MD Notes

creation date: 2025-07-29 23:19
tags: Pharmacology

Antihyperglycemics

The typical prescribing order is as follows, moving down the list to improve glycemic control:

  1. Metformin
  2. SGLT2i
  3. GLP-1 (may be skipped if needle-adverse)
  4. DPP-4
  5. Sulfonylurea

Biguanide

Mechanism of action

Enhances the effect of insulin:

  • Reduce insulin resistance by inhibiting mitochondrial glycerophosphate dehydrogenase (mGPD) which reduces hepatic gluconeogenesis and intestinal glucose absorption
  • Increases peripheral insulin sensitivity which increases peripheral glucose update and glycolysis
  • Lowers postprandial and FBG levels
  • Reduces LDL, increases HDL
Additional characteristics
  • Glycemic efficacy: reduce HbA1C by 1.2-2% over 3 months
  • Weight loss or stabilization
  • No risk of hypoglycemia
  • Beneficial effect on dyslipidemia
  • Reduces risk of macroangiopathic complications of diabetes
Adverse effects
  • Metformin-associated lactic acidosis (especially in elderly or patients with renal insufficiency or CHF)
  • Vitamin B12 deficiency
  • Metallic taste in mouth
Contraindications

  • Renal failure

  • IV contrast (due to reduction in elimination)

  • Heart failure, resp failure, shock, sepsis

  • Alcoholism/severe liver failure

  • Chronic pancreatitis, starvation ketosis, ketoacidosis

  • Simultaneous sulfonylurea use (due to increased cardiovascular mortality)

  • Note: should be paused prior to surgery.

Examples
  • Metformin
  • Many other medication classes have combination drugs with metformin

Incretins are digestive tract hormones that increases insulin secretion from the beta-cells of the pancreas. The two major incretins are GLP-1 and GIP.

Normal GLP-1 action: released on food intake, degraded by DPP-4

DPP-4 inhibitors

Dipeptidyl peptidase-4 inhibitors (gliptins)

Mechanism of action

Indirectly increases endogenous incretin by inhibiting DPP-4. This results in greater insulin secretion and decreased glucagon secretion.

Additional characteristics
  • Glycemic efficacy: reduce HbA1C by 0.5-0.75% over 3 months
  • No risk of hypoglycemia on its own as insulin release is glucose-dependent
Adverse effects
  • Gastrointestinal symptoms (milder than GLP-1 agonist)
  • Arthralgia
  • Increased satiety due to delayed gastric emptying
  • Nasopharyngitis and URTI
  • Urinary infections
  • Increased risk of pancreatitis
  • Worsening renal function
  • Headache, dizziness
Contraindications
  • Liver failure
  • Renal failure
Examples
  • Sitagliptin (Januvia)
  • Saxagliptin (Onglyza)
  • Linagliptin (Trajenta)
  • Alogliptin (Nesina)

With metformin:

  • Sitagliptin/metformin (Janumet)
  • Saxagliptin/metformin (Komboglyze)
  • Linagliptin/metformin (Jentadueto)
  • Alogliptin/metformin (Kazano)

GLP-1 receptor agonists

Glucagon-like peptide-1 receptor agonist

Mechanism of action

Incretin mimetic drugs bind to the GLP-1 receptors and are resistant to DPP-4 degradation. This results in increased insulin secretion, decreased glucagon secretion, and reduced gastric emptying.

Additional characteristics
  • Glycemic efficacy: reduce HbA1C by 0.5-1.5% over 3 months
  • Subcutaneous injection (except semaglutide which is also PO)
  • Weight loss
  • No risk of hypoglycemia
  • Cardiovascular benefit (MACE)
Adverse effects
  • Gastrointestinal symptoms
  • Pancreatitis and possibly pancreatic cancer
  • Potential risk of medullary thyroid cancer (evidence unclear)
Contraindications
  • Preexisting symptomatic GI motility disorders
  • Chronic pancreatitis or family history of pancreatic cancer
  • Personal or family history of medullary thyroid cancer
Examples

In order of effect magnitude:

  • Tirzepatide (GIP/GLP-1ra) (Mounjaro)
  • Semaglutide (Ozempic; Wegovy)
  • Liraglutide (Victoza; Saxenda)
  • Dulaglutide (Trulicity)
  • Exenatide (Byetta)
  • Lixisenatide (Adlyxine)

SGLT-2 inhibitors

Sodium-glucose cotransporter 2 inhibitors (gliflozins)

Mechanism of action

Reversible inhibition of SGLT-2 in the proximal tubule of the kidney. This decreases glucose reabsorption in the kidney resulting in glycosuria and polyuria.

Additional characteristics
  • Glycemic efficacy: reduces HbA1C by 0.6% over 3 months
  • Particularly effective for young, compliant patients without significant renal failure (even more-so with males due to reduced risk of UTI)
  • Promotes weight loss
  • Reduces blood pressure
  • Reduces cardiovascular risk in diabetics with cardiovascular disease (MACE)
    • Mortality benefits for CHF
    • Potential benefits for kidney disease
Adverse effects
  • UTIs, genetals infections due to glucosuria
  • Dehydration can cause weight loss and orthostatic hypotension
  • Severe diabetic ketoacidosis
  • May increase risk of lower limb amputation and bladder/breast cancer
Contraindications
  • Chronic kidney disease
  • Recurrent urinary tract infections
  • Peripheral arterial disease (relative due to risk of amputation)
Examples
  • Dapagliflozin (Forxiga)
  • Empagliflozin (Jardiance)
  • Canagliflozin (Invokana)

With metformin:

  • Dapagliflozin/metformin (Xigduo)
  • Empagliflozin/metformin (Synjardy)
  • Canagliflozin/metformin (Invokamet)

Alpha-glucosidase inhibitor

Not used in practice

Mechanism of action

Inhibits alpha-glucosidase, a brush border enzyme expressed by intestinal epithelial cells, which breaks down complex carbohydrates into simple sugars such as glucose.

Inhibition results in reduced carbohydrate breakdown and thus reduced glucose absorption.

Additional characteristics
  • Glycemic efficacy: reduce HbA1C by 0.8% over 3 months
  • No risk of hypoglycemia
  • Particularly effective for controlling postprandial blood glucose levels
Adverse effects
  • Gastrointestinal symptoms including flatulence and bloating due to degradation of undigested carbohydrates by intestinal bacteria
Contraindications
  • Severe renal failure
  • Inflammatory bowel disease
  • Conditions associated with malabsorption
Examples
  • Acarbose

Insulin secretagogue

Sulfonylureas

Mechanism of action

Blocks ATP-sensitive potassium channels of pancreatic beta-cells which depolarizes the cell membrane resulting in insulin secretion.

Extrapancreatic effects (decreased hepatic gluconeogenesis and increased peripheral insulin sensitivity) are suggested but evidence is unclear.

Additional characteristics
  • Glycemic efficacy: reduces HbA1c by 1.2% over 3 months
  • Not frequently used
  • Patients should not be overweight, do not drink alcohol, and adhere to consistent dietary routine
Adverse effects
  • Life-threatening hypoglycemia, particularly in cases of:
    • Simultaneous intake of CYP2C9 inhibitors
    • Renal failure
    • Decreased carbohydrate intake
    • Elevated glucose utilization
    • Sulfonylurea overdose
  • Alcohol intolerance (first-generation agents)
  • Weight gain
  • Hematological changes (granulocytopenia, hemolytic anemia)
  • Allergic skin reactions
  • Macrovascular cardiovascular complications associated
  • Beta-cell apoptosis
Contraindications
  • Beta blocker use
  • Severe cardiovascular comorbidity
  • Obesity
  • Sulfonamide allergy (eg. sulfa antibiotics, thiazide diuretics)
  • Severe liver and kidney failure
Examples

First generation:

  • Chlorpropamide
  • Tolbutamide
    Second generation:
  • Glyburide (Diabeta)
  • Gliclazide (Diamicron) - main one still used
  • Glimepiride (Amaryl)

Meglitinides

Not used in practice

Mechanism of action

Similar mechanism as sulfonylurea except binds at a different site at the beta-cells with lower affinity.

Additional characteristics
  • Glycemic efficacy: reduces HbA1C by 0.75% over 3 months
  • Lower affinity means shorter duration of action - should be taken shortly before meals
  • Tolerated well by patients with chronic kidney disease
Adverse effects
  • Life-threatening hypoglycemia, especially in patients with renal failure (but less risk than sulfonylurea use)
  • Weight gain
  • Hepatoxicity, rarely
Contraindications
  • Severe liver failure
  • Sulfonylurea use (increased risk of hypoglycemia)
Examples
  • Nateglinide (Starlix)
  • Repaglinide (Gluconorm)

Thiazolidinediones (TZDs)

Not used in practice - cardiovascular harm outweighs benefits

Mechanism of action

Activation of transcription factor PPARγ (peroxisome proliferator-activated receptor of gamma type) which increases transcription of genes involved in glucose and lipid metabolism. This results in:

  • Increased adipokine levels and insulin sensitivity
  • Increased storage of fatty acids in adipocytes
  • Reduced free fatty acids
  • Increased glucose utilization and hepatic glucose production
Additional characteristics
  • Glycemic efficacy: reduces HbA1C by 1% in 3 months
  • Possible monotherapy for patients with severe renal failure
  • Favourable effect on lipids (decrease triglycerides and LDL, increased HDL)
  • No risk of hypoglycemia
  • Onset of action is delayed by several weeks
Adverse effects
  • Increased risk of heart failure
  • Increased risk of bone fractures (osteoporosis)
  • Fluid retention and edema
  • Weight gain
  • Increased cardiovascular complications (rosiglitazone)
Contraindications
  • Congestive heart failure (NYHA III-IV)
  • Liver failure
  • History of bladder cancer or macrohematuria of unknown origin (pioglitazone)
Examples
  • Pioglitazone (Actos)
  • Rosiglitazone (Avandia)