Diabetes Management

Categories:

  • 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

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