STEPTRACKERPHARMACOLOGY + ENDOCRINOLOGY | ENDOCRINE | HIGH-YIELD REVIEW

Diabetes Drugs

Glucose-lowering drugs either supply insulin, make the body release or respond to more of it, or get rid of glucose another way — and only some cause hypoglycemia.

FOCUS ON
Insulins: rapid (lispro, aspart, glulisine), short (regular — only one given IV: DKA, hyperkalemia), intermediate (NPH), long (glargine, detemir, degludec). Adverse: hypoglycemia, hypokalemia, weight gain, lipodystrophy. Metformin (first-line T2DM): ↓ hepatic gluconeogenesis, ↑ insulin sensitivity (AMPK); no hypoglycemia, weight neutral; GI upset, B12 deficiency, lactic acidosis (hold with eGFR < 30, contrast, hypoxia). Sulfonylureas (glipizide, glyburide, glimepiride): close β-cell KATP → insulin release; hypoglycemia, weight gain. Meglitinides: same, short. TZDs (pioglitazone): PPAR-γ; weight gain, edema/HF, fractures, bladder cancer. GLP-1 agonists (semaglutide, liraglutide, dulaglutide; tirzepatide = GIP + GLP-1): weight loss, ↓ CV events; nausea, pancreatitis, medullary thyroid cancer (MEN2). DPP-4 inhibitors (-gliptins): weight neutral. SGLT2 inhibitors (-gliflozins): glycosuria; ↓ HF and CKD progression; UTIs, genital yeast, euglycemic DKA, Fournier gangrene. α-glucosidase inhibitors (acarbose): flatulence. Pramlintide (amylin).
CLASS · DRUGS
MECHANISM
ADVANTAGES
ADVERSE
Rapid/short insulin
lispro, aspart, regular
Exogenous insulin → GLUT4 uptake, ↓ gluconeogenesis, K⁺ into cells
Mealtime coverage; regular IV for DKA, HHS, hyperkalemia
Hypoglycemia, hypokalemia
Basal insulin
NPH, glargine, detemir, degludec
Steady background insulin
T1DM, advanced T2DM
Nocturnal hypoglycemia (NPH peaks), weight gain
Metformin
Biguanide: ↓ hepatic gluconeogenesis (AMPK, mitochondrial effects), ↑ peripheral uptake
First-line; no hypoglycemia; weight neutral/loss; PCOS
Diarrhea, B12 deficiency, lactic acidosis (renal failure, sepsis, contrast)
Sulfonylureas
glipizide, glyburide, glimepiride
Close KATP channel → depolarize β cell → Ca²⁺ → insulin release
Cheap, potent
Hypoglycemia (glyburide in elderly/renal), weight gain; disulfiram-like (1st gen)
Meglitinides
repaglinide, nateglinide
KATP closure, short-acting
Postprandial; sulfa allergy
Hypoglycemia
Thiazolidinediones
pioglitazone, rosiglitazone
PPAR-γ agonist → ↑ insulin sensitivity, adiponectin
No hypoglycemia; NASH benefit
Weight gain, edema, HF, fractures, hepatotoxicity, bladder cancer
GLP-1 receptor agonists
semaglutide, liraglutide, exenatide
↑ Glucose-dependent insulin, ↓ glucagon, slow gastric emptying, satiety
Weight loss, ↓ MACE, injectable or oral
Nausea, pancreatitis, gallstones, medullary thyroid carcinoma (MEN2 contraindication)
Tirzepatide
Dual GIP + GLP-1 agonist
Large weight and A1c reduction
GI effects
DPP-4 inhibitors
sitagliptin, saxagliptin, linagliptin
Block incretin breakdown → ↑ GLP-1, GIP
Oral, weight neutral
Nasopharyngitis, pancreatitis, joint pain; saxagliptin HF
SGLT2 inhibitors
empagliflozin, dapagliflozin, canagliflozin
Block proximal-tubule glucose reabsorption
↓ HF hospitalization, ↓ CKD progression, weight loss
Genital mycotic infections, UTI, euglycemic DKA, volume depletion, Fournier gangrene
α-Glucosidase inhibitors
acarbose, miglitol
↓ Brush-border carbohydrate digestion
Postprandial glucose
Flatulence, diarrhea; treat their hypoglycemia with glucose, not sucrose
Pramlintide
Amylin analog → ↓ glucagon, slow emptying
T1 and T2 on insulin
Hypoglycemia with insulin, nausea
Glucagon
Hepatic glycogenolysis
Severe hypoglycemia, β-blocker overdose
Needs glycogen stores

Picture it — insulin time-action profiles

insulin effect06121824hours after injectionrapid (lispro)regularNPHglargine
How long each insulin worksRapid analogs peak within about an hour and cover meals; regular insulin peaks at 2–4 hours (and is the one given IV); NPH peaks around 6–10 hours, the source of nocturnal lows; glargine gives a flat basal level for about a day.

Schematic diagrams, not to scale.

Mechanism — how sulfonylureas trigger release

Glucose → ATP in β cell
→
KATP closesSulfonylureas close it directly
→
Depolarization → Ca²⁺ influx
→
Insulin release even if glucose low→ hypoglycemia

Diazoxide opens the same channel → used for insulinoma.

Weight and hypoglycemia

DRUG
WEIGHT
HYPO RISK
Insulin, SU, TZD
↑
Yes (not TZD)
Metformin, DPP-4i
Neutral
No
GLP-1 RA, SGLT2i
↓
No

How it's tested

COMMON CONFUSIONDKA on an SGLT2 inhibitor can occur with nearly normal glucose — check ketones and the anion gap.
THE TRAPHold metformin before iodinated contrast or in acute kidney injury, shock or hypoxia — lactate accumulates.
YOUR APPROACHT2DM → metformin → add by comorbidity: ASCVD (GLP-1 RA), HF or CKD (SGLT2i), obesity (GLP-1 RA/tirzepatide), cost (SU).

If you see… think…

Insulin type for IV use → regular insulin
Diabetes drug causing B12 deficiency → metformin
Lactic acidosis after contrast CT → metformin
Weight gain, edema, HF exacerbation → pioglitazone
Diabetes drug contraindicated with MEN2 history → GLP-1 receptor agonist
Vulvovaginal candidiasis on new diabetes pill → SGLT2 inhibitor
Hypoglycemia in elderly with CKD on oral agent → glyburide
Flatulence on diabetes drug → acarbose
DKA with glucose 180 mg/dL → SGLT2 inhibitor (euglycemic DKA)
Drug opening KATP for insulinoma → diazoxide