Non-insulinotropic Diabetes Medications

Non-insulinotropic diabetes medications are used to treat type 2 diabetes by methods other than increasing insulin secretion. This group of medications includes the biguanides, thiazolidinediones, alpha-glucosidase inhibitors, sodium–glucose transport protein 2 inhibitors, and amylin analogs. Mechanisms of action vary, but they can include increasing peripheral insulin sensitivity, reducing glucagon release, inhibiting gluconeogenesis, slowing glucose absorption, and increasing satiety. Metformin is the initial medication of choice; others may be used as an alternative monotherapy or as adjunctive therapy. Most of these medications are not associated with severe hypoglycemia, except for amylin analogs or when medications are used in conjunction with other hypoglycemic agents.

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Overview

Diabetes mellitus, type 2

  • Caused by: 
    • Peripheral insulin resistance: cell insulin receptors do not respond appropriately to insulin
    • Beta-cell dysfunction: long-term ↑ in insulin demand → defective insulin secretion
  • Results in hyperglycemia
  • Pharmacologic management can target:
    • Insulin release
    • Insulin resistance
    • Glucagon release
    • Gluconeogenesis
    • Glucose uptake

Classification

Hyperglycemic medications can be classified on the basis of their mechanism of action: 

Insulinotropic drugs: ↑ insulin secretion

  • Sulfonylureas
  • Meglitinides
  • Glucagon-like peptide-1 (GLP-1) analogs
  • DPP-4 inhibitors

Non-insulinotropic drugs: do not affect insulin release 

  • ↓ Insulin resistance:
    • Biguanides
    • Thiazolidinediones (TZDs)
  • ↓ Glucose absorption/reabsorption:
    • Alpha-glucosidase inhibitors
    • Sodium–glucose transport protein 2 (SGLT2) inhibitors
  • ↓ Gastric emptying and glucagon secretion: amylin analogs

Biguanides

Metformin is the only available medication in the biguanide drug class.

Pharmacodynamics

  • The mechanism of action for metformin is not well understood, but it appears to help in the management of type 2 diabetes by:
    • ↓ Gluconeogenesis in:
      • Liver
      • Kidneys
    • ↓ GI glucose absorption
    • ↓ Insulin resistance
    • ↑ Uptake of glucose by:
      • Muscle
      • Adipose tissue
  • Physiologic effect:
    • Fasting and postprandial glucose
    • Weight stabilization or reduction
    • LDL 
    • HDL
Graphic summarizing the actions of metformin

Graphic summarizing the actions of metformin

Image by Lecturio.

Pharmacokinetics

  • Absorption: oral
  • Distribution:
    • Concentrates in:
      • Liver
      • Kidneys
      • GI tract
    • Negligible protein binding
  • Excretion: by the kidneys (unmetabolized)

Indications

  • Type 2 diabetes:
    • Drug of choice for most cases
    • Well tolerated
    • Low cost 
    • No risk of hypoglycemia with monotherapy
  • Polycystic ovary syndrome (no longer 1st-line treatment)

Adverse effects

  • GI effects (improves with dose reduction or discontinuation):
    • Metallic taste
    • Diarrhea 
    • Anorexia 
    • Nausea and vomiting
  • Lactic acidosis:
    • Rare
    • Common in individuals with concurrent renal and hepatic disease
    • Due to impairment of lactic acid metabolism in hepatocytes → released in bloodstream
  • Vitamin B12 deficiency
    • Occurs during long-term therapy 
    • Due to ↓ GI absorption of vitamin B12
    • Rarely results in megaloblastic anemia

Contraindications

  • Severe renal disease
  • History of lactic acidosis
  • Severe hepatic dysfunction
  • Diabetic ketoacidosis
  • Avoid use:
    • Surgery
    • Iodinated contrast agents 
    • Hypoperfusion states

Drug interactions

Drugs associated with increased metformin toxicity:

  • Ethanol
  • Iodinated contrast agents
  • Topiramate

Thiazolidinediones

Medications in this class

  • Pioglitazone
  • Rosiglitazone

Pharmacodynamics

  • Work on:
    • Muscle
    • Adipose tissue
  • Ligands of peroxisome proliferator–activated receptors (PPARs)
  • Activation of PPARs → ↑ transcription of genes involved in: 
    • Lipid and glucose metabolism
    • Insulin signal transduction
    • Adipocyte and other tissue differentiation
  • ↑ Insulin sensitivity → ↑ glucose uptake and utilization
TZD mechanism of action Non-insulinotropic Diabetes Medications

Thiazolidinediones (TZDs) work in adipocytes by binding peroxisome proliferator–activated receptor gamma (PPARG). Peroxisome proliferator–activated receptor gamma combines with retinoid X receptor (RXR) to facilitate transcription of multiple genes related to glucose utilization and metabolism.

Image by Lecturio.

Pharmacokinetics

  • Absorption: 
    • Well absorbed orally
    • Delayed onset of action
  • Distribution: highly protein-bound
  • Metabolism: 
    • Extensive hepatic metabolism
    • Cytochrome P450 system
    • Pioglitazone has active metabolites.
  • Excretion: 
    • Pioglitazone: mostly in feces
    • Rosiglitazone: mostly in urine

Indications

TZDs are used for the treatment of type 2 diabetes:

  • Not generally used in initial therapy
  • More often used as 2nd- or 3rd-line therapy
  • Can be combined with other agents
  • Pioglitazone is useful in individuals with concurrent nonalcoholic steatohepatitis (NASH).

Adverse effects

  • Weight gain:
    • Adipocyte proliferation
    • Fluid retention
  • ↑ Risk of congestive heart failure and cardiovascular events (especially with rosiglitazone)
  • Bone demineralization and ↑ fragility 
  • Hepatotoxicity
  • Possible ↑ bladder cancer risk (pioglitazone)

Contraindications

  • Class III or IV congestive heart failure
  • Liver failure

Drug interactions

  • ↑ Hypoglycemic effect:
    • Other antidiabetic medications
    • Androgens
    • Direct-acting antiviral agents
    • Antidepressants
  • Fluid retention: 
    • Pregabalin
    • Insulin
  • ↑ Risk of ischemic events:
    • Vasodilators
    • Insulin

Alpha-Glucosidase Inhibitors

Medications in this class

  • Acarbose 
  • Miglitol

Pharmacodynamics

  • Alpha glucosidases: 
    • Intestinal brush border enzymes 
    • Convert carbohydrates → monosaccharides 
    • Only monosaccharides can be transported from the gut lumen → bloodstream
  • Competitive inhibition → ↓ carbohydrate digestion in the proximal small intestine → deferred to distal small intestine
  • Results in slowed glucose absorption → ↓ post-meal glycemic excursion
Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors competitively inhibit enzymes used to convert carbohydrates to monosaccharides (such as glucose) in the proximal small intestine. This process defers digestion to the distal small intestine, slowing glucose absorption and blunting postprandial blood glucose spikes.

Image by Lecturio.

Pharmacokinetics

  • Absorption:
    • Acarbose: most is not absorbed
    • Miglitol: completely absorbed
  • Metabolism:
    • Acarbose: degraded in the intestine by bacteria and digestive enzymes
    • Miglitol: none
  • Excretion:
    • Acarbose: mostly in feces
    • Miglitol: mostly in urine

Indications

Alpha-glucosidase inhibitors are used to treat type 2 diabetes as either:

  • Monotherapy (generally not 1st-line)
  • Adjunctive therapy

Adverse effects

  • GI discomfort (due to fermentation of undigested carbohydrates in the colon):
    • Flatulence
    • Bloating
    • Diarrhea
    • Abdominal pain
  • ↑ Liver enzymes

Contraindications

  • Renal impairment
  • Hepatic impairment
  • GI motility disease
  • Predisposition to bowel obstruction
  • Inflammatory bowel disease

Sodium–glucose transport protein 2 (SGLT2) Inhibitors

Medications in this class

  • Dapagliflozin
  • Empagliflozin 
  • Canagliflozin 
  • Ertugliflozin

Pharmacodynamics

  • SGLT2:
    • Located in the proximal tubule 
    • Responsible for glucose reabsorption
  • Inhibition of SGLT2 → ↓ reabsorption of filtered glucose
  • Result: ↑ urinary glucose excretion and ↓ blood glucose level
Non-insulinotropic Diabetes Medications

Sodium–glucose transport protein 2 (SGLT2) is expressed in the proximal tubule:
Sodium–glucose transport protein 2 is responsible for reabsorption of approximately 90% of filtered glucose. Glucose is normally imported into the proximal renal tubular cell with a sodium ion. This ion is driven by Na efflux out of the cell by the Na+/K+-ATPase (green circle). Glucose exits from the cell into the bloodstream through glucose transporter 2 (GLUT2).
Inhibition of SGLT2 results in increased renal excretion of glucose, thus lowering blood glucose levels.

Image by Lecturio.

Pharmacokinetics

  • Absorption: rapid oral absorption
  • Distribution: protein-bound
  • Metabolism:
    • Hepatic
    • Glucuronidation
    • Minimal cytochrome P450–mediated metabolism
  • Excretion: in urine and feces

Indications

Sodium–glucose transport protein 2 inhibitors are used for the treatment of type 2 diabetes:

  • Adjunctive therapy
  • Not typically used as initial therapy
  • Help with weight loss
  • Potential morbidity and mortality benefit for individuals with cardiovascular and renal comorbidities

Adverse effects

  • Glucosuria → ↑ risk of genitourinary tract infections
  • Osmotic diuresis leads to:
    • Polyuria
    • Hypovolemia
    • Hypotension
    • AKI
  • ↑ Risk of fractures
  • ↑ Risk of diabetic ketoacidosis

Contraindications

  • Severe renal impairment (less effective)
  • Frequent urinary tract infections
  • Type 1 diabetes
  • Diabetic ketoacidosis

Amylin Analogs

Pramlintide is the only medication in the amylin analog class.

Pharmacodynamics

  • Amylin is usually cosecreted with insulin by beta cells in the pancreas.
  • This secretion is deficient in type 1 diabetes and relatively deficient in type 2 diabetes.
  • Analogs help with glucose control by:
    • Slowing gastric emptying and ↑ satiety → ↓ food intake
    • ↓ Postprandial glucagon secretion
Amylin effects

The function of amylin in glucose regulation:
Amylin is a peptide that is normally released by pancreatic beta cells in conjunction with insulin. There is a deficiency of amylin in diabetes, so analogs can be given to promote satiety, slow gastric emptying, and decrease inappropriate glucagon secretion.

Image by Lecturio.

Pharmacokinetics

  • Absorption: given as a subcutaneous injection
  • Metabolism:
    • Renal
    • Active metabolite
  • Excretion: in urine

Indications

  • Used in types 1 and 2 diabetes
  • Individuals should be on prandial insulin.
  • Administered immediately prior to meals

Adverse effects

  • Nausea and vomiting
  • Anorexia
  • Hypoglycemia (usually in type 1 diabetes)

Contraindications

  • Gastroparesis
  • Hypoglycemia unawareness

Drug interactions

  • ↑ Hypoglycemic effect with other antidiabetic medications
  • May delay absorption of oral medications

Comparison of Antidiabetic Medications

The following table compares the different (noninsulin) type 2 diabetes mellitus medications:

Table: Comparison of different (noninsulin) type 2 diabetes mellitus medications
DrugMechanismIndicationsAdverse effects
Sulfonylureas
  • Act on K channels of beta cells
  • ↑ Insulin release
  • Adjunctive therapy
  • Severe hyperglycemia (if contraindications to other agents)
  • Hypoglycemia
  • Weight gain
  • Disulfiram-like reaction
  • Hepatitis
  • Hemolytic anemia
Meglitinides
  • Adjunctive therapy
  • Can replace sulfonylureas in individuals with an allergy
  • Hypoglycemia
  • Weight gain
  • Respiratory tract infections
GLP-1 agonists
  • Incretin mimetic
  • Acts on beta and alpha cells
  • ↑ Insulin release
  • ↓ Glucagon release
  • ↓ Gastric emptying and appetite
  • Adjunctive therapy
  • Weight management
  • Nausea and vomiting
  • Diarrhea
  • Pancreatitis
  • Kidney injury
DPP-4 inhibitors
  • Prevents breakdown of GLP-1
  • ↑ Insulin release
  • ↓ Glucagon release
Adjunctive therapy
  • Nasopharyngitis
  • Arthralgia
  • Hepatic dysfunction
  • Pancreatitis
Biguanides
  • ↓ Insulin resistance
  • ↓ Gluconeogenesis
  • Drug of choice
  • Can be used as monotherapy
  • GI symptoms
  • Lactic acidosis
  • Vitamin B12 deficiency
Thiazolidinediones
  • Activation of PPARs
  • ↑ Transcription of genes for lipid and glucose utilization
  • ↓ Insulin resistance
  • Adjunctive therapy
  • Pioglitazone: concurrent NASH
  • Weight gain/fluid retention
  • Cardiovascular events
  • Hepatotoxicity
  • Osteoporosis
Alpha-glucosidase inhibitors
  • Inhibit conversion of carbohydrates to monosaccharides
  • Slowed glucose absorption
  • ↓ Postprandial glucose excursionxs
  • Can be used as monotherapy (not 1st-line)
  • Adjunctive therapy
  • GI symptoms
  • ↑ Liver function tests
SGLT2 inhibitors
  • Inhibit reabsorption of glucose in the proximal renal tubule
  • ↑ Urinary glucose excretion
  • Adjunctive therapy
  • Cardiovascular and renal benefit
  • Genitourinary infections
  • Diabetic ketoacidosis
  • Volume depletion
Amylin analogs
  • Slowing gastric emptying
  • ↑ Satiety
  • ↓ Postprandial glucagon secretion
  • Used in types 1 and 2 diabetes
  • Use in conjunction with prandial insulin
  • Nausea
  • Hypoglycemia

The effects of diabetes medications on weight may be a factor in choosing therapy:

  • Weight loss:
    • GLP-1 mimetics
    • SGLT2 inhibitors
  • Weight neutral:
    • α-glucosidase inhibitors
    • DPP-4 inhibitors
  • Weight gain:
    • Insulin
    • Sulfonylureas
    • Thiazolidinediones
    • Meglitinides

References

  1. Nolte Kennedy, M.S. (2012). Pancreatic hormones & antidiabetic drugs. In: Katzung, B. G., Masters, S. B., & Trevor, A. J. (Eds.), Basic & Clinical Pharmacology, 12th ed. McGraw-Hill Education, pp. 743–765. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
  2. Wexler, D.J. (2021). Metformin in the treatment of adults with type 2 diabetes mellitus. UpToDate. Retrieved September 12, 2021, from https://www.uptodate.com/contents/metformin-in-the-treatment-of-adults-with-type-2-diabetes-mellitus
  3. Inzucchi, S.E., Lupsa, B. (2020). Thiazolidinediones in the treatment of type 2 diabetes mellitus. (Ed.), UpToDate. Retrieved September 12, 2021, from https://www.uptodate.com/contents/thiazolidinediones-in-the-treatment-of-type-2-diabetes-mellitus
  4. McCulloch, D. (2019). Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus. UpToDate. Retrieved September 12, 2021, from https://www.uptodate.com/contents/alpha-glucosidase-inhibitors-and-lipase-inhibitors-for-treatment-of-diabetes-mellitus
  5. DeSantis, A. (2020). Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus. UpToDate. Retrieved September 12, 2021, from https://www.uptodate.com/contents/sodium-glucose-co-transporter-2-inhibitors-for-the-treatment-of-hyperglycemia-in-type-2-diabetes-mellitus
  6. Dungan, K. (2021). Amylin analogs for the treatment of diabetes mellitus. UpToDate. Retrieved September 12, 2021, from https://www.uptodate.com/contents/amylin-analogs-for-the-treatment-of-diabetes-mellitus
  7. Scheen, A.J. (2015). Pharmacokinetics, pharmacodynamics, and clinical use of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease. Clin Pharmacokinet 54:691–708. https://pubmed.ncbi.nlm.nih.gov/25805666/

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