ENDO 9+10: Type 2 Diabetes Pharmacology

Understanding Type 2 Diabetes (T2D)

T2D is a chronic and complex disease that happens because of two major problems:

1. Insulin resistance – The body’s cells (especially in muscles, fat, and the liver) don’t respond properly to insulin. This means glucose (sugar) doesn’t enter the cells efficiently, leading to high blood sugar.

2. Beta-cell dysfunction – The pancreas, which produces insulin, gets worse at making insulin over time. When blood sugar rises, beta-cells are supposed to release insulin, but in T2D, they don’t work as well.

Because of these two problems, blood sugar stays high, leading to chronic hyperglycemia (persistently high blood glucose). That’s why treatment focuses on improving insulin sensitivity and supporting insulin production.

What Causes Insulin Resistance and Beta-Cell Dysfunction?

Both genetics (inherited factors) and environmental factors (diet, activity levels) play a role. Some key contributors include:

• Obesity – A major risk factor, especially with a sedentary lifestyle and a high-fat diet.

• Western lifestyle – Not enough physical activity and eating too many processed or high-calorie foods.

• Cellular insulin signaling issues – Normally, insulin binds to receptors on cells to trigger glucose uptake. But in insulin resistance, there’s a problem with how the signal gets passed inside the cell. This leads to:

  • Less glucose entering muscle and fat cells

  • Increased glucose production by the liver (making the problem worse)

Since insulin resistance + beta-cell dysfunction work together to raise blood sugar, treatments target both issues.

How is Type 2 Diabetes Treated?

The goal is to lower blood sugar and prevent complications using:

1. Lifestyle changes (first-line treatment)

2. Medications (when lifestyle alone isn’t enough)

Lifestyle Modifications (Healthy Behaviors)

These include sleep, weight loss, diet, and exercise.

1⃣ Sleep

• Poor sleep (too little <6 hours or too much >8 hours) worsens blood sugar control and increases A1C.

• Consistent, uninterrupted sleep is best.

2⃣ Weight Loss

• Losing 5–10% of body weight improves metabolism and insulin sensitivity.

• Losing 10–15% or more can even send diabetes into remission (meaning blood sugar normalizes without meds).

3⃣ Nutrition

• Reduce calorie intake to promote weight loss.

• Low Glycemic Index (GI) foods – These release glucose more slowly, preventing spikes in blood sugar.

• Best diets for diabetes:

  • Mediterranean diet – Whole grains, fruits, veggies, seafood, beans, and nuts.

  • Low-carb diet – Limits blood sugar spikes.

4⃣ Exercise

• Minimize sitting – Take breaks every 30 minutes.

• Aerobic exercise (e.g., walking, jogging, cycling)

  • At least 150 min/week of moderate-intensity exercise (30 min/day, 5 days a week).

  • Even 30 min/week improves metabolic health.

  • Best done after meals to maximize blood sugar control.

  • Increases insulin-independent glucose uptake (GLUT4 helps muscles absorb glucose even without insulin).

• Resistance training (2x per week) – Builds muscle, improving long-term blood sugar control.

💡 How Exercise Works at the Cellular Level

• At rest, glucose entry into muscles is low because GLUT1 transporters only allow a small amount in.

• During exercise:

  • The body first uses stored glycogen for energy.

  • As glycogen depletes, glucose uptake from the blood increases.

  • This process improves insulin sensitivity over time.

When to Start Medications?

• If A1C is ≥1.5% above target, start medication immediately.

• If lifestyle changes alone don’t work within 3 months, start medications.

• A1C targets should be individualized:

  • Younger, healthier patients → Lower A1C target.

  • Older patients with multiple health conditions → More relaxed A1C target to avoid hypoglycemia.

Medications for Type 2 Diabetes

💊 Oral Hypoglycemics (Pills to Lower Blood Sugar)

• Can be used alone or combined as the disease progresses.

• There are multiple drug classes, each targeting different parts of the disease (we’ll go deeper into these when you cover pharmacotherapy).

Final Takeaways

🔹 T2D is caused by both insulin resistance and beta-cell dysfunction.
🔹 Lifestyle changes are first-line treatment (diet, exercise, weight loss, and good sleep).
🔹 Exercise improves glucose uptake through insulin-independent mechanisms (GLUT4 activation).
🔹 Medications should be started if blood sugar remains high despite lifestyle efforts.
🔹 A1C targets must be individualized based on patient factors.

Biguanides (Metformin) – First-Line Glucose-Lowering Medication in T2D

Metformin is the first-line treatment for type 2 diabetes (T2D) unless contraindicated because it is:

• Effective → Lowers HbA1c by approximately 1-1.5%.

• Low cost → Affordable and widely available.

• Weight neutral → Does not cause weight gain (may even cause slight weight loss).

• No hypoglycemia → Does not excessively lower blood glucose (hence, called a euglycemic agent).

• Long-term safety record → Used for decades with well-established safety.

• Potential heart benefits → May reduce major adverse cardiovascular events (MACE).

• Neutral for heart failure (HF) and diabetic kidney disease (DKD) → Does not worsen these conditions.

Mechanism of Action (MOA)

The exact mechanism is not fully understood, but it primarily targets insulin resistance and acts mainly on the liver to reduce glucose production.

How does Metformin work?

1. Activates AMPK (AMP-activated protein kinase)

   • Metformin inhibits mitochondrial respiratory chain complex 1, reducing ATP (cellular energy).

   • Less ATP means more AMP, which activates AMPK.

   • AMPK inhibits gluconeogenesis (glucose production in the liver), reducing blood glucose levels.

2. Main effects:

   • Decreases hepatic glucose production (reduces gluconeogenesis, which is a major effect).

   • Decreases intestinal glucose absorption.

   • Increases glucose uptake in muscle and fat (by improving insulin receptor binding and increasing glucose transporter levels).

Key Notes on Insulin and Metformin

• Metformin does NOT act on pancreatic beta cells → It does not increase insulin secretion.

• Since it does not directly increase insulin, it does not cause hypoglycemia.

• It requires some insulin secretion to work effectively.

Metformin in Clinical Use

• Only available biguanide in Canada.

• Used alone or in combination therapy (e.g., with DPP-4 inhibitors, SGLT2 inhibitors).

• Dosing:

  • Initial: 500 mg BID (twice daily).

  • Usual: 1000 mg BID.

  • Max: 2000 mg per day.

• Time to Effect:

  • Lowers fasting blood glucose within 3-5 days.

  • Maximal effects in 1-2 weeks.

Side Effects of Metformin

Common (Mild) Side Effects

• Gastrointestinal (GI) issues (up to 20% of patients):

  • Diarrhea

  • Metallic taste

  • Nausea

  • Loss of appetite (anorexia)

  • Cramps

  • Often transient (disappear within 1-2 weeks)

  • Solution: Start low and increase dose slowly to improve tolerance.

  • Extended-release (Glumetza) has fewer GI side effects.

Serious but Rare Side Effect: Lactic Acidosis

• Life-threatening but very rare.

• Due to stalled gluconeogenesis, leading to lactic acid buildup.

• Symptoms:

  • Weakness

  • Abdominal pain

  • Hyperventilation (rapid breathing)

  • Altered mental status

2⃣ How Metformin Can Lead to Lactic Acidosis

• Normally, the liver converts lactate (a byproduct of metabolism) into glucose via gluconeogenesis.

• But metformin blocks gluconeogenesis, so lactate can build up instead of being converted into glucose.

• Too much lactate lowers blood pH, leading to lactic acidosis (a rare but serious side effect).

Metformin and the Kidneys

• Excreted unchanged by the kidneys → No metabolism.

• In renal impairment, metformin accumulates, increasing the risk of lactic acidosis.

• Dosage adjustments based on GFR:

  • GFR 30-60 mL/min → Use with caution.

  • GFR <30 mL/min → Contraindicated (do NOT use).

Metformin and Vitamin B12 Deficiency

• Interferes with calcium-dependent B12 absorption in the terminal ileum.

• Long-term use can cause B12 deficiency.

• Monitor B12 levels regularly.

• Solution: Increase calcium intake to prevent malabsorption.

Cardiovascular and Renal Considerations

• Neutral for heart failure (HF) and diabetic kidney disease (DKD).

• GLP-1 RAs & SGLT2 inhibitors (which improve cardiovascular and renal outcomes) work independently of metformin.

• Metformin should NOT delay the use of GLP-1 RAs or SGLT2 inhibitors in high-risk patients (e.g., those with established cardiovascular disease, heart failure, or CKD).

Key Takeaways

1. Metformin is the first-line drug for T2D due to high efficacy, low cost, and long-term safety.

2. Works mainly by decreasing hepatic glucose production (inhibits gluconeogenesis via AMPK activation).

3. Does NOT increase insulin secretion → No risk of hypoglycemia.

4. Weight neutral with possible slight weight loss.

5. Common GI side effects (diarrhea, nausea) but usually transient.

6. Serious but rare risk: Lactic acidosis (contraindicated in GFR <30 mL/min).

7. Can cause B12 deficiency → Monitor B12 levels, increase calcium intake if needed.

8. Should not delay the use of GLP-1 RAs or SGLT2 inhibitors in high-risk patients.

Second-Line Glucose-Lowering Medications: Incretins (GLP-1 Receptor Agonists & DPP-4 Inhibitors)

What are Incretins?

• Hormones released from the gut in response to eating, primarily glucagon-like peptide-1 (GLP-1)

  • GLP-1 directly stimulates insulin release !!!

GLP-1 directly stimulates insulin release—but only when blood glucose is high. It works by:

1. Binding to GLP-1 receptors on pancreatic β-cells.

2. Increasing cAMP levels inside β-cells.

3. Triggering more calcium influx, which stimulates insulin secretion.

**GLP IS SECRETED FROM THE L CELLS IN THE INTESTINE

• Decreases glucagon secretion

• "Incretin effect": Oral glucose causes more insulin release than IV glucose due to these hormones.

• The incretin effect is reduced in type 2 diabetes (T2D).

GLP-1 Receptor Agonists (GLP-1 RAs)

• Mimic natural GLP-1 to increase glucose-dependent insulin secretion.

• Other effects:

  • ↓ Appetite (hypothalamus).

  • ↓ Gastric emptying (slows digestion).

  • ↓ Liver glucose production.

  • Main effect: ↑ Insulin secretion (only when glucose is high) & ↓ Glucagon secretion.

    • Decrease glucagon secretion = decreases glycogen breakdown into glucose = PREVENTS GLUCOSE SECRETION FROM LIVER

  • Protects & promotes β-cell growth.

• MOA: Activates GLP-1 receptors (GPCR), increasing cAMP → ↑ Calcium → Insulin release.

1. GLP enters

2. TMAC

3. ATP activates cAMP

4. cAMP

5. Epac2 and PKA

6. Activates RYR / IP3R

7. Stimulates ER to release INTRACELLULAR CALCIUM

** The ATP that is activating cAMP comes from GLUCOSE (Glucose —> ATP —> K+ —> Depolarization —> Ca release)

This means that GLP is glucose DEPENDENT !

• Why they're safe: Work only when glucose is high → low hypoglycemia risk.

Clinical Benefits of GLP-1 RAs

✔ A1C reduction: 0.6-1.4% (high efficacy).
✔ Weight loss: 1.1-4.4 kg/year (appetite suppression).
✔ Cardiovascular benefit: ↓ Risk of heart complications (MACE).
✔ No hypoglycemia (unless combined with insulin or sulfonylureas).

✖ Side effects: GI issues (nausea, vomiting, diarrhea).
✖ Rare risks: Pancreatitis, medullary thyroid cancer (contraindicated if personal/family history).
✖ Costly & injectable (except oral semaglutide).

GLP-1 Receptor Agonists Overview

Why is Native GLP-1 Not Used?

• GLP-1 is rapidly degraded by DPP-4 (half-life: 2 minutes).

• Therapeutic drugs are modified to resist DPP-4 and extend their action.

1⃣ What Are GIP and GLP-1? (Background & Physiology)

Both GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) are incretins—gut hormones that enhance insulin release in response to food.

Where Are They Made?

• GIP is secreted by K-cells (found in the duodenum & proximal jejunum).

• GLP-1 is secreted by L-cells (found in the ileum & colon).

What Do They Do?

So, both increase insulin secretion when glucose is high, but GLP-1 does more—it slows digestion and reduces appetite.

2⃣ Why Do GIP & GLP-1 Have a Short Half-Life? (DPP-4 Degradation)

• Both GIP and GLP-1 have very short half-lives (4-7 minutes) because of an enzyme called DPP-4 (dipeptidyl peptidase-4), which rapidly inactivates them.

• This is why we use DPP-4 inhibitors (like sitagliptin) to prolong their effects!

3⃣ Tirzepatide (Mounjaro) – A "Twincretin" (GLP-1 & GIP Agonist)

Tirzepatide is a dual agonist of both GLP-1 & GIP receptors—meaning it mimics both incretins.

How Was Tirzepatide Designed? (Peptide Engineering)

• Scientists took the GIP sequence and modified it to also bind to GLP-1 receptors.

• The final drug retains:

  • 9 amino acids from GIP

  • 4 amino acids from GLP-1

  • 10 shared amino acids

How Does Tirzepatide Work?

✅ Acts on both GIP & GLP-1 receptors → enhances insulin release when glucose is high
✅ Suppresses glucagon (so the liver makes less glucose)
✅ Delays gastric emptying (slows digestion, leading to better glucose control)
✅ Reduces appetite & food intake
✅ Increases insulin sensitivity
✅ Promotes significant weight loss (~20%)

4⃣ Why Is Tirzepatide Long-Lasting? (Once-Weekly Dosing)

Tirzepatide is designed to resist DPP-4 degradation and bind to albumin, which keeps it in circulation longer.

• It contains two special amino acid modifications (Aib) at positions 2 and 13, which make it DPP-4 resistant.

• It also has a fatty acid side chain (eicosanedioic acid) that binds to albumin, increasing its half-life to ~5 days.

• This allows for once-weekly dosing!

5⃣ Clinical Use of Tirzepatide

• Indication: Type 2 diabetes (adjunct to diet & exercise)

• Administration: Subcutaneous injection, once weekly

• Dosing:

  • Start at 2.5 mg/week

  • Can increase up to 15 mg/week

• Main Effects:
  ✅ Lowers glucose (high efficacy, but no hypoglycemia risk)
  ✅ Improves insulin sensitivity
  ✅ Reduces body weight significantly (~20%)

6⃣ Side Effects & Safety Considerations

7⃣ Other Potential Benefits of GLP-1 Agonists

Beyond diabetes & weight loss, GLP-1 receptor agonists may also help with:

• Lower risk of Alzheimer’s disease 🧠

• Less addiction behaviors (smoking, alcohol, drugs) 🚬🍷

• Lower schizophrenia risk & improved mental health

🔑 Summary – What You Should Remember

1. GIP & GLP-1 are incretins that stimulate insulin release when glucose is high.

2. GLP-1 also slows digestion, suppresses appetite, and reduces glucagon.

3. DPP-4 degrades both incretins → reason for DPP-4 inhibitors & GLP-1 agonists.

4. Tirzepatide is a dual agonist ("Twincretin") → mimics both GIP & GLP-1.

5. It lowers glucose, improves insulin sensitivity, promotes weight loss (~20%), and has a long half-life (~5 days), allowing for once-weekly dosing.

1⃣ What is DPP-4 & Why Do We Inhibit It? (Physiology & Rationale)

What is DPP-4?

• Dipeptidyl peptidase-4 (DPP-4) is an enzyme (protease) found both on cell surfaces and in circulation.

• Its main job is to break down incretin hormones—especially GLP-1 and (to some extent) GIP.

• This means DPP-4 normally limits the effects of incretins, reducing glucose-dependent insulin release and allowing glucagon to increase blood sugar.

Why Do We Inhibit DPP-4?

• If we block DPP-4, then GLP-1 and GIP levels remain higher for longer, leading to:
  ✅ Increased insulin release in response to glucose
  ✅ Decreased glucagon levels (less liver glucose production)
  ✅ Better blood glucose control

2⃣ How Effective Are DPP-4 Inhibitors?

• A1C reduction: ~0.5-0.7% (modest compared to GLP-1 RAs).

• Hypoglycemia risk: Very low/negligible (because it works in a glucose-dependent manner).

• Weight effect: Weight neutral (doesn't cause gain or loss).

• Cardiovascular effects: Mostly neutral for major adverse cardiovascular events (MACE) & heart failure (HF).

3⃣ Why Are DPP-4 Inhibitors ORAL but GLP-1 RAs Are Injected?

• DPP-4 inhibitors are small molecules that can survive stomach acid, so they are given as oral tablets.

• GLP-1 receptor agonists (like liraglutide) are peptides—they would be broken down by stomach enzymes if taken orally, so they must be injected.

4⃣ The Four Main DPP-4 Inhibitors

5⃣ Side Effects of DPP-4 Inhibitors

6⃣ Why Are GLP-1 RAs Better for Glucose Control & Weight Loss?

• DPP-4 inhibitors only prolong natural GLP-1 levels, which are relatively low.

• **GLP-1 receptor agonists (like liraglutide) provide supra-physiological levels of GLP-1, leading to:
  ✅ More insulin release
  ✅ Greater glucagon suppression
  ✅ Stronger weight loss effects

Thus, GLP-1 receptor agonists are preferred if weight loss is a goal.

🔑 Summary: What You Need to Remember

1) DPP-4 is an enzyme that degrades GLP-1 and GIP.
2) DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) prolong incretin action, increasing insulin & lowering glucagon.

3) They lower A1C by ~0.5-0.7%, are weight neutral, and do NOT cause hypoglycemia.
4) They are oral drugs (unlike GLP-1 RAs, which require injection).
5) Sitagliptin & alogliptin are excreted renally (dose adjust in CKD); linagliptin is excreted in bile (good for CKD).
6) Main side effects: Nasopharyngitis, headache, rare pancreatitis & joint pain.
7) GLP-1 receptor agonists are more effective for glucose control & weight loss.

1⃣ What is SGLT-2 & Why Do We Inhibit It? (Physiology & Rationale)

How is Glucose Normally Handled by the Kidney?

• Every day, your kidneys filter ~180 g of glucose from the blood.

• Normally, 100% of this glucose is reabsorbed (so, net 0 g/day is lost in urine).

• Where does glucose reabsorption happen?

  • 90% is reabsorbed in the proximal tubule (S1 segment) by SGLT-2 + GLUT-2.

  • 10% is reabsorbed later (S3 segment) by SGLT-1 + GLUT-1.

• What happens in hyperglycemia?

  • If blood glucose exceeds 10 mmol/L, SGLT-2 reaches its max capacity.

  • Extra glucose spills into urine (glycosuria).

  • This point is called the Renal Threshold for Glucose (RTG).

How Do SGLT-2 Inhibitors Work?

• These drugs block SGLT-2, reducing glucose reabsorption.

• This lowers RTG, so glucose starts appearing in urine even at lower blood glucose levels.

• End result:
  ✅ Less glucose reabsorbed → More glucose lost in urine
  ✅ Lower blood sugar without increasing insulin
  ✅ Weight loss (~2-3 kg) due to calorie loss
  ✅ No hypoglycemia (because insulin is not increased)

2⃣ How Effective Are SGLT-2 Inhibitors?

• A1C reduction: ~0.5-0.7% (similar to DPP-4 inhibitors).

• Hypoglycemia risk: Very low (since it doesn’t increase insulin).

• Weight effect: Causes weight loss (2-3 kg).

• Cardiovascular benefits: Some reduce MACE (heart attacks, strokes) & HF risk.

3⃣ The Three Main SGLT-2 Inhibitors

4⃣ Side Effects of SGLT-2 Inhibitors

5⃣ Special Considerations

• Efficacy is reduced in CKD → Since SGLT-2 is located in the kidney, if kidney function is low, the drug won’t work as well.

• Hold before major surgery → Due to risk of euglycemic DKA.

🔑 Summary: What You Need to Remember

1⃣ SGLT-2 normally reabsorbs 90% of glucose in the kidney.
2⃣ Blocking SGLT-2 leads to glucose loss in urine, lowering blood sugar without increasing insulin.
3⃣ A1C lowering: ~0.5-0.7%.
4⃣ Causes weight loss (~2-3 kg) & has no hypoglycemia risk.
5⃣ Empagliflozin & canagliflozin reduce MACE & HF risk. Dapagliflozin reduces HF risk but not MACE.
6⃣ Main side effects: UTIs, increased urination, low BP, rare euglycemic DKA.
7⃣ Canagliflozin uniquely causes bone fractures.
8⃣ Less effective in CKD & should be held before surgery.

1⃣ What is Alpha-Glucosidase & Why Do We Inhibit It? (Physiology & Rationale)

How are Carbohydrates Normally Broken Down?

• Carbohydrates (starches, sucrose, maltose) cannot be absorbed directly.

• Alpha-glucosidase enzymes (found in the small intestine brush border) break them down into monosaccharides (glucose, fructose) so they can be absorbed.

• After a meal, this process leads to a rapid rise in blood glucose (postprandial spike).

How Do Alpha-Glucosidase Inhibitors (AGIs) Work?

• They block alpha-glucosidase enzymes, slowing carbohydrate digestion.

• This delays glucose absorption, blunting postprandial glucose spikes.

• They do NOT affect fasting glucose—only post-meal glucose levels.

End result:
✅ Slower glucose absorption → Lower postprandial glucose spikes
✅ Minimal effect on fasting glucose
✅ No risk of hypoglycemia (unless combined with insulin/SU)

2⃣ How Effective Are Alpha-Glucosidase Inhibitors?

• A1C lowering: ~0.7-0.8% (similar to SGLT-2 inhibitors).

• Postprandial glucose drop: 2.2-2.8 mmol/L.

• Hypoglycemia risk: Very low (unless combined with insulin/SU).

• Weight effect: No weight gain.

3⃣ The Main Alpha-Glucosidase Inhibitor

4⃣ Side Effects of Acarbose

🔹 How to reduce side effects? Start with low doses and increase gradually.

5⃣ Special Considerations

When & How to Take It?

• Must be taken with the first bite of a meal for maximum effect.

• Not useful if the patient skips meals or eats low-carb diets.

Who Should Take It?

• Best for patients with postprandial hyperglycemia.

• Not recommended for initial therapy if A1C >8.5% (too mild).

What If Hypoglycemia Occurs?

• AGIs don’t cause hypoglycemia, but if combined with insulin/SU, hypoglycemia can still happen.

• Key point: If hypoglycemia occurs, only pure glucose (dextrose) can be used to treat it because AGIs block sucrose breakdown.

• Alternative options if glucose is unavailable: Milk, honey (already broken down into absorbable sugars).

🔑 Summary: What You Need to Remember

1⃣ Alpha-glucosidase enzymes break down complex carbs into glucose for absorption.
2⃣ Acarbose blocks these enzymes, slowing carbohydrate digestion & reducing postprandial glucose spikes.
3⃣ A1C lowering: ~0.7-0.8%.
4⃣ Only effective when taken with meals & does not affect fasting glucose.
5⃣ Main side effects: GI issues (flatulence, diarrhea, bloating), minimized by slow dose titration.
6⃣ No weight gain & very low hypoglycemia risk unless combined with insulin/SU.
7⃣ If hypoglycemia occurs, treat with pure glucose (not sucrose!)

Insulin Secretagogues

What are they?
Insulin secretagogues are medications that stimulate insulin secretion from pancreatic β-cells. They help lower blood glucose by increasing the body's natural insulin production.

Sulfonylureas (SUs)

Main idea: These drugs stimulate insulin secretion from pancreatic β-cells by closing ATP-sensitive potassium (KATP) channels.

Mechanism of Action:

• Pancreatic β-cells have KATP channels made up of:

  • SUR1 (sulfonylurea receptor, the drug target)

  • Kir6.2 (a pore that lets potassium in/out)

• Normally, glucose metabolism produces ATP, which closes the KATP channel, leading to membrane depolarization. This opens calcium (Ca²⁺) channels, triggering insulin release.

• Sulfonylureas mimic this process by binding to SUR1 → closes KATP channels even when glucose is low → causes continuous insulin release → lowers blood sugar.

• This makes them effective at lowering glucose but also increases hypoglycemia risk, especially in fasting states.

Key Effects:

✅ Rapid glucose reduction (Fasting glucose ↓ by 3.3-3.9 mmol/L, A1C ↓ by 0.7-1.3%)
✅ Inexpensive and widely available
❌ Can cause hypoglycemia (especially glyburide)
❌ Causes weight gain (1.2-3.2 kg)
❌ Does not work if β-cells are nonfunctional (best in early Type 2 DM)

Sulfonylurea Drugs:

1. Glyburide (Most potent but highest risk of hypoglycemia)

   • Dose: 5 mg/day, max 20 mg/day (BID if >10 mg)

   • Use with caution in CKD (avoid if GFR <30 mL/min)

   • Slower onset, longer duration → useful for overnight glucose control

   • More hypoglycemia risk than other SUs

2. Gliclazide (Preferred over glyburide, lower hypoglycemia risk)

   • Dose: 80-320 mg/day (BID if >160 mg)

   • Faster onset, shorter duration → better postprandial glucose control

   • Safer in CKD, but reduce dose if GFR <30 (avoid if <15 mL/min)

   • Modified release (MR) version available

3. Glimepiride (Longest duration, lowest required dose)

   • Dose: 1-4 mg/day (max 8 mg/day)

   • Rapid onset + long duration → good for once-daily dosing

   • Similar hypoglycemia risk to gliclazide

   • Safer than glyburide but avoid if GFR <15 mL/min

⏳ Older long-acting SU (chlorpropamide, 24-72h duration) is rarely used due to extreme hypoglycemia risk.

Clinical Considerations:

• Best for: Early-stage T2DM with functional β-cells.

• Avoid in: Elderly, CKD, hepatic dysfunction, or high hypoglycemia risk.

• Convenient daily dosing, but not durable long-term (β-cell function declines over time).

• Neutral cardiovascular effects (MACE & HF risk not increased).

Meglitinides (Shorter-acting secretagogues)

Main idea: Similar to sulfonylureas but faster-acting, shorter duration, and lower hypoglycemia risk.

Mechanism of Action:

• Like sulfonylureas, meglitinides close KATP channels in β-cells, leading to insulin release.

• However, they bind to a different site and have a faster onset and shorter duration (4-7h).

• Insulin release is more glucose-dependent → lower hypoglycemia risk, especially if a meal is skipped.

Key Effects:

✅ Rapid-acting (mimics normal insulin secretion)
✅ Less hypoglycemia than sulfonylureas (safer for irregular meal schedules)
✅ Safer in kidney disease (no GFR adjustment)
❌ Short duration = requires TID dosing
❌ More expensive than SUs (~8x the cost)
❌ Weight gain (1.4-3.3 kg)

Meglitinide Drug Example:

Repaglinide

• Dose: 0.5-4 mg/day

• Taken just before meals (15-30 min before first bite)

• Ideal for: Patients with sulfa allergies, irregular meal schedules, or late postprandial hypoglycemia.

Final Takeaways:

When to Choose What?

• If cost and convenience matter → Use sulfonylureas (gliclazide preferred over glyburide).

• If patient has irregular meals or sulfa allergy → Use meglitinides (repaglinide).

• If patient is high-risk for hypoglycemia (elderly, CKD) → Consider alternatives (e.g., DPP-4 inhibitors, GLP-1 agonists).

Thiazolidinediones (TZDs) – Insulin-Sensitizing Agents

Instead of just focusing on lowering blood sugar, this class of drugs also tackles insulin resistance, which is a core issue in type 2 diabetes (T2D).

Mechanism of Action

TZDs work by activating a nuclear receptor called PPAR-gamma (PPARγ), which is mainly found in fat cells (adipose tissue) but also in smaller amounts in muscle, heart, and liver.
Here’s what happens step by step:

1. PPARγ Activation

   • PPARγ is a receptor inside the cell that responds to natural ligands (like fatty acids) and drug ligands (like TZDs).

   • When TZDs bind to PPARγ, the receptor changes shape and pairs with another receptor called RXR (Retinoid X Receptor).

   • This pairing triggers the activation of specific genes involved in glucose and fat metabolism.

2. Effects on Glucose Metabolism

   • Increases insulin sensitivity → Helps the body respond better to insulin.

   • Increases GLUT-4 transporters → More glucose uptake into muscle and fat cells.

   • Reduces gluconeogenesis → Less glucose is made by the liver.

3. Effects on Fat Metabolism

   • Redistributes fat from visceral (belly) fat to subcutaneous (under the skin) fat.

   • Encourages the storage of fatty acids in fat tissue instead of letting them circulate in the blood.

   • Reduces fat accumulation in the liver and muscles → This helps with insulin resistance.

🔹 Key takeaway: TZDs help lower insulin resistance by shifting fat storage, improving glucose uptake, and decreasing liver glucose production.

Clinical Effects of TZDs

• Reduces fasting blood glucose by 2.2–3.3 mmol/L.

• Lowers A1C by 0.8–0.9% → moderate effectiveness.

• Takes time to work → 2 weeks for initial effect, 6–12 weeks for full effect because it works through gene regulation.

• No risk of hypoglycemia since it does not directly increase insulin secretion.

• Causes weight gain (2.5–5 kg) due to both fluid retention and increased fat storage.

Examples of TZDs

1. Rosiglitazone

   • Dose: 4 mg daily (max 8 mg/day)

   • Metabolized by CYP2C8 and CYP2C9

2. Pioglitazone

   • Dose: 15–30 mg daily

   • Metabolized by CYP2C8 and CYP3A4

🔹 Both drugs can be taken with or without food.

Concerns & Side Effects of TZDs

TZDs are not first-line due to safety concerns:

1. Fluid retention & edema → Leads to heart failure

2. Weight gain → Mostly due to increased fat and fluid retention.

3. Bone fractures → Decreases osteoblast activity (cells that build bone).

4. Cardiovascular risk

   • Heart failure risk → Contraindicated in NYHA Class III/IV heart failure.

   • Possible increased risk of heart attack (MI) → Rosiglitazone was once restricted due to this concern.

📌 Because of these risks, TZDs are rarely used today.

Insulin Therapy in Type 2 Diabetes

If a patient has severe symptoms or metabolic decompensation, insulin should be started right away.

How Insulin Works

• Activates insulin receptors on cells.

• Regulates the metabolism of carbohydrates, fats, and proteins.

Types of Insulin Used in T2D

• Basal insulin (long-acting) → Used as the first step in T2D treatment.

• Bolus insulin (rapid or regular) → Used for mealtime glucose control.

• Premixed insulin → A combination of basal and bolus insulin.

Effects of Insulin in T2D

• A1C lowering by 0.9–1.2% (highest efficacy).

• Risk of hypoglycemia → Especially with bolus insulin.

• Weight gain of ~4–5 kg → Insulin promotes fat storage.

📌 Most T2D patients start with a single dose of long-acting insulin at night.

Key Takeaways

1. TZDs improve insulin sensitivity and work by activating PPARγ receptors, which regulate glucose and fat metabolism.

2. They shift fat from visceral (bad) to subcutaneous (less bad) and reduce glucose production by the liver.

3. Main side effects: fluid retention, weight gain, fractures, and heart failure risk → These make them unpopular.

4. Insulin is used in severe cases of T2D when oral medications aren’t enough.

5. Insulin is the most effective A1C-lowering therapy but carries risks of hypoglycemia and weight gain..

Key Takeaways for Type 2 Diabetes Treatment:

1. Every patient is different

   • Some people struggle more with high blood sugar after meals, while others have high fasting blood sugar.

   • Some have poor insulin production, while others have strong insulin secretion but high resistance.

   • Why does this matter? Because treatment should be personalized based on these patterns, as well as other factors like weight and other health conditions.

2. Diet, exercise, and education are the foundation of diabetes management.

   • Think of medication as a “booster”—it works best when paired with lifestyle changes.

3. Different drugs target different aspects of glucose regulation:

   • Increasing insulin secretion:

     • Sulfonylureas (e.g., glyburide)

     • Meglitinides (e.g., repaglinide)

     • GLP-1 receptor agonists (e.g., liraglutide, semaglutide)

     • DPP-4 inhibitors (e.g., sitagliptin)

   • Reducing glucose absorption from food:

     • Acarbose (slows carbohydrate digestion in the gut)

   • Improving insulin sensitivity (reducing insulin resistance):

     • Metformin (decreases liver glucose production, increases muscle glucose uptake)

     • Thiazolidinediones (TZDs, e.g., pioglitazone, rosiglitazone) (enhance insulin action via PPAR-gamma)

   • Blocking glucose reabsorption in the kidneys:

     • SGLT2 inhibitors (e.g., empagliflozin, canagliflozin) (help excrete excess glucose in urine)

4. Combination therapy is common.

   • Many drugs have different mechanisms, so using them together improves blood sugar control while minimizing side effects.

5. Metformin is the first-line treatment unless contraindicated.

   • Why? Because it lowers blood sugar effectively, doesn’t cause weight gain or hypoglycemia, and has cardiovascular benefits.

   • Treatment goal: Reach blood sugar targets within 3-6 months of diagnosis.

6. In patients with cardiovascular disease, prioritize medications that also provide heart protection.

   • Best choices:

     • SGLT2 inhibitors (e.g., empagliflozin) – Reduces risk of heart failure.

     • GLP-1 receptor agonists (e.g., liraglutide) – Reduces risk of heart attacks/strokes.

   • Why? Because T2D patients have a higher risk of cardiovascular disease.

7. For patients worried about hypoglycemia or weight gain, prefer agents that avoid these risks.

   • Better choices:

     • DPP-4 inhibitors (e.g., sitagliptin) – No weight gain, low hypoglycemia risk.

     • GLP-1 receptor agonists (e.g., semaglutide) – Help with weight loss, no hypoglycemia risk.

     • SGLT2 inhibitors (e.g., canagliflozin) – Promote weight loss, no hypoglycemia risk.

   • Avoid: Sulfonylureas and insulin (because they cause weight gain and hypoglycemia risk).

8. Insulin is necessary for severe cases.

   • If someone has severe hyperglycemia or metabolic decompensation (body is failing to regulate sugar), start insulin immediately.

   • Otherwise, try oral meds first, but many patients eventually need insulin as diabetes progresses.

9. Pharmacists play a key role in counseling.

   • Patients need to understand:

     • Medications help control blood sugar, but don’t replace lifestyle changes.

     • Preventing complications (especially cardiovascular disease) is a priority.

     • The goal isn’t just normal blood sugar—it’s long-term health!

Orlistat: A Medication for Weight Loss

• What does it do?

  • Prevents the digestion and absorption of fats from food by blocking enzymes (lipases) in the gut.

  • This means about 30% of dietary fat gets excreted in stool instead of being absorbed.

• Who benefits?

  • Overweight or obese individuals who need help with weight loss.

  • Helps lower A1C by 0.2-0.4% (small effect).

• Side effects?

  • GI issues: Bloating, oily stools, urgent bowel movements.

  • Why? Because undigested fat is expelled instead of absorbed.

• Important counseling points:

  • Works only if the patient eats fat-containing meals (otherwise, it has no effect).

  • Patients should take a multivitamin (since fat-soluble vitamins might not be absorbed properly).

  • Most side effects occur early on and improve over time.

Metabolic Surgery (a.k.a. Bariatric Surgery)

• Who qualifies?

  • People with T2D and BMI > 25 kg/m² (especially those with obesity).

• Why does it work?

  • Reduces stomach size or alters digestion, leading to less food intake and hormonal changes that improve blood sugar control.

  • In some cases, T2D goes into remission after surgery.

• Who benefits the most?

  • Those with newly diagnosed diabetes (less than 5–8 years).

  • Why? Because their pancreas still produces insulin, so weight loss can restore its function.

Final Takeaways

• Not all patients with T2D are the same!

  • Choose treatment based on their unique needs (cardiovascular risk, weight, hypoglycemia risk).

• Lifestyle changes remain the cornerstone of treatment.

  • Medications support but don’t replace healthy habits.

• Metformin is usually first-line.

  • Additional drugs are added based on patient characteristics.

• Some medications offer benefits beyond glucose control.

  • SGLT2 inhibitors → Reduce heart failure risk.

  • GLP-1 receptor agonists → Reduce heart attack/stroke risk.

• Weight management is key in diabetes.

  • GLP-1 receptor agonists and SGLT2 inhibitors help with weight loss.

  • Orlistat is an option for additional weight control.

  • Metabolic surgery can be life-changing for eligible patients.