NPH Insulin: Properties and Clinical Use

Diabetes Mellitus (DM)

• DM is a chronic metabolic disease marked by elevated blood glucose levels
• The cause is insufficient production of insulin to maintain glucose homeostasis

Core Defects in DM

• Type 1 diabetes involves a lack of insulin secretion and affects approximately 10% of DM patients
• Type 2 diabetes is characterized by insufficient insulin secretion and insulin resistance, affecting about 90% of DM patients

Pharmacotherapy of Type 1 Diabetes Mellitus: Learning Objectives

• Identify different insulin products, their administration routes, indications, and the rationale for their specific uses
• Learn the types of insulin regimens suitable for treating patients with insulin-dependent DM (type 1)
• Understand the factors influencing insulin absorption after subcutaneous administration
• Recognize and describe the side effects of insulin therapy

Exogenous Insulin: Pharmacokinetics

• Insulin is administered through subcutaneous (SC), intramuscular (IM), or intravenous (IV) injections
• Recombinant human insulin is used in therapies
• Insulin is metabolized in the liver and kidney by glutathione-insulin transhydrogenase ("insulinase"), which reduces disulfide bridges between the A and B chains
• The plasma half-life of insulin is 3-5 minutes

Insulin Delivery

• Insulin is mainly administered via the subcutaneous route
• Intravenous delivery is reserved for ketoacidosis or when requirements change rapidly
• Long-acting insulin should never be administered intravenously, intramuscularly, or via infusion devices
• Insulin pumps use programmed basal infusion rates and premeal boluses
• SubQ insulin infusion devices often use rapid-acting insulin

Insulin Dosing Regimens

• Panel A: less frequently used mixture of rapid or short-acting insulin + Neutral Protamine Hagedorn (NPH)
• NPH is not a true basal coverage as it peaks, unlike glargine and patients are at risk for nocturnal hypoglycemia from the evening NPH dose
• Panel B: the second NPH dose peaks at 7:00 AM
• This method may be useful for patients in whom nocturnal hypoglycemia and fasting hyperglycemia are particularly troublesome.
• Panel C: A typical basal (e.g., glargine) and bolus as premeal (lispro) regimen.
• Panel D: Continuous subQ insulin with rapid-acting insulin (RA) and RA premeal boluses.

Factors Affecting Insulin Absorption After SubQ Administration

• Site of administration
• Type of insulin administered
• SubQ blood flow
• Regional muscular activity at the site of administration
• Volume of injection
• Concentration of insulin
• Depth of injection, with intramuscular injections resulting in faster absorption than subcutaneous ones
• The abdomen is the preferred injection site in the morning due to its 20-30% faster insulin absorption compared to the arm

Exogenous Insulin Forms

• Many forms of insulin are available in the U.S.
• Ultra-rapid-acting (URA) has a shorter onset compared to rapid-acting insulins
• Rapid-acting (RA) – has a rapid onset and short action
• Short-acting (SA) – has a short onset
• Intermediate-acting (IA) – has a moderate onset
• Long-acting (LA) has a slow onset and no peak

Summary Characteristics of Insulins:

• Insulins lispro, aspart, glulisine have an onset of action in 5-15 min, peak action in 1-1.5 h, effective duration of 3-4 h
• Human regular has an onset of action of 30-60 min, peak action in 2 h, effective duration of 6-8 h
• Technosphere inhaled insulin has an onset of action in 5-15 min, peak action in 1 h, effective duration of 3 h
• Human NPH has an onset of action of 2-4 h, peak action in 6-7 h, effective duration of 10-20 h
• Insulin glargine has an onset of action in 0.5-1 h, no peak, effective duration of ~24 h
• Insulin detemir has an onset of action in 0.5-1 h, no peak, effective duration of 17 h
• Insulin degludec has an onset of action in 0.5-1.5 h, no peak, effective duration of >42 h

Ultra Rapid Acting Insulins

• Ultra-rapid Lispro and Ultra-rapid Aspart are available
• Contain either niacinamide or Treprostinil sodium (local vasodilators) and sodium citrate (vascular permeability enhancer), imparting an ultra-rapid nature
• Studies show rapid serum insulin levels after injection in children, adolescents, and adults

Rapid Acting Insulins

• Lispro, Aspart, and Glulisine have a fast onset and short duration
• Require pre-prandial injection for optimal effect
• Onset in 5-15 min
• Shorter duration of 3-4 hr

Rapid Acting Insulin: Technosphere Inhaled

• Human recombinant insulin administered via inhalation
• Faster onset in 5-15 minutes
• Shorter duration is shown at 3 hr
• Inhaled insulin may cause a decline in lung function (FEV₁), requiring spirometry testing before and during treatment
• Inhaled insulin is contraindicated in patients with asthma, COPD, smokers, and those who recently quit smoking

Regular Acting Insulin

• Regular Insulin is crystalline Zn2+ and synthesized by the β cells of pancreas islets and contains 51 a.a. peptide
• Requires pre-prandial injection
• Onset occurs in 0.5-1 hr
• Duration extends for 6-8 hr
• Recombinant human insulin is delivered SubQ, IM, or IV, and phosphate-buffered insulin is often used in continuous infusion pumps

Intermediate-Acting Insulin

• Isophane Insulin, also known as Neutral Protamine Hagedorn
• Onset occurs in 2-4 hr
• Duration lasts for 10-20 hr

Intermediate Acting Insulin: Isophane or NPH

• NPH is usually mixed with regular, lispro, aspart, or glulisine insulin and is typically given twice daily
• Mixing allows for both a rapid onset and an extended duration of action
• NPH has unpredictable absorption, with variability over 50%
• Clinical use is declining because of its adverse pharmacokinetic profile and the availability of more predictable long-acting insulin analogs

Long-Acting Insulins

• Glargine, detemir, and degludec have a slow onset and no peak

Side Effects of Insulin

• Hypoglycemia may result in loss of consciousness, convulsions, brain damage, and death
• Lipohypertrophy is a lipogenic action
• All Insulins are associated with modest weight gain
• Insulin coma involves loss of a consciousness with insulin overdose and a rapid onset
• Treatment involves glucose administration and glucagon administration if the patient is disoriented

Drugs to Elevate Blood Glucose: Glucagon

• Glucagon is released from α cells of the pancreas in response to low blood glucose
• Stimulates gluconeogenesis and glycogenolysis
• Available in injectable (subQ, i.m, i.v) and intranasal forms
• Contraindicated in patients with pheochromocytoma and insulinomas
• Uses include severe hypoglycemia and decreasing GI motility for radiologic exams

Pharmacotherapy of Type 2 Diabetes Mellitus: Learning Objectives

• Identify and describe mechanisms of action of GLP-1 receptor agonists, DPP-4 inhibitors, sulfonylureas, metformin, thiazolidinediones, SGLT2 inhibitors, amylin analogs, and glucosidase inhibitors
• Identify and describe the side effects of GLP-1 receptor agonists, DPP-4 inhibitors, sulfonylureas, metformin, thiazolidinediones, SGLT2 inhibitors, amylin analogs, and glucosidase inhibitors
• Discuss properties that may affect drug use
• Identify and describe clinically significant drug-drug interactions with insulin and other hypoglycemic agents
• Explain the pharmacological bases for glucagon use and its side effects

Core Defects in DM: Revisited

• Type 1 diabetes (~10% of DM) has no insulin secretion, leading to hyperglycemia
• Type 2 diabetes (~90% of DM) deals with insufficient insulin secretion and insulin resistance, also leading to hyperglycemia

Stimulation of Insulin Secretion with Secretagogues

• Addresses the initial stages of pharmacotherapy for type 2 diabetes mellitus

Glucagon-Like Peptide 1 (GLP-1)

• GLP-1 is a gut-derived peptide hormone with various metabolic effects
• It increases insulin secretion and decreases glucagon secretion, which decreases blood glucose
• It also helps to increase insulin sensitivity and decrease body weight
• GLP-1 augments glucose-stimulated insulin secretion, not stimulating insulin release at low glucose levels
• Intestinal GLP-1 secretion is decreased in T2DM

GLP-1 Receptor Agonists (GLP-1RAs)

• GLP-1 receptor agonists (RAs act like GLP-1 and alleviate endogenous GLP-1 deficiency in type 2 diabetes mellitus
• Causes increase in insulin secretion, decrease in glucagon secretion, increase in insulin signaling, adipocyte differentiation and decrease in fat accumulation
• Decreases appetite and gastric emptying
• Lowers blood glucose, Body weight, increase insulin sensitivity

GLP-1 Receptor Agonists: Warnings and Side Effects

• FDA BBW for risk of Thyroid C-cell tumors and contraindicated in patients with personal/family history of MTC or patients with multiple endocrine neoplasm syndrome type 2 (MEN-2)
• May be linked to greater risk of pancreatitis and risk for hypoglycemia if given with other secretagogues or insulin
• Common side effects include nausea (44%), vomiting (13%), diarrhea (13%), and decreased appetite

GLP-1 Receptors Agonists: Drugs and Administration

• Dulaglutide: Given SubQ once weekly and has GLP-1R agonist action.
• Semaglutide: It comes in oral and injectable (SubQ) forms, acting as a GLP-1R agonist. Oral given once daily, 30 minutes before food and the injectable given subQ once weekly, anytime.
• Tirzepatide: acts GIP-R and GLP-1R agonist. The medication is given subQ once weekly, any time.
• all GLP-1R agonists should avoided in patients. with gastroparesis

DPP4 Inhibitors

• DPP4 increases endogenous GLP-1 levels with blood glucose reduction
• DPP4 is negative regulator of GLP-1
• It's an enzyme that inactivates GLP-1 by cleaving 2 N-terminal residues
• DPP4 inhibitors increase half life (from 2-5min) and concentration of GLP-1

DPP4 Inhibitors: Drugs, Side Effects, and Interactions

• Sitagliptin, Saxagliptin, Alogliptin, and Linagliptin are DPP4 inhibitors
• Mnemonic: Sita played Saxaphone Along with Lina
• Linagliptin binds selectively to DPP-IV and Alogliptin is given once daily
• Common side effects include predisposition to nasopharyngitis, upper respiratory tract infections, and hypersensitivity reactions (anaphylaxis, angioedema, Stevens-Johnson syndrome) within the first 3 months of use
• Drug interaction include risk of hypoglycemia when used with sulfonylurea

Sulfonylureas (SU)

• Sulfonylureas stimulate insulin secretion by inhibiting the ATP-sensitive K+-channel in pancreatic β-cells
• independent of glucose, hence they can cause hypoglycemia
• They stimulate the release of somatostatin

Second-Generation Sulfonylureas:

• Glipizide is less hypoglycemic with extensive hepatic metabolism
• Glyburide has a short plasma t₁ with biologic effects lasting for 24 hours
• Glimepiride is effective as a once-a-day dosing

General Considerations for Sulfonylureas

• well absorbed orally
• highly protein bound
• higher risk for hypoglycemia and associated with weight gain
• hepatic or renal insufficiency leads to accumulation leading to hypoglycemia
• cross the placenta leading to depletion of fetal insulin, therefore if pregnant, use insulin. only glyburide are not teratogenic from animal studies

Sulfonylureas and Glycemic Control

• Sulfonylureas (SU) fail to protect against progressive B-cell failure and lack glycemic durability

Stimulation of Insulin Sensitivity with Insulin Sensitizers

• Focuses on ways to improve the body's response to insulin

Tissue Insulin Resistance in Type 2 Diabetes

• Tissue insulin resistance is a key defect in T2DM
• Adipose tissue regulates functions of other tissues, and inflammatory signalling results in reduced insulin signalling
• Increased circulating fatty acids (FFA) lead to lipid accumulation, causing insulin resistance and impaired insulin secretion

Metformin (a biguanide)

• As per ADA, metformin is 1st drug for type 2 diabetes and promotes normal blood glucose levels
• Does not stimulate insulin release and does not cause hypoglycemia even in high doses
• Lowers LDL, increases HDL, does not cause weight gain or might be weight neutral

Metformin: Mechanism of Action

• Metformin inhibits gluconeogenesis and lowers blood glucose
• It inhibits Complex I of the electron transport chain, increasing [AMP]
• Elevated [AMP] suppresses gluconeogenesis through FBP1 inhibition and antagonizes glucagon action
• Metformin reduces lipid accumulation and improves insulin resistance via AMPK activation; this also improves hepatic insulin sensitivity

Metformin: Side Effects

• Common side effects are nausea, diarrhea (20% of patients), abdominal discomfort, metallic taste, and anorexia
• It can decrease absorption of vitamin B12 and folate, supplementation is indicated for elderly patients
• Rare but fatal "lactic acidosis" in diabetics with significant renal insufficiency

TZDs (Thiazolidinediones)

• TZDs lower blood glucose by improving insulin secretion and sensitivity
• Act as insulin sensitizers"
• Decrease FFA, Glycerol, and Inflammatory cytokines
• Increases adipocyte differentiation, and decrease inflammation and lipolysis

Rosiglitazone

• Rosiglitazone has a Black Box Warning stating it has the potential to increase occurrence of CHF and myocardial infarction (MI)

Pioglitazone

• Pioglitazone similar to Rosiglitazone as a Black Box Warning
• Warning & precaution as risk of developing cancer with use of pioglitazone for >1yr

Pioglitazone and Rosiglitazone: Advantages, Cautions, and Use

• Unlike insulin secretagogues, they don't induce hypoglycemia
• Chronic use lowers plasma TG (10-15%) and increases HDL
• Metabolized by the liver and monitor liver function
• Treatment with Type 2 DM alone or in combo therapy

TZD - Side Effects

• ↑ weight gain (peripheral, NOT central)
• ↑ fluid retention → peripheral edema
• PPARy-mediated ↑ Na+ reabsorption in distal tubes
• risk with sulfonylureas and or insulin

Inhibition of Glucose Reabsorption

• SGLT2 inhibitors are used

SGLT2 Inhibitors: Mechanism

• SGLT2 inhibition results in glucosuria and reduced blood glucose
• SGLT2 inhibitors reduce renal glucose reabsorption and lower glucose thresholds
• Glucose spill-over into urine reduces blood glucose levels

SGLT2 Inhibitors: Drugs

• Canagliflozin/ertugliflozin/dapagliflozin/empagliflozin/bexagliflozin Drug-Drug interactions: UGT Enzyme Inducers Common side effects: ketoacidosis warning (discontinue if DKA), genital infections, and can increase kidney injuries. Contraindications: renal impairment

Miscellaneous Therapeutic Approaches:

• Focuses on amylin analogs and α-glucosidase inhibitors

Amylin Analog:

• Amylin is an islet amyloid polypeptide
• Secreted from Pancreatic β-cells and released during food consumption
• slow gastric emptying
• Suppresses abnormal postprandial glucose output
• Stimulates satiety, leading to decrease in caloric intake

AMYLIN ANALOG: Pramlintide

• Pramlintide is given SubQ for Types 1 & 2 DM and if using with insulin administer separately
• causes increased of hypoglycemia, therefore adjust insulin dose accordingly
• common effect is nausea can be minimized by slow titration and cause severe hypoglycemic
• delays gastric emptying and in patient with gastroparesis use is cautioned

a-Glucosidase Inhibitors: Mechanism

• α-GLUCOSIDASE INHIBITORS are also known starch blockers
• They reduce digestion and absorption of complex starches by competitively inhibiting the a-glucosidases

α-GLUCOSIDASE INHIBITORS: Caution and Side Effects

• Acarbose, in chronic use, significantly elevates liver enzymes and has led to fatal hepatitis
• Miglitol
• Common side effects include bloating, abdominal discomfort, diarrhea, and flatulence (20-30%)
• Contraindications are with inflammatory bowel disease, and require monitoring serum aminotransferase levels

Pharmacotherapy Summary:

• Pros and Cons of various drug classes for diabetes treatment
• Drug classes include GLP-1 receptor agonists, DPP-4 inhibitors, Sulfonylureas, Biguanides, TZDs, and SGLT2i
• Also includes pros with weight loss, hypoglycemia risk not increased, decreased MACE, decreased mortality, cost
• Cons include high cost, edemas, UTIs, Increased risk, contraindications, etc
• Please refer to the table for full details.

Explore the characteristics of Neutral Protamine Hagedorn (NPH) insulin, including its use in combination with rapid-acting insulins. Understand its limitations, onset, and duration of action. Learn about its impact on blood sugar levels and appropriate regimen adjustments.