Updated: 12/21/2019

Diabetes Drugs

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  • Snapshot
    • A 45-year-old woman comes to her primary care physician complaining of pain with urination. She thinks she has a urinary tract infection. She states that this would be the 5th time in the past 3 months. The patient has poorly controlled type II diabetes mellitus. She had a hernia repair as a child. She takes metformin and danagliflozin. Her mother had end stage kidney disease. (Adverse effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors)
  • Introduction
    • Drugs
      • 10 classes
    • Mechanism of action
      • depends on class
      • Overview of Diabetes Drugs
      • Class
      • Example
      • ↑ Insulin secretion
      • ↑ Insulin utilization
      • ↓ Glucose production
      • Glucose absorption/ excretion
      • Weight
      • Hypoglycemia
      • Insulin
      • Insulin
      • ++
      • Biguanides
      • Metformin
      • +
      • ++
      • None
      • Sulfonylureas
      • Glyburide
      • ++ (glucose independent)
      • +
      • +
      • ++
      • Meglitinides
      • Repaglinide
      • ++ (glucose independent)
      • +
      • Glitazones (thiazolidinediones)
      • Pioglitazone
      • ++
      • +/-
      • +
      • Glucagon-like peptide-1 (GLP-1) mimetics (incretin mimetics)
      • Exenatide
      • ++ (glucose dependent)
      • +
      • +
      • Gipeptidyl peptidase-4 (DPP-4) inhibitors
      • Sitagliptin
      • ++ (glucose dependent)
      • +
      • Sodium-glucose co-transporter-2 (SGLT-2) inhibitors
      • Dapagliflozin
      • ↑ Excretion
      • None
      • None
      • α-glucosidase inhibitors
      • Acarbose
      • ↓ Absorption
      • None
      • None
      • Amylin analog
      • Pramlintide
      • +
      • +
      • +
    • Adverse effects
      • contraindicated during pregnancy and breastfeeding
        • except insulin
        • except metformin in some cases
      • hypoglycemia
        • combination therapy increases risk
        • increased risk when used peri-operatively
          • due to irregular food intake and fasting
  • Insulin
    • Drugs
      • have differing onsets, peaks, and durations of action based on preparation
      • Preparation
      • Onset
      • Peak
      • Duration
      • Lispro, aspart, and glulisine (rapid-acting)
      • ~15 min
      • 30 min-2 hr
      • 3-4 hrs
      • Regular (short-acting)
      • ~30 min-1 hr
      • 2-5 hr
      • 4-12 hr
      • NPH (intermediate)
      • 1-2 hr
      • 6-12 hr
      • 14-24 hr
      • Glargine and detemir (long-acting)
      • 2-4 hr
      • Flat
      • ~24 hr
    • Mechanism of action
      • binds transmembrane insulin receptor
        • activates tyrosine kinase phosphorylate specific substrates in each tissue type
      • liver
        • ↑ glycogenesis
          • converts glucose to glycogen as storage
        • ↓ glycogenolysis
        • ↓ gluconeogenesis
      • muscle
        • ↑ uptake of glucose
        • ↑ glycogen and protein synthesis
        • ↑ K+ uptake
      • adipose tissue
        • ↑ lipid synthesis
          • increase triglyceride storage
    • Clinical use
      • given parenterally (subcutaneous (SQ) or intravenous (IV))
        • often the easiest to titrate during acute illness or infection, though caution should still be used
      • type I diabetes mellitus (DM)
      • type II DM
        • if weight loss, exercise, and oral antidiabetics are not sufficient
        • if patient has end stage renal disease (ESRD)
      • gestational diabetes
      • life-threatening hyperkalemia
        • increases intracellular K+
      • steroid-induced hyperglycemia
    • Adverse effects
      • hypoglycemia
      • weight gain
      • hypokalemia
      • early morning hyperglycemia
        • with evening insulin
          • due to negative feedback from nocturnal hypoglycemia (i.e., glucagon stimulation)
      • lipodystrophy at injection site
      • hypersensitivity reaction (very rare)
  • Biguanides
    • Drugs
      • metformin
    • Mechanism of action
      • ↓ gluconeogenesis
        • exact mechanism unknown
      • ↑ intestinal glucose absorption
        • ↓ postprandial glucose levels
      • may also
        • ↑ insulin sensitivity
        • ↑ glycolysis
        • ↓ low-density lipoprotein (LDL) and ↑ high-density lipoprotein (HDL)
    • Clinical use
      • first-line for type II DM
    • Adverse effects
      • no hypoglycemia
      • possible weight loss
      • nausea, vomiting, and gastrointestinal symptoms
      • lactic acidosis
        • high-risk in elderly and renal insufficiency
      • contraindications
        • chronic kidney disease
        • liver failure
        • chronic pancreatitis
        • sepsis
  • Sulfonylureas
    • Drugs
      • first generation
      • second generation
        • glyburide
          • long half-life
        • glimepiride
        • glipizide
          • short half-life
    • Mechanism of action
      • glucose normally triggers insulin release from pancreatic β cells by increasing intracellular ATP
        • → closes K+ channels → depolarization → ↑ Ca2+ influx → insulin release
      • sulfonylureas mimic action of glucose by closing K+ channels in pancreatic β cells
        • → depolarization → ↑ Ca2+ influx → insulin release
      • continued use results in
        • ↓ glucagon release
        • ↓ hepatic gluconeogenesis
        • ↑ insulin sensitivity in muscle and liver
    • Clinical use
      • type II DM
        • stimulate release of endogenous insulin
      • cannot be used in type I DM due to complete lack of islet function
    • Adverse effects
      • disulfiram-like effects/alcohol intolerance
      • hypoglycemia
      • weight gain
      • granulocytopenia and hemolytic anemia
      • contraindicated
        • kidney failure
        • liver failure
        • sulfonamide allergy
        • severe cardiovascular disease
  • Meglitinides (Sulfonylurea Analogs)
    • Drugs
      • repaglinide
      • nateglinide
    • Mechanism of action
      • similar to sulfonylureas
      • increase insulin secretion
    • Clinical use
      • consider repaglinide in chronic kidney disease
    • Adverse effects
      • hypoglycemia
        • more short-acting than sulfonylureas, so less risk
      • weight gain
      • hepatotoxicity
      • contraindications
        • liver failure
        • severe renal failure
        • don’t use with sulfonylureas
  • Glitazones (Thiazolidinediones)
    • Drugs
      • pioglitazone
      • rosiglitazone
    • Mechanism
      • bind and activate to nuclear receptors involved in transcription of genes mediating insulin sensitivity
        • peroxisome proliferator-activating receptors (PPARs)
        • increase transcription of genes involving glucose and lipid metabolism
      • ↑ insulin sensitivity in peripheral tissue
      • ↓ gluconeogenesis
      • ↑ insulin receptor numbers
      • ↓ triglycerides
    • Clinical use
      • consider in severe renal failure
    • Adverse effects
      • less risk of hypoglycemia
      • weight gain
      • edema
      • cardiotoxicity
      • osteoporosis
      • contraindications
        • liver failure
        • severe congestive heart failure
        • history of bladder cancer/active bladder cancer
          • for pioglitazone
  • GLP-1 Analogs
    • Drugs
      • exenatide
      • liraglutide
      • albiglutide
    • Mechanism of action
      • GLP-1 agonist
        • GLP-1 is an incretin normally released from the small intestine that aids glucose-dependent insulin secretion
          • ↑ insulin
          • ↓ glucagon release
          • slow gastric emptying
          • increase satiety
      • GLP-1 normally degraded by DPP-4, but incretin mimetics are resistant to degradation
    • Clinical use
      • type II DM
        • patients requiring 2 drugs and looking to lose weight
          • e.g., metformin and exenatide
    • Adverse effects
      • weight loss
      • no risk of hypoglycemia
      • gastrointestinal complaints
      • pancreatitis and pancreatic cancer
      • contraindications
        • higher risk of hypoglycemia if given with sulfonylureas
        • gastrointestinal motility disorders
        • gastroparesis
  • DPP-4 Inhibitors (-gliptins)
    • Drugs
      • sitagliptin
      • saxagliptin
    • Mechanism of action
      • inhibit DPP-4, which normally breaks down GLP-1
        • indirectly increases endogenous incretin
        • ↑ insulin
        • ↓ glucagon release
        • slow gastric emptying
        • increase satiety
    • Adverse effects
      • gastrointestinal complaints
      • arthralgia
      • increased risk of pancreatitis
      • contraindications
        • severe renal failure
        • liver failure
  • SGLT-2 Inhibitors (-gliflozins)
    • Drugs
      • canagliflozin
      • dapagliflozin
      • empagliflozin
    • Mechanism of action
      • inhibits sodium-dependent glucose co-transporter in proximal tubule of kidney
        • ↓ glucose reabsorption in kidney
        • ↑ glycosuria
    • Clinical use
      • consider in young males
        • less risk of urinary tract infections
    • Adverse effects
      • weight loss
      • reduces blood pressure
      • urinary tract infections
      • genital infections (i.e., yeast infection)
      • polyuria
      • dehydration
      • severe diabetic ketoacidosis
      • contraindications
        • chronic kidney disease
        • anatomical or functional urinary tract anomalies
  • α-Glucosidase Inhibitors
    • Drugs
      • acarbose
      • miglitol
    • Mechanism of action
      • inhibits α-glucosidases in intestinal brush border
        • delayed sugar hydrolysis
        • delayed intestinal glucose absorption
        • ↓ postprandial hyperglycemia
        • ↓ insulin demand
    • Clinical use
      • type II DM
        • as monotherapy or in combination with other agents
    • Adverse effects
      • no hypoglycemia
      • gastrointestinal upset
        • undigested carbohydrates ends up in colon
          • degraded by intestinal bacteria
          • results in increase in flatulence and diarrhea
      • contraindications
        • inflammatory bowel disease
        • other malabsorption disorders
        • severe renal failure
  • Amylin Mimetics
    • Drugs
      • pramlintide
    • Mechanism of action
      • synthetic analogue of human amylin that acts in conjunction with insulin
        • basis for drug mechanism is the observation that more insulin is secreted with oral glucose load compared to intravenous
      • ↓ release of glucagon
      • delay gastric emptying
      • increase satiety
    • Clinical use
      • type I and II DM
    • Adverse effects
      • hypoglycemia
        • especially if given with insulin
      • gastrointestinal complaints
      • contraindications
        • gastroparesis

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Questions (2)

(M2.EC.17.4768) A 43-year-old female presents to her endocrinologist for a new patient appointment. She initially presented three months ago as a referral for a new diagnosis of type II diabetes mellitus. At that time, her HbA1c was found to be 8.8%, and she was started on metformin. Her metformin was quickly uptitrated to the maximum recommended dose. At the same visit, her body mass index (BMI) was 31 kg/m^2, and the patient was counseled on the importance of diet and exercise for achieving better glycemic control. Today, the patient reports complete adherence to metformin as well as her other home medications of atorvastatin and lisinopril. She also started a daily walking routine and has lost two pounds. Her HbA1c today is 7.6%, and her BMI is stable from her last visit. The patient is discouraged by her slow weight loss, and she would like to lose an additional 5-10 pounds.

Which of the following would be the best choice as a second agent in this patient?

QID: 109069
1

Exenatide

53%

(19/36)

2

Glipizide

19%

(7/36)

3

Repaglinide

8%

(3/36)

4

Pioglitazone

11%

(4/36)

5

Sitagliptin

6%

(2/36)

M 7 E

Select Answer to see Preferred Response

(M2.EC.17.4872) A 72-year-old man presents to the emergency department for a change in his behavior. The patient's wife called 911 and he was brought in by emergency medical services. She noticed that he seemed somnolent and not very responsive. The patient has a past medical history of type II diabetes, obesity, osteoarthritis, and migraine headaches. His current medications include naproxen, insulin, atorvastatin, metformin, ibuprofen, omeprazole, and fish oil. His temperature is 99.5°F (37.5°C), blood pressure is 170/115 mmHg, pulse is 80/min, respirations are 19/min, and oxygen saturation is 98% on room air. On physical exam, the patient is somnolent and has a Glasgow Coma Scale of 11. Cardiac and pulmonary exams are notable for bibasilar crackles and a systolic murmur that radiates to the carotids. Neurological exam is deferred due to the patient's condition. Laboratory values are shown below.

Hemoglobin: 12 g/dL
Hematocrit: 36%
Leukocyte count: 9,500 cells/mm^3 with normal differential
Platelet count: 199,000/mm^3

Serum:
Na+: 144 mEq/L
Cl-: 98 mEq/L
K+: 4.0 mEq/L
HCO3-: 16 mEq/L
BUN: 44 mg/dL
Glucose: 202 mg/dL
Creatinine: 2.7 mg/dL
Ca2+: 9.2 mg/dL
AST: 12 U/L
ALT: 22 U/L

The patient is started on IV fluids. Which of the following represents the best next step in management?

QID: 109549
1

Insulin

14%

(7/51)

2

Potassium

2%

(1/51)

3

Bicarbonate

2%

(1/51)

4

Insulin and potassium

37%

(19/51)

5

Discontinue the patient's home medications

45%

(23/51)

M 7 C

Select Answer to see Preferred Response

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