Diabetes Mellitus: Types, Treatments, Pathophysiology

• The pharmacology of Diabetes Mellitus will be discussed
• This lesson is for year 2 students in the Endocrine and Breast module
• The lecturer is Prof Steve Safrany 341
• This lesson takes place in January 2024

Learning Outcomes

• Mechanism of action of insulin, therapeutic, and adverse effects should be described
• Differences between types of insulin, preparations, and regimens, including identification of their advantages and disadvantages, should be compared
• Potential future directions for insulin therapy in diabetes mellitus, including new insulin formulations, devices and tech should be discussed
• Principles of pharmacotherapy of type 2 diabetes, including drug classes, mechanisms of action and adverse effects should be recognized
• The clinical efficacy of antidiabetic drugs, including their effects on glycemic control, weight, blood pressure, lipid profiles, and other outcomes should be evaluated

Diagnosis

• Diagnosis can be achieved through the following tests

• Fasting Plasma Glucose ≥7.0 mmol/L (126 mg/dL)

• HbA1c ≥48 mmol/mol (equivalent to 6.5%)

• Two-hour plasma glucose after 75g oral glucose load (oral glucose tolerance test (OGTT)) ≥11.1 mmol/L (200 mg/dL)

• Random plasma glucose in the presence of the symptoms of hyperglycaemia, where ≥11.1 mmol/L (200 mg/dL)

Type 2 vs Type 1 Diabetes

• Type 2 diabetes is characterized by insulin resistance with relative insulin deficiency
• In Type 2 Hyperglycemia develops gradually with progressive decline in beta-cell function
• Type 2 can be treated with oral medications
• Type 2 diabetes is associated with increasing age and obesity
• Type 1 diabetes is characterized by absolute insulin deficiency
• Type 1 involves an abrupt onset of hyperglycemia and propensity for DKA development
• Type 1 requires insulin
• Type 1 is associated with auto antibodies
• Type 1 is the predominant type of diabetes diagnosed in individuals <30 years old

Management of DM (Diabetes Mellitus)

• Type 2 treatment requires a multidisciplinary approach
• Patient education & support should be provided for type 2
• Lifestyle modifications (diet, physical activity, & weight loss) are necessary for type 2 treatment
• Pharmacologic therapies (oral, GLP-1 agonists, insulin) should be considered for use in type 2
• Bariatric surgery can be considered as a treatment for type 2
• Type 1 treatment requires a multidisciplinary approach
• Patient education & support is required for type 1
• Dietary advice (carb counting, glycaemic index diets, dietary advice) and physical activity advice is needed for type 1
• Insulin therapy (injections or insulin pump) is required for type 1
• Newer treatments are on the horizon (islet cell, stem cell)

Indications for Insulin

• Insulin is indicated for type 1 diabetes
• Insulin is indicated for inadequately controlled type 2 diabetes
• Insulin is indicated for temporary use under certain circumstances:
• Hospitalisation/surgery
• Pregnancy
• Renal disease (when there are limited options for oral medications)
• To initially attain glycemic control in patients with severe new onset type 2 diabetes

A Century of Insulin Therapy

• The first human was treated around 1920
• NPH insulin became available around 1950
• Pump therapy and human insulin started being used around 2000
• Finally, insulin analogs were created around 2020

Treatment of Type 1 Diabetes

• Insulin replacement therapy is required
• Dosages should be adjusted according to carbohydrate intake, exercise regimen, and blood glucose profile
• Blood glucose levels should be tested and insulin adjusted appropriately
• Monitor for any potential complications

Bolus Insulin

• Rapid or short-acting insulin is given before meals
• It is used for coverage of food intake or correction of hyperglycemia
• Short acting includes regular insulin
• Rapid acting includes asparat, lispro, and glulisine and (Insulin human) inhalation powder

Basal Insulin

• Aims to mimic physiologic insulin secretion
• Maintains euglycemia in the fasting state
• Intermediate acting insulin use includes NPH, given once or twice daily
• Long acting includes glargine, detemir, and degludec, given once daily

NPH-Intermediate Acting Insulin

• Stands for Neutral protamine Hagedorn
• Includes Humulin N, Novolin N, Novolin NPH, and isophane insulin
• Created in 1936 as first basal insulin
• A suspension of crystalline zinc insulin combined with the positively charged polypeptide, protamine*
• Intermediate duration of action (10-20 hours)
• Can be combined with other insulins
• A peak in action increases the risk of hypoglycemia

Insulin Glargine-Basal Insulin

• Peak less 24-hour insulin
• Involves insulin molecule modifications:
• Substitution of glycine at A21
• Addition of two arginines at B30
• A unique release pattern at injection site

Pharmacodynamics of Insulin

• Aspart/Lispro/Glulisine

• Onset of action: 5-15 minutes

• Peak (hr): 1-2

• Duration (hr): 4-6

• Regular insulin

• Onset of action: 30-60 minutes

• Peak (hr): 2-4

• Duration (hr): 6-10

• Human NPH

• Onset of action: 1-2 hours

• Peak (hr): 4-8

• Duration (hr): 10-20

• Glargine

• Onset of action: 1-2 hours

• Peak (hr): Flat

• Duration (hr): ~24

• Detemir

• Onset of action: 0.8-2 hours

• Peak (hr): Flat

• Duration (hr): Up to 24

• Degludec

• Onset of action: 1 hour

• Peak (hr): Flat

• Duration (hr): Up to 42

Insulin Administration Regimens

• Conventional regimens involve basal insulin only
• Conventional regimens also involve twice daily mixed split
  • Intermediate (N) + Short (Regular or Rapid acting)
• 70/30 or 75/25 insulin
  • 70-75% N
  • 25-30% R or Rapid acting
• Basal-bolus regimens involve long-acting insulin + rapid-acting insulin with each meal
• Continuous subcutaneous insulin infusion is administered via insulin pump

Pharmacokinetic Advantages of the Insulin Pump (CSII)

• Uses only rapid acting insulin
• One injection site is used
• Basal insulin requirements are supplied as mini-boluses every 5 minutes (Closed loop technology)

Automated Insulin Delivery Systems

• Comprise of an insulin pump and continuous glucose monitor (CGM) with integrated functioning
• Allows for automatic adjustment of insulin delivery
• Algorithm adjusts basal rates based on glucose
• Patients needs to administer pre-meal insulin boluses
• Benefits: increased time spent in target glucose range and less incidence of severe hypoglycemia
• Issues: cost is high

Inhaled Insulin

• Rapid acting insulin is adsorbed onto carrier particles
• It is delivered via inhalation
• Medium time from maximum effect is 53 minutes
• Duration of action is 160 minutes
• Approved to cover prandial insulin requirements in non-smoking adults with DM who are free of pulmonary disease
• Rarely used – less effective than subcutaneous insulin
• Has potential for pulmonary toxicity

Insulin Side Effects

• Very safe treatment when used appropriately
• Hypoglycemia is the most common complication
• Insulin Lipodystrophies
  • Lipoatrophy
    • Localized loss of subcutaneous fat at injection sites
  • Lipohypertrophy
    • Swelling of subcutaneous fat at injection sites
• Allergies can occur, which can be local (itching, burning, erythema, hive formation) or systemic (urticaria/bronchospasm)

Summary of Insulin

• Insulin is used to treat both type 1 and type 2 diabetes
• Multiple daily injections (basal-bolus) are most commonly used
• Hypoglycemia is a common side effect of insulin therapy and patient education should be provided
• Basal-bolus regimen via subcutaneous injections or continuous insulin infusion most closely simulates normal insulin physiology

Principles of Glucose Lowering Agents in Type 2 Diabetes

• Multiple drugs areavailable, each with tissue specific action
• All agents are contraindicated in pregnancy except glyburide (sulfonylurea) and metformin
• Can be used in any combination except sulfonylureas should not be used with meglitinides
• Metformin is generally the first drug of choice
• Treatment can start with multiple classes of drugs

Insulin Resistance

• Associated clinical conditions include
• Hypertension (Prehypertension)
• Type 2 Diabetes
• Impaired Glucose Tolerance
• Atherosclerosis (Endothelial Dysfunction)
• Obesity (Central Visceral)
• Dyslipidemia
  • ↓HDL
  • ↑ LDL
  • ↑TG
• Polycystic Ovary Disease
• Decreased Fibrinolytic Activity
• Acanthosis Nigricans

Metformin (Glucophage)

• Action: Acts on the liver, reduces hepatic glucose output, decreases glucose absorption in the large intestine, and increases insulin-mediated glucose utilization in peripheral tissues
• Associated with mild weight loss
• Does not cause hypoglycemia
• lowers HbA1c as much as 2%
• Most commonly prescribed drug for T2D

Side Effects and Contraindications of Metformin

• Can produce GI upset – anorexia, nausea, and diarrhea
• Can produce Lactic Acidosis
• Can cause Vitamin B12 deficiency
• Contraindications include patients prone to metabolic acidosis, T1D, and renal failure
  • Lower dose eGFR 30-45ml/min
  • Avoid eGFR <30ml/min

Insulin Secretagogues

• Sulfonylureas’ names are Glipizide, glimepiride, glyburide
• Their action stimulates pancreatic insulin secretion for 12-24 hours
• Their mechanism is that they bind K+ channels/sulfonylurea receptors (SUR) in B cells, resulting in K+ accumulation and depolarization, causing Ca2+ entry and insulin release
• They have an immediate effect mostly on pre-meal glucose
• They are metabolized hepatically and excreted via the kidney
• They are contraindicated for those with T1DM, DKA, or a sulfa allergy
• Adverse effects include hypoglycemia, weight gain, hunger
• They lower A1c up to 1.5%

Meglitinides/Glinides

• E.g. repaglinide
• Action: Stimulates insulin secretion for 3-4 hours
• Mechanism: Same as sulfonylureas
• Results in fast onset
• Side effects: lowers glucose 2-4 hours after meal, weight gain
• Disadvantage: requires patient compliance
• Contraindications: T1DM, liver failure, DKA, sulfa allergy
• Metabolism: hepatic by CYP 450 enzymes system, 96% metabolites excreted via GI tract
• Efficacy: Lowers A1c ~ 1.4%

Alpha-Glucosidase Inhibitors

• E.g. Acarbose
• Mechanism: competitively inhibit enzymes in the small intestinal brush border to break down oligosaccharides and disaccharides into monosaccharides
• Action: delay gut carbohydrate absorption, increases GLP-1
• Effects: post-prandial glucose only
• Administration: pill taken with meals
• Side effects: Flatulence, abdominal bloating
• Contraindications: Gl disorders, esp. IBD
• Metabolism: Renally excreted as unchanged drug
• Does not induce hypoglycemia
• Efficacy: Lowers A1c ~ 0.4%

Incretin Hormones

• They are released from the gut after eating and enhance insulin secretion
• GLP-1 and GIP are the main incretin hormones that mediate this effect
• In Type 2 Diabetes Mellitus (T2DM) the effect is often impaired
• This may contribute to poor glucose regulation and reduced insulin secretion from the pancreas

GLP-1 Receptor Agonists (GLP-1 RA)

• E.g. Semaglutide, liraglutide, dulaglutide
• Mechanism: enhancement of glucose-dependent insulin secretion, slowed gastric emptying, & reduction of postprandial glucagon & food intake
• Action: Potent glucose-dependent insulin secretion, inhibits glucagon secretion, indirectly slows gastric emptying, stimulates satiety
• Administration: subcutaneous injection (daily or weekly), semaglutide also available oral
• Side effects: GI (nausea, vomiting, diarrhea), pancreatitis (<1% risk)
• Contraindications: Pancreatitis
• Does not induce hypoglycemia
• Efficacy: Lowers A1c 0.5-1.4%, weight loss
• In patients with T2D & CVD taking GLP-1 RA (liraglutide, semaglutide, dulaglutide), there is reduction in ASCVD outcomes and CV mortality

GIP/GLP-1 Receptor Agonist

• E.g. Tirzepatide
• Mechanism: Synthetic dual-acting agonist targeting GIP and GLP-1 receptors
• Action: GIP enhances effects of GLP-1. Potent glucose-dependent insulin secretion, inhibits glucagon secretion, indirectly slows gastric emptying, stimulates satiety
• Administration: subcutaneous injection weekly
• Side effects: GI (nausea, vomiting, diarrhea), pancreatitis (<1% risk)
• Contraindications: Pancreatitis
• Does not induce hypoglycemia
• Efficacy: Lowers A1c 2%, weight loss

DPP IV Inhibitors

• E.g. Sitagliptin, linagliptin, vildagliptin, saxagliptin
• Action: Increases duration of action of GLP-1 and GIP
• Mechanism: Inhibits dipeptidyl peptidase-4 with 80% inhibition at 24 hours
• Metabolism:
  • For Sitagliptin and Saxagliptin, the drugs are not metabolized and are excreted unchanged through the kidneys
  • Linagliptin is hepatically metabolized
• Administered once daily by mouth
• Contraindications: pancreatitis
• Adverse effects: gastrointestinal
• Does not induce hypoglycemia and is weight neutral
• Efficacy: Lowers A1c ~0.7%

SGLT2 Inhibitors

• E.g. Empagliflozin, canagliflozin, dapagliflozin
• Mechanism: Excretion of 50-100 grams glucose/day
• Metabolism: Mainly hepatic with some metabolites excreted via kidney
• Contraindications: Severe renal impairment, ESRD, or on dialysis
• Side effects: Vulvovaginal candidiasis, vulvovaginal mycotic infection, urinary tract infections, and polyuria, small risk of euglycemic DKA
• Efficacy: lowers A1c by as much as 0.7 % (canagliflozin 0.9-1%)
• Weight loss of ~ 2.2%
• • Cardiovascular risk benefit
  • Also approved for heart failure and CKD

Summarized Drug Table

• Biguanide (metformin)

  • Adverse Effects: Diarrhea, abdominal pain, lactic acidosis
    • Effect on Weight: Decrease
    • Caution: Contraindicated in GFR <30

• Sulfonylureas (glipizide)

  • Adverse Effects: Weight gain, hypoglycemia
  • Effect on Weight: Increase
  • Caution: Reduced renal clearance in kidney failure

• Alpha-glucosidase inhibitors (acarbose)

  • Adverse Effects: Abdominal discomfort
  • Effect on Weight: Neutral
  • Caution: Avoid in kidney disease

• Thiazolideniones (pioglitazone)

  • Adverse Effects: Weight gain, heart failure, osteoporosis, bladder CA
  • Effect on Weight: Increase
  • Caution: CV events/mortality (rosiglitazone)

• DPP IV inhibitor (sitagliptin)

  • Adverse Effects: Nausea, rash
  • Effect on Weight: Neutral
  • Caution: pancreatitis

• GLP-1 agonist (semaglutide)

  • Adverse Effects: Nausea, vomiting, pancreatitis (rare)
  • Effect on Weight: Decrease
  • Caution: Pancreatitis, HF (saxagliptin)

• SGLT-2 inhibitor (dapagliflozin)

  • Adverse Effects: Genital yeast infection, euglycemic DKA
  • Effect on Weight: Decrease
  • Caution: Caution with PAD

Explore the pathophysiology, treatments, and distinctions between type 1 and type 2 diabetes mellitus. Questions cover insulin resistance, insulin deficiency, and novel approaches to insulin therapy. Test your knowledge of diabetes management and complications.