OHA LIVE class Notes 2.pdf

Dm.

1. Management of Type 2 Diabetes: Oral Anti-Diabetic Agents
Introduction: A Guiding Principle and A Shift in Terminology
A quote to consider when choosing an oral anti-diabetic agent: "There is nothing more deceptive
than the obvious fact." This is highly relevant given the complexity and wide array of available
drugs.
Correction in Terminology:
The older term was OHA (Oral Hypoglycemic Agent).
The current, more accurate term is OAD (Oral Anti-diabetic Agent).
Reason for Change: Not all modern oral anti-diabetic drugs cause hypoglycemia. The new
term reflects the diverse mechanisms of action beyond simply lowering blood sugar. Only two
classes—Sulfonylureas and Meglitinides—are true "hypoglycemic" agents.
The Evolving Pathophysiology of Type 2 Diabetes
The Triumvirate (Older Concept): Historically, diabetes was understood as a disease involving
three primary abnormalities:
1.Pancreas: Defective insulin secretion.
2.Liver: Excessive glucose production.
3.Skeletal Muscle: Impaired glucose uptake (insulin resistance).
The Ominous Octet (Modern Concept): Our understanding has expanded significantly, especially
with the discovery of incretins. There are now at least eight recognized pathophysiological defects
in Type 2 Diabetes:
1.Pancreas (Beta-cell): Decreased insulin secretion.
2.Intestines: Decreased incretin effect.
3.Pancreas (Alpha-cell): Increased glucagon secretion.
OHA Live Class Notes

2. 4.Liver: Increased hepatic glucose production.
5.Brain: Neurotransmitter dysfunction.
6.Muscle: Decreased glucose uptake.
7.Adipose tissue: Increased lipolysis.
8.Kidney: Increased glucose reabsorption.
Implications for Treatment:
It is very difficult for a single drug to target all eight mechanisms.
This complexity drives the modern trend towards early combination therapy to address
multiple defects simultaneously.
Early combination therapy is also crucial for beta-cell preservation.
Initial Treatment Strategy Based on HbA1c
The initial approach to managing Type 2 Diabetes is guided by the patient's baseline HbA1c level.
HbA1c < 7%:
Lifestyle Modification (LSM) only. No medication is needed at this stage.
HbA1c 7% - 8.5%:
Initiate Monotherapy (a single agent).
HbA1c 8.5% - 10%:
Initiate Dual Therapy (two agents from different classes).
HbA1c > 10%:
Ideally, start Insulin in combination with oral agents.

3. Drug Class: Alpha-Glucosidase Inhibitors
These drugs are designed to target the absorption of carbohydrates from the gut.
Mechanism of Action:
Analogy: Think of the process in the intestine where starch is broken down into sucrose, and
sucrose is then broken down into glucose, which is finally absorbed. These drugs act as a
roadblock.
They inhibit the alpha-glucosidase enzyme in the brush border of the small intestine.
This enzyme is essential for breaking down complex carbohydrates (polysaccharides, sucrose)
into simple, absorbable sugars (monosaccharides, glucose).
By inhibiting this enzyme, they delay carbohydrate absorption, which blunts the post-
prandial glucose spike.
The drug itself is not absorbed into the bloodstream; it works locally within the intestine and is
excreted.
Drugs Available: Acarbose (25-50 mg), Voglibose (0.2-0.3 mg).
Clinical Use & Efficacy:
Administration: Must be taken with the first bite of each meal because it needs to mix with
the food to be effective. If forgotten, taking it later is useless.
Primary Target: Excellent for controlling post-prandial hyperglycemia (high blood sugar
after meals).
Ideal Patient: Someone whose diet is rich in complex carbohydrates (e.g., rice, potatoes,
bread) or who has isolated post-prandial glucose spikes.
Efficacy: Modest. It is not potent enough for monotherapy if HbA1c is high. It can lower
HbA1c by about 0.5%. It works best as an add-on to other agents like Metformin or
Sulfonylureas.
Advantages:

4. No Hypoglycemia: Since it does not affect insulin secretion or sensitivity, it does not cause
hypoglycemia on its own.
Good for Fasting Patients: Ideal for patients who fast (e.g., during Ramadan or Navratri). They
can take the pill only when they eat, without risk of hypoglycemia during the fasting period.
Safe in High-Risk Groups: A good choice for the elderly, those who live alone, or professional
drivers, where hypoglycemia would be dangerous.
Adverse Effects:
Very common GI side effects: Flatulence, bloating, abdominal discomfort, and diarrhea.
Reason: Undigested carbohydrates travel to the colon, where they are fermented by bacteria,
producing gas.
These side effects are the main reason for poor patient compliance.
Drug Class: Biguanides (Metformin)
Metformin is the cornerstone of Type 2 Diabetes management and is the recommended first-line agent.
Mechanism of Action: Metformin is an insulin sensitizer. Its primary role is to combat insulin
resistance.
1.Liver (Major Effect): It primarily acts on the liver to reduce hepatic glucose output. It
decreases gluconeogenesis (the creation of new glucose) and glycogenolysis (the breakdown
of stored glucose). This makes it highly effective at controlling fasting blood sugar.
2.Muscle: It increases insulin sensitivity in peripheral tissues like muscle, promoting glucose
uptake via GLUT4 transporters.
3.Intestine: It increases anaerobic glucose metabolism in the gut and beneficially alters the
gut microbiota.
Clinical Use & Dosing:
Monotherapy Protocol (HbA1c 7-8.5%):

5. 1.Start: Metformin 500 mg, once daily, with or immediately after dinner. This timing
targets the high fasting glucose levels often seen in the morning.
2.Titrate after 2-4 weeks: If control is not achieved, increase to 500 mg twice daily (after
breakfast and dinner).
3.Further Titration: If needed, increase the evening dose first: 500 mg (morning) and 1000
mg (evening).
4.Maximum Dose: Increase to the optimal dose of 1000 mg twice daily (2000 mg/day).
It is crucial to titrate the dose up and not leave patients on a sub-therapeutic dose.
Advantages:
No Hypoglycemia: Does not cause hypoglycemia as it doesn't stimulate insulin secretion.
Weight Neutral/Mild Weight Loss: Beneficial for overweight or obese patients.
Efficacy: Reduces HbA1c by approximately 1-1.5%.
Cardiovascular Benefits: Considered to have positive cardiovascular outcomes.
Affordable: Very cost-effective.
Adverse Effects & Cautions:
GI Intolerance: The most common side effect is diarrhea, bloating, and abdominal discomfort.
Taking it with food helps. About 10% of patients cannot tolerate it.
Vitamin B12 Deficiency: Long-term use can impair B12 absorption. Periodic monitoring or
supplementation is recommended.
Lactic Acidosis: A rare but serious complication. The risk is negligible in patients with normal
organ function but increases significantly in states of severe renal failure, cardiac failure, liver
failure, or septic shock. It is often withheld in hospitalized, critically ill patients.

6. Drug Class: Thiazolidinediones (TZDs or "Glitazones")
Like Metformin, TZDs are insulin sensitizers, but they work through a different mechanism. Pioglitazone
is the only TZD currently in use.
Mechanism:
Acts as a PPAR-γ agonist .
This activation promotes the creation of new, small, highly insulin-sensitive fat cells
(adipocytes).
This leads to a "lipid steal" phenomenon, where fat is redistributed from visceral areas (like
the liver and muscle) to subcutaneous adipose tissue, thereby improving insulin sensitivity in the liver and muscles.
Clinical Use:
Dose: 15-45 mg once daily.
Slow Onset of Action: It takes 3-4 months to see the maximum effect.
Primary Indication: Excellent choice for patients with significant insulin resistance and Non-
alcoholic fatty liver disease (NAFLD).
Advantages:
No Hypoglycemia.
Durable Effect & Beta-cell Preservation.
Inexpensive.
Adverse Effects & Contraindications:
Fluid Retention & Weight Gain: Causes fluid retention and can lead to weight gain.
Heart Failure: Contraindicated in patients with NYHA Class III-IV heart failure.
Fracture Risk: Increases the risk of fractures, especially in postmenopausal women.

7. Bladder Cancer: A historical concern. Contraindicated in patients with active or a history of
bladder cancer.
Macular Edema: Can cause or worsen diabetic macular edema.
Drug Class: Sulfonylureas (SUs)
These are insulin secretagogues, meaning they stimulate the pancreas to release more insulin.
Mechanism of Action:
Analogy: These drugs climb onto the pancreas and "squeeze" it, forcing it to release stored
insulin, regardless of whether the patient has eaten.
They act on the beta-cells by blocking the ATP-sensitive potassium (K-ATP) channels.
This blockage leads to membrane depolarization, influx of calcium, and subsequent release
(exocytosis) of insulin granules.
Drugs Available:
2nd Generation: Glibenclamide (high risk of hypoglycemia, generally avoided).
3rd Generation: Glimepiride (0.5-4 mg), Gliclazide (SR 30-120 mg). These are safer and
preferred.
Clinical Use:
Highly efficacious and very inexpensive, making them a common choice when cost is a major
issue.
Also a good choice for lean, catabolic diabetics who are losing weight, as SUs are anabolic
and can help with weight gain.
They are started when monotherapy fails or in patients with more advanced disease needing a significant drop in HbA1c.
Adverse Effects & Cautions:

8. Hypoglycemia: This is the most significant and dangerous side effect. Because they stimulate
insulin release independent of food intake, patients are at high risk if they skip a meal.
CRITICAL PATIENT EDUCATION: Patients must be told to take the drug 15-30 minutes
before a meal and to skip the dose if they skip the meal.
Weight Gain: An average of 3.5-4 kg is common.
Sulfonylurea Failure:
Primary Failure: No response from the start, often in patients with severe beta-cell
exhaustion.
Secondary Failure: The drug stops working over time due to the progressive nature of
beta-cell decline in diabetes. SUs do not preserve beta-cell function.
Drug Class: Incretin-Based Therapies
This class of drugs works by enhancing the "incretin effect."
The Incretin Effect: The observation that oral glucose stimulates a much greater insulin release
than an equivalent IV dose. This is due to gut hormones, GLP-1 and GIP, which are released after a
meal. They signal the pancreas to release insulin in a glucose-dependent manner (i.e., only when
blood sugar is high). In Type 2 Diabetes, this effect is blunted.
The Problem: Endogenous incretins are broken down very quickly (in minutes) by an enzyme
called DPP-4 .
1. DPP-4 Inhibitors ("Gliptins")
Mechanism:
Analogy: Imagine incretins are waiters who count the number of rotis (carbohydrates) you eat
and signal the kitchen (pancreas) to send out a proportional amount of a dish (insulin). The
DPP-4 enzyme is like a manager that quickly fires these waiters. DPP-4 inhibitors stop this
manager, allowing the waiters to work longer and do their job properly.
They block the DPP-4 enzyme, increasing the lifespan of the body's own GLP-1 and GIP.

9. This restores glucose-dependent insulin secretion.
Drugs Available: Sitagliptin, Vildagliptin, Linagliptin, Teneligliptin.
Advantages:
Very Low Risk of Hypoglycemia: They only work when blood glucose is high.
Weight Neutral: Do not cause weight gain or loss.
Well-Tolerated: Generally have few side effects.
Key Features:
Linagliptin is the preferred choice for patients with Chronic Kidney Disease (CKD) as it does
not require dose adjustment.
Saxagliptin is associated with an increased risk of hospitalization for heart failure.
Efficacy: Moderately effective, reducing HbA1c by about 0.7-1%. They primarily target post-
prandial glucose.
2. Oral GLP-1 Receptor Agonists (Oral Semaglutide)
Mechanism: Instead of protecting endogenous incretins, this is a synthetic GLP-1 analog that
directly stimulates the GLP-1 receptor. It provides pharmacological (supra-physiological) levels of
GLP-1.
Effects:
Stimulates glucose-dependent insulin release.
Suppresses glucagon secretion.
Slows gastric emptying and increases satiety (feeling of fullness). This central effect is
what leads to significant weight loss.
Oral Semaglutide (Rybelsus):
Administration: Must be taken on a completely empty stomach with a small sip of water
(≤120 mL). The patient must wait at least 30 minutes before eating, drinking, or taking any
other medication.

10. Titration: Start at 3 mg daily for one month (acclimatization dose), then increase to the
therapeutic dose of 7 mg. Can be further increased to 14 mg if needed.
Efficacy: Highly efficacious for both glucose control and weight loss.
Side Effects: GI side effects (nausea, vomiting) are very common, especially during titration.
Indication: An excellent option for obese patients where weight loss is a primary goal.
Drug Class: SGLT2 Inhibitors ("Flozins")
This is a revolutionary class of drugs that works entirely through the kidneys and offers significant
cardiovascular and renal protection.
Mechanism:
They inhibit the Sodium-Glucose Co-transporter 2 (SGLT2) in the proximal tubule of the
kidney.
This transporter is responsible for reabsorbing ~90% of the glucose filtered by the glomeruli
back into the blood.
By blocking SGLT2, these drugs cause the body to excrete excess glucose in the urine (glucosuria), effectively lowering blood sugar in an insulin-independent manner.
Drugs Available: Dapagliflozin (5-10 mg), Empagliflozin (10-25 mg), Canagliflozin.
Multi-system Benefits (The "Cardio-Renal-Metabolic" Drug):
1.Glycemic Control: Lowers HbA1c by ~1%.
2.Weight Loss: Due to the loss of calories via glucosuria.
3.Blood Pressure Reduction: Through mild osmotic diuresis.
4.Renal Protection:
They reduce intraglomerular pressure by causing afferent arteriole
vasoconstriction, protecting the kidneys from hyperfiltration damage. This is why they are
indicated for CKD even in non-diabetics.

11. 5.Cardiovascular Protection: Proven to significantly reduce the risk of hospitalization for heart
failure and major adverse cardiovascular events (MACE). They are indicated for heart failure
(HFrEF & HFpEF) even in non-diabetics.
Adverse Effects:
Genital Mycotic Infections (Yeast Infections): The most common side effect due to glucose
in the urine.
Urinary Tract Infections (UTIs): Increased risk.
Euglycemic Diabetic Ketoacidosis (eDKA): A rare but serious risk. The patient is in
ketoacidosis, but their blood sugar is normal or only mildly elevated (<250 mg/dL) because
the drug is forcing glucose out through the urine. Patients should be warned to stop the drug
if they are sick, unable to eat, or undergoing surgery.
Volume Depletion/Hypotension: Can occur due to the diuretic effect.
Practical Treatment Algorithms & Combination Therapy
HbA1c 8.5-10%: Starting Dual Therapy
When monotherapy fails or the initial HbA1c is in this range, the choice of the second agent depends
on the patient's profile. Metformin remains the foundational drug.
Patient with Established ASCVD, Heart Failure, or CKD:
First Choice: Add an SGLT2 Inhibitor (e.g., Dapagliflozin 10mg or Empagliflozin 10mg). This is
the standard of care for organ protection, irrespective of HbA1c.
Second Choice: A GLP-1 Receptor Agonist.
Patient with High Hypoglycemia Risk (e.g., elderly):
Choice: Add a DPP-4 Inhibitor (e.g., Vildagliptin 50mg BID, Sitagliptin 100mg OD, or
Linagliptin 5mg OD).
Titrate Metformin up to 1000mg BID. The gliptin dose is usually fixed.

12. Patient where Cost is a Major Issue OR a Lean Patient:
Choice: Add a Sulfonylurea.
Glimepiride: Start at 0.5-1 mg before breakfast. Titrate up as needed to a max of 4 mg/day.
Gliclazide SR: Start at 30 mg before breakfast. Titrate up to a max of 120 mg/day.
Titrate Metformin up alongside the SU.
Patient who is Obese and Weight Loss is a Priority:
First Choice: Add an SGLT2 Inhibitor.
Second Choice: Add a GLP-1 Receptor Agonist (Oral Semaglutide) if affordable.
Patient with NAFLD / Severe Insulin Resistance:
Choice: Add Pioglitazone (15mg, titrate to 45mg), provided there are no contraindications
like heart failure.
Triple Therapy
If a patient is not controlled on maximum doses of two agents, add a third drug from a different class
based on the principles above.
Example 1: Patient on Metformin + SU. Add an SGLT2i (if CV/renal risk) or a DPP4i.
Example 2: Patient on Metformin + DPP4i. Add an SGLT2i (if CV/renal risk) or an SU (if cost is an
issue).

13. Goal Preferred Agents Agents to Avoid
Minimize Hypoglycemia
Metformin, DPP-4i, SGLT2i, TZD,
GLP-1 RA
Sulfonylureas
Promote Weight Loss
GLP-1 RA (most potent), SGLT2i,
Metformin
Sulfonylureas, Pioglitazone,
Insulin
Cost is a Major Issue
Sulfonylureas, Metformin,
Pioglitazone
GLP-1 RA, SGLT2i, DPP-4i
Established CV/Renal
Disease
SGLT2i, GLP-1 RA
Caution with Saxagliptin
(HF risk)
Summary of Agent Selection by Goal
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