Diabetes Management

  • 1) Insulin Sensitizers: Lower Glucose by their actions on the liver, muscle and adipose tissue
  • A) Biguanides
    • MOA: Increases hepatic AMPK, inhibits mitochondrial hepatic gluconeogenesis and lipogenesis, increases peripheral uptake
    • Reduces hepatic gluconeogenesis and glycogenolysis
    • Metformin (Glucophage)
    • 500mg once to twice daily or 850mg once daily
      • Double dose after 5-7 days if no GI SE
      • Max: 850mg BID or 1000mg BID, lower dose if GI SE
    • 1st line therapy for T2DM, works on the liver
      • Inhibits mGPD and Complex 1
    • Improves fasting and postprandial hyperglycemia and hypertriglyceridemia in obese w/DM w/o Weight gain
      • Decreases A1c by 0.7-1.5%
    • Potential ASCVD benefit
    • SE: Lactic Acidosis in renal/liver failure (alcohol misuse), diarrhea
      • 20% GI upset, nausea, vomiting, no hypoglycemia
      • 2/2 decreasing glucose absorption in the GI tract
      • B12 deficiency
      • Good for obese patients
    • CI: Acute Renal Failure, Liver Failure, Sepsis, GFR \<30
      • Stop 48hrs before being given contrast
  • B) Glitazones/Thiazolidinediones (TZD)
    • MOA: Bind PPPAR-gamma nuclear transcription regulator, agonists, sensitizing peripheral tissue to insulin and increasing adiponectin
    • Increased GLUT1 and GLUT4, decreased FFA, decreased hepatic glucose output, increase adiponectin, and decreased adipocyte resistance, no hypoglycemia
    • Works on muscle and adipose tissue
    • Used in combo with metformin = no hypoglycemia
    • Can reduce insulin dose up to 50%, but edema increases 10-15%
    • Receptors also found in the collecting tubule of the nephron and stimulate increased sodium resorption (similar to aldosterone)
      • May use spironolactone to treat
    • Rosiglitazone (Avandia)
    • SE: increase LDL (15%), total cholesterol, and HDL (10%), decrease FFA (8-15%), Angina or MI increase risk, edema
    • Pioglitazone (Actos)
    • Lowers TG (9%), and increases HDL (15%), edema
    • SE: Weight gain, fluid retention and CHF, Hepatotoxic
    • CI: NYHA Class III/IV, Liver dysfunction
    • Black box for HF increased risk
    • Generally, not used in CKD
  • 2) Secretagogues: Stimulate insulin secretion by binding the sulfonylurea receptor
  • A) Sulfonylureas
    • MOA: Closes K+ channels in pancreatic B cell membrane, causing the cell to depolarize, releasing insulin via increased Ca2+ influx
    • 1st Gen:
    • SE: Disulfram-like effects (Hyponatremia, flushing)
    • Chlorpropamide
    • Tolbutamide
    • Tolazamide
    • 2nd Gen:
    • 100x more potent, use in caution with CVD
      • Skip dose if pt too sick to eat (must be taken with meals, heavy sugar beverages, soda, juice, sweet tea)
    • Glimepiride (Amaryl)
    • Glipizide (Glucotrol)
      • CI: Liver failure
    • Glyburide (Diabeta)
      • CI: Liver disease, CKD
    • SE: Hypoglycemia (especially on an empty stomach), weight gain
    • Sulfonylurea poisoning
    • Treatment
      • Excessive amounts of Dextrose
      • Severe: Octreotide
  • B) Meglitinide analogs
    • MOA: Similar to Sulfonylureas, different binding site on Beta cell membrane
    • Take prior to meals
    • No sulfur moiety, no disulfram reaction
    • Repaglinide (Prandin)
    • SE: Hypoglycemia (worse with renal failure), WT gain
    • Nateglinide (Starlix)
    • D-Phenylalanine Derivative
    • Reduced postprandial risk in BP like Repaglinide
    • SE: Hypoglycemia (worse with renal failure), Wt gain
  • 3) Secretagogues: Mimic incretin effect or prolong incretin action
  • A) Glucagon-like peptide 1 (GLP1) receptor agonists
    • MOA: Increase glucose dependent insulin secretion, decreases glucagon release, delays gastric emptying, increases satiety
    • Mimic incretins
    • More potent than DPP-4 Inhibitors
    • Decrease food intake, increase insulin, decrease glucagon, decrease gastric emptying
    • Associated with weight loss
    • Now preferred over insulin for most patients when injectable therapy is indicated
    • Dulaglutide (Trulicity)
    • 3rd most weight loss
    • Exenatide (Byetta, Bydureon)
    • CI: GFR \<30
    • Liraglutide (Victoza)
    • 6mg subq once daily for a week, then 1.2mg daily
      • 340B @ CAMC
    • 2nd most weight loss
    • LEADER Trial
      • Has FDA indication for ASCVD benefit
      • Decreased CV death by 22%, ACM by 15%
    • Has shown CKD benefit
    • Lixenatide
    • Least weight loss
    • Reduces CV mortality, may reduce CKD
    • Semaglutide (Rybelsus, Ozempic)
    • Ozempic: 0.25mg weekly for 4 weeks, then 0.5mg weekly up to 2mg weekly
    • Rybelsus: 3mg oral tablet, once daily
      • Only oral GLP-1 available
    • Most weight loss of group
    • SE: Weight loss, Nausea/Vomiting, pancreatitis, weight loss
    • Lower risk of hypoglycemia, decrease CVD/MI/Stroke, decrease progression of albuminuria
    • Black box warning of increased risk of thyroid C-cell tumors
    • RCI: History of Pancreatitis
  • B) DPP4 Inhibitors
    • MOA: Inhibits DPP-4 enzyme that deactivates GLP-1
    • Block the degradation of GLP-1 and GIP, thereby increasing insulin
    • Can't be used with GLP-1s
    • Once daily, few SE
    • Linagliptin (Tradjenta)
    • No dose adjustment for renal failure
    • Saxagliptin (Onglyza)
    • Increased risk of HF (only one in class)
    • Sitagliptin (Januvia)
    • Alogliptin
    • Increased risk of HF (not used)
    • SE: weight neutral, mild urinary or respiratory infections, nasopharyngitis
    • Potential increased risk of HF, joint pain, increased risk of pancreatitis
  • 4) Slow intestinal absorption of glucose
  • A) Alpha-glucosidase inhibitors
    • MOA: Inhibits intestinal brush-border alpha-glucosidases, decreasing disaccharide absorption
    • Delayed carbohydrate hydrolysis and glucose absorption in the SI, increasing absorption in the large intesine
    • Decreases postprandial hyperglycemia
    • Acarbose (Precose)
    • Decreases postprandial hyperglycemia by 30-50%, decrease A1c by 0.5-1%, flatulence in 20-30%, abdominal pain
    • 3 times daily
    • Decreases intestinal CHO absorption
    • Miglitol (Glyset)
    • CI: Decreased renal function
    • SE: Diarrhea, Flatulence
  • 5) Inhibit reabsorption of filtered glucose in the kidney
  • A) Sodium glucose co-transporter 2 inhibitors (SGLT2 Inhibitors)
    • MOA: Blocks reabsorption of glucose in proximal convoluted tubule
    • Causes glucosuria, weight loss is common
    • Causes osmotic diuresis, decreasing BP
    • Decreases progression of renal disease, Decreases CVD and MI risk if ASCVD
      • May improve CKD, still do not use if GFR \<30
    • Canagliflozin (Invokana)
    • Has shown CKD benefit, decreased CV death by 38%, ACM by 32%, HF hospitalization by 35%
    • EMPA-REG Outcome Trail
    • Dapagliflozin (Farxiga)
    • Has shown CKD benefit
    • Empagliflozin (Jardiance)
    • Has shown CKD benefit
    • Has FDA indication for ASCVD benefit, improving HF outcomes
    • EMPEROR Trials
      • HFpEF: Improved outcomes/Hospitalizations/QOL, Not mortality, reduced instance of hyperkalemia
      • HFrEF: Improved outcomes/Hospitalizations, improved eGFR, reduced instance of hyperkalemia
    • Ertugliflozin (Steglatro)
    • Check Cr prior to initiation
    • Indication: Type 2 DM or ASCVD (or give GLP-1) with metformin
    • Careful in amputation, severe PVD, neuropathy, diabetic foot ulcers
    • SE: Increases glucosuria, weight loss, UTIs, Genital infections, vaginal yeast infections, hyperkalemia, dehydration, orthostatic hypotension, Fournier's gangrene, Triple risk of DKA (Euglycemic DKA), risk of lower limb infection/ulceration/amputations
    • Hold for 24hrs prior to surgery or extreme sports
    • Decreases risk of MI, stroke, CVD death
  • 6) Glucagon suppression and slowing gastric emptying
  • A) Amylin Analogs
    • Pramlintide (Symlin)
    • Delays gastric emptying and decreases glucagon
    • SE: hypoglycemia (always given with insulin), nausea/V
  • 7) Other
  • Aldose Reductase Inhibitors
    • Epalrestat
  • Colesevelam (Welchol)
  • Bromocriptine (Cycloset)
  • Sitagliptin/Metformin (Janumet)

Insulin Preparations

  • Fast Acting:
  • Lispro (Humalog), Aspart (Novolog), Glulisine (Apidra)
  • Peak: 0.5-1.5 hours
  • Duration: 3-5 hours
  • Peak coincides with food peak
  • Short Acting:
  • Regular Insulin (Humulin R, Novolin R)
  • Peak: 2-4 hours
  • Duration: 5-8 hours
  • Peak may follow food peak
  • Intermediate Acting:
  • NPH Insulin (Humulin N, Novolin N)
  • Peak: 4-12 hours
  • Duration: 14+ hours
  • Long Acting:
  • Detemir (Levemir)
    • Peak: 4-9 hours
    • Duration: 12-24 hours
    • May require BID administration
  • Glargine (Lantus)
    • Peak: None
    • Duration: 14+ hours
    • Peakless effect less likely to cause hypoglycemia
    • Formulations with higher concentrations of glargine (300 vs 100u/mL) have longer duration (30+ hours)
  • Ultra-Long Acting:
  • Degludec (Tresiba)
    • Peak: None
    • Duration: 42+ hours
    • Formation of a soluble hexamer at the injection site
  • Sliding Scale
  • No basal insulin given, only reactively
  • Good with Basal-Bolus patient with Sliding scale on top prn