34.2 Endocrine Pharmacology I: Diabetes Mellitus Drugs (Metformin, Sulfonylureas, SGLT2 Inhibitors, GLP-1 Agonists, DPP-4 Inhibitors, Thiazolidinediones, Insulins), Choosing Therapy by Comorbidity, DKA and HHS, and Hypoglycemia

Why this area matters

Diabetes is among the leading causes of death in the Philippines and a major cause of kidney failure, blindness and amputation. Board items test:

• how each drug works and its adverse effects;
• which drug to choose for a given comorbidity;
• safe insulin use;
• the emergency treatment of DKA, HHS and hypoglycemia.

Oral & Injectable Antidiabetic Therapeutics

• Metformin (Biguanide):
  • Mechanism: Activates AMP-activated protein kinase (AMPK) and inhibits mitochondrial glycerophosphate dehydrogenase. Decreases hepatic gluconeogenesis and glycogenolysis, increases peripheral insulin sensitivity and glucose uptake, and decreases intestinal glucose absorption.
  • Clinical Advantages: First-line oral therapy for Type 2 Diabetes; does not cause hypoglycemia (euglycemic agent); weight-neutral or modest weight loss; reduces cardiovascular morbidity.
  • Adverse Effects:
    1. Gastrointestinal Distress ($20\text{--}30\%$): Diarrhea, abdominal cramps, nausea, bloating (transient; minimized by slow titration and taking with meals).
    2. Vitamin B12 Deficiency: Long-term use impairs calcium-dependent ileal absorption of the B12-intrinsic factor complex, causing peripheral neuropathy and megaloblastic macrocytic anemia.
    3. Lactic Acidosis (Rare, but fatal in $50\%$ of cases): Metformin blocks hepatic conversion of lactate to glucose. Sepsis, hypoxemia, dehydration, shock, and renal failure trigger severe lactic acidosis.
    4. Renal Cutoffs: Do not initiate if $\text{eGFR} < 45\text{ mL/min/1.73m}^2$; permanently discontinue / strictly contraindicated if $\text{eGFR} < 30\text{ mL/min/1.73m}^2$. Withhold at the time of iodinated contrast in patients with eGFR below 30 or acute kidney injury, restarting after 48 hours once renal function is stable.
• Sulfonylureas (Glimepiride, Gliclazide, Glipizide):
  • Mechanism: Bind and close the sulfonylurea receptor-1 (SUR1) subunit of ATP-sensitive potassium channels ($K_{ATP}$) on pancreatic $\beta$-cell membranes. Membrane depolarization opens voltage-gated $Ca^{2+}$ channels, triggering exocytosis of preformed insulin granules.
  • Adverse Effects: Hypoglycemia (most common; long-acting glibenclamide/glyburide carries highest risk; glipizide and gliclazide are safer in elderly and renal impairment) and weight gain.
• SGLT2 Inhibitors (Empagliflozin, Dapagliflozin, Canagliflozin):
  • Mechanism: Selectively block the sodium-glucose cotransporter 2 in the renal proximal convoluted tubule, preventing glucose and sodium reabsorption, producing therapeutic glucosuria ($70\text{--}80\text{ g/day}$) and osmotic diuresis.
  • Benefits: Weight loss ($2\text{--}3\text{ kg}$), systolic blood pressure reduction ($3\text{--}5\text{ mmHg}$), robust preservation of renal function in CKD, and marked mortality reduction in heart failure.
  • Adverse Effects: Genital mycotic infections (vulvovaginal candidiasis, balanitis; due to urinary glucose fueling fungal growth), urinary tract infections, volume depletion/hypotension, and Euglycemic Diabetic Ketoacidosis (euDKA) (serum glucose $< 250\text{ mg/dL}$ with elevated anion gap metabolic acidosis and ketonemia; triggered by surgery, severe infection, or low-carbohydrate diets; withhold prior to scheduled surgery).
• GLP-1 Receptor Agonists (Semaglutide, Liraglutide, Dulaglutide):
  • Mechanism: Synthetic incretin mimetics resistant to dipeptidyl peptidase-4 (DPP-4) degradation. Stimulate glucose-dependent insulin secretion, suppress inappropriate postprandial glucagon secretion, delay gastric emptying, and centrally promote satiety.
  • Benefits: Exceptional HbA1c reduction, profound weight loss, and proven atherosclerotic cardiovascular disease (ASCVD) risk reduction.
  • Adverse Effects & Contraindications: Nausea, vomiting, diarrhea, acute pancreatitis. Strictly contraindicated in patients with a personal or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine Neoplasia type 2 (MEN 2).
• DPP-4 Inhibitors (Sitagliptin, Linagliptin, Vildagliptin):
  • Mechanism: Inhibit the DPP-4 enzyme, prolonging the half-life of endogenous GLP-1 and GIP; weight-neutral, negligible hypoglycemia risk.
  • Linagliptin Pearl: Linagliptin undergoes non-renal (fecal and biliary) elimination and requires no dosage adjustment across any stage of renal impairment.

Basal-Bolus Insulin Pharmacokinetics

• Rapid-Acting (Lispro, Aspart, Glulisine): Recombinant amino acid modifications prevent hexamer dimerization, promoting instantaneous monomeric absorption. Onset $10\text{--}15\text{ min}$, peak $1\text{ hr}$, duration $3\text{--}4\text{ hrs}$. Injected immediately before or with meals for postprandial glycemic coverage.
• Short-Acting (Regular Insulin): Native human zinc-insulin hexamers. Onset $30\text{--}60\text{ min}$, peak $2\text{--}3\text{ hrs}$, duration $6\text{--}8\text{ hrs}$. The standard insulin for intravenous infusion in Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS).
• Intermediate-Acting (NPH - Neutral Protamine Hagedorn): Complexed with protamine and zinc. Onset $1\text{--}2\text{ hrs}$, peak $4\text{--}8\text{ hrs}$, duration $12\text{--}18\text{ hrs}$. Cloudy suspension; erratic absorption prone to nocturnal hypoglycemia.
• Long-Acting (Glargine, Detemir, Degludec):
  • Glargine: Micro-precipitates in subcutaneous tissue at neutral physiological pH, slowly releasing insulin monomers; peakless, duration $24\text{ hrs}$.
  • Degludec: Forms soluble multi-hexamers, providing an ultra-flat basal profile with duration $> 42\text{ hrs}$.

Other glucose-lowering drugs

• Thiazolidinediones (pioglitazone):
  • PPAR-gamma agonists that improve insulin sensitivity;
  • cause weight gain, fluid retention and heart failure (contraindicated in NYHA III to IV heart failure), fractures and bladder cancer concerns;
  • do not cause hypoglycemia alone;
  • help fatty liver disease.
• Alpha-glucosidase inhibitors (acarbose):
  • delay intestinal carbohydrate absorption, lowering post-meal glucose;
  • cause flatulence and diarrhea;
  • hypoglycemia that occurs with combined drugs must be treated with glucose, not sucrose.
• Meglitinides (repaglinide): short-acting secretagogues taken with meals; they cause hypoglycemia.

Choosing therapy

• Lifestyle measures and metformin are the foundation unless contraindicated.
• Add drugs by comorbidity, independent of HbA1c:
  • established atherosclerotic cardiovascular disease: a GLP-1 receptor agonist or SGLT2 inhibitor with proven cardiovascular benefit;
  • heart failure: an SGLT2 inhibitor;
  • chronic kidney disease with albuminuria: an SGLT2 inhibitor (down to the approved eGFR), and finerenone in some patients;
  • obesity: a GLP-1 receptor agonist (semaglutide) or dual GIP/GLP-1 agonist (tirzepatide);
  • cost concerns: metformin, sulfonylureas (gliclazide) and human insulin are inexpensive and widely available in the Philippines.
• Targets:
  • HbA1c below 7% for most adults;
  • less strict (below 8%) for older adults with limited life expectancy or frequent hypoglycemia.
• Insulin is started when glucose is very high (HbA1c over 10% or symptoms of catabolism), and in type 1 diabetes, pregnancy and serious illness.
  • Start with basal insulin (about 10 units or 0.1 to 0.2 units/kg at night) and titrate by fasting glucose.
  • Add prandial insulin as needed.
• Insulin side effects are hypoglycemia, weight gain and lipohypertrophy, which is why injection sites are rotated.

DKA, HHS and hypoglycemia

• Diabetic ketoacidosis:
  1. IV fluids: isotonic saline 1 to 1.5 L in the first hour, then adjusted.
  2. Potassium:
     • if K is below 3.3 mmol/L, give potassium before insulin, because insulin drives potassium into cells;
     • if K is 3.3 to 5.2, add potassium to the fluids;
     • if K is above 5.2, recheck before adding it.
  3. Insulin: regular insulin infusion at about 0.1 units/kg/hour (with or without an initial bolus).
  4. Dextrose: add 5% dextrose when glucose falls to about 200 to 250 mg/dL, and continue insulin until the anion gap closes.
  5. Bicarbonate: only if pH is below 6.9.
  6. Transition to subcutaneous insulin, overlapping 1 to 2 hours before stopping the infusion.
  7. Treat the precipitant: infection, missed insulin, MI.
• Hyperosmolar hyperglycemic state:
  • older patients with type 2 diabetes;
  • very high glucose (often over 600 mg/dL) and high osmolality with little ketosis;
  • severe dehydration and confusion;
  • fluid replacement is the priority, followed by lower-dose insulin, potassium replacement and a slow fall in osmolality to avoid cerebral edema.
• Hypoglycemia (glucose below 70 mg/dL; severe if help is needed):
  • conscious: 15 to 20 g of fast-acting carbohydrate (glucose tablets, juice, candy), recheck in 15 minutes and repeat, then a snack;
  • unconscious: IV dextrose (D50 in adults, D10 in children) or glucagon IM, SC or intranasal;
  • sulfonylurea-induced hypoglycemia may recur for many hours, so the patient is admitted for observation, and octreotide may help;
  • beta-blockers mask tremor and palpitations, but not sweating;
  • alcohol impairs gluconeogenesis.