatening)

risk increased with:

1. renal failure
2. severe liver disease
3. severe infection
4. hypoxia
5. alcohol intake
• Vitamin B12 deficiency

long-term → neuropathy

Contraindications

• eGFR < 30 mL/min
• severe hepatic dysfunction
• shock/acute hypoxia (risk of lactic acidosis)
• alcoholism
• unstable HF

Monitoring

• Baseline + annual renal function
• B12 levels if long-term neuropathy symptoms

Dose Principles

• Start low to reduce GI effects

example: 500 mg daily with food

• Titration is slow

up to 1.5–2 g/day depending on tolerance

INSULIN

What is insulin?

Hormone produced by pancreatic beta cells in islets of Langerhans

Physiologic Action

Insulin binds to tyrosine kinase receptors,cell membrane receptor, activating intracellular signaling(ip3):

Major metabolic effects:

1. Promotes glucose uptake

via GLUT-4 in skeletal muscle + adipose tissue

2. Stimulates glycogenesis

liver + muscles store glycogen

3. Inhibits gluconeogenesis and glycogenolysis
4. Promotes lipogenesis

and inhibits lipolysis

5. Increases protein synthesis

So insulin is anabolic.

Insulin Preparations

Based on onset and duration:

• Rapid-acting

lispro, aspart, glulisine

peak 1–2 h

• Short-acting

regular insulin

peak 2–4 h

• Intermediate-acting

NPH

• Long-acting

glargine, detemir

relatively peakless

• Ultra-long-acting

degludec

Clinical Uses

• Type 1 diabetes (required)
• Type 2 diabetes when oral drugs fail
• Gestational diabetes mellitus (GDM)
• Hyperkalemia (drives K+ into cells with glucose)
• DKA treatment

Adverse Effects

• Hypoglycemia (most important)

sweating, palpitations, confusion, coma

• Weight gain
• Lipodystrophy at injection site

lipoatrophy or lipohypertrophy

• Rare allergy

Contraindications

• Absolute: none
• Relative cautions: hypoglycemia unawareness

Monitoring

• CBG/glucose logs
• HbA1c 3–6 monthly
• Injection technique + site rotation

Metformin vs Insulin – Key Differences

Pregnancy / Gynecology relevance

Gestational Diabetes

• First-line therapy: diet + exercise
• If not controlled:
• Insulin = preferred
• Metformin = acceptable alternative, safe in most cases

PCOS

• Metformin helps:
• ↓ insulin resistance
• ↑ ovulation
• ↓ risk of miscarriage in some cases

Fetal considerations

• Insulin does not cross placenta
• Metformin crosses placenta but evidence suggests safety

Clinical exam pearls

• Metformin = first-line oral for T2DM because no hypoglycemia + improves mortality.
• Stop metformin temporarily before contrast studies if renal impairment risk.
• Hypoglycemia from insulin is worsened by renal failure, exercise, missed meals, alcohol.
• Rotating insulin injection sites prevents lipodystrophy.
• Metformin improves PCOS infertility via ↓ insulin resistance.

Metformin in Pregnancy

Placental transfer

• Crosses placenta freely → fetal serum levels similar to maternal.

Is it safe?

• Large studies show no increase in congenital malformations.
• Accepted in most guidelines for:
• Gestational diabetes (GDM)
• Type 2 diabetes in pregnancy
• PCOS-related infertility / early pregnancy continuation (still debated)

Why use it?

• Can avoid insulin injections
• Less maternal hypoglycemia than insulin
• Less maternal weight gain
• Useful if mother overweight/obese with insulin resistance

When to avoid or use cautiously

• Renal impairment (eGFR <30)
• Conditions with risk of hypoxia / sepsis → lactic acidosis risk

Dosing in pregnancy

• Start low: 500 mg OD or BD with meals
• Increase gradually up to 2–2.5 g/day divided doses
• Continue dietary and exercise counseling

Side effects during pregnancy

• Mostly maternal GI upset
• Rare lactic acidosis
• Possible risk of SGA babies in some studies (not conclusive)

Breastfeeding

• Very small levels in breastmilk
• Considered safe for breastfeeding mothers

PCOS pregnancy relevance

• Used pre-pregnancy to induce ovulation
• Some continue through first trimester to reduce miscarriage risk (still controversial)
• Improves insulin resistance → ↓ GDM risk later

Insulin in Pregnancy

Placental transfer

• Does not cross placenta → no direct fetal exposure.
• This is why it’s preferred therapy when medications required.

When used

• First-line pharmacologic agent for:
• Gestational diabetes uncontrolled with lifestyle therapy
• Pregestational type 1 diabetes
• Pregestational type 2 diabetes if oral meds inadequate/discontinued
• DKA treatment during pregnancy

Target glycemic control in pregnancy (critical exams)

Common targets (institution-specific):

• fasting glucose <95 mg/dL (5.3 mmol/L)
• 1-hr postprandial <140 mg/dL (7.8)
• 2-hr postprandial <120 mg/dL (6.7)

Insulin regimen considerations in pregnancy

• Basal–bolus commonly used
• Higher doses needed as pregnancy progresses due to insulin resistance from placental hormones:
• HPL, progesterone, cortisol, growth hormone
• Dose increases mostly in:
• 2nd trimester
• 3rd trimester dramatically ↑ until delivery

DKA risk higher in pregnancy

• Can occur at lower glucose level
• Fetal mortality high → urgent management

Breastfeeding

• Safe, no secretion risk
• Hypoglycemia risk for mother if calorie intake low while feeding

Maternal + Fetal Risks Without Treatment

Poorly controlled diabetes → complications

• Maternal
• Preeclampsia
• Polyhydramnios
• Infections
• Operative delivery
• Fetal
• Macrosomia → shoulder dystocia
• Stillbirth
• Congenital anomalies (pregestational diabetes)
• Neonatal hypoglycemia
• Respiratory distress syndrome

Metformin vs Insulin in Pregnancy — Summary Table

OB/GYN Exam High-Yield Points

• Insulin is preferred for GDM because it does not cross placenta.
• Metformin is acceptable when women refuse or cannot take insulin.
• Type 1 diabetics must remain on insulin throughout pregnancy.
• Metformin is continued in PCOS until early pregnancy in some practices but evidence mixed.
• If glycemic control fails on metformin → add insulin.
• Insulin resistance rises during pregnancy due to HPL.