Diabetes Mellitus: Pathophysiology and Complications

Diabetes Mellitus (DM)

• A group of metabolic disorders characterized by chronically elevated blood glucose and abnormal metabolism of carbohydrates, fats, and proteins.

Acute Complications of DM

• Diabetic ketoacidosis (DKA)
• Hyperosmolar hyperglycemic syndrome (HHS)

Chronic Complications of Hyperglycemia

• Microvascular complications
• Macrovascular complications
• Neuropathic complications

Pathophysiology of Type 1 DM

• Results from autoimmune destruction of pancreatic β-cells
• Leads to absolute deficiency of insulin due to islet cell antibody
• Typically presents in children and adolescents, but can occur at any age

Type 2 Diabetes Mellitus (T2DM)

• Characterized by multiple defects, accounting for 90%–95% of DM cases
• Impaired insulin secretion due to:
• Reduced incretin effect
• Incretin hormones affected: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)
• Insulin resistance manifested by:
• Excessive hepatic glucose production
• Decreased skeletal muscle uptake of glucose
• Increased lipolysis and free fatty acid production
• Additional characteristics:
• Excess glucagon secretion
• Upregulation of sodium-glucose cotransporter-2 (SGLT-2) in the kidney, leading to increased glucose reabsorption and contributing to hyperglycemia

Gestational Diabetes Mellitus (GDM)

• A type of DM that occurs in women during pregnancy

Diabetes Complications

Microvascular Complications

• Retinopathy
• Neuropathy
• Nephropathy

Macrovascular Complications

• Coronary heart disease (CHD)
• Stroke
• Peripheral vascular disease

Clinical Presentation of Diabetes Mellitus

Type 1 Diabetes Mellitus

• Patients often exhibit symptoms in the days or weeks preceding diagnosis, including polyuria, polydipsia, polyphagia, weight loss, fatigue, and lethargy.
• Individuals are often thin and prone to developing Diabetic Ketoacidosis (DKA) in the absence of adequate insulin supply, with many patients initially presenting with DKA.
• Symptom onset can be triggered by infection, trauma, or psychological stress.

Type 2 Diabetes Mellitus

• Most patients are asymptomatic or experience mild fatigue at the time of diagnosis, with many cases incidentally discovered through routine laboratory testing (e.g., plasma glucose or A1C) or development of complications (e.g., myocardial infarction, stroke).
• Mild hyperglycemia may exist for years prior to diagnosis, resulting in microvascular and macrovascular complications often being present at the time of diagnosis.
• Most patients are overweight or obese.

Diagnostic Criteria for Diabetes Mellitus (DM)

• A1C ≥6.5% is a criterion for diagnosing DM
• Fasting plasma glucose (FPG) ≥126 mg/dL is another criterion for diagnosing DM
• Oral glucose tolerance test (OGTT) ≥200 mg/dL is also a criterion for diagnosing DM
• Random plasma glucose ≥200 mg/dL with classic symptoms of hyperglycemia or hyperglycemic crisis is the fourth criterion for diagnosing DM

Prediabetes

• Prediabetes is a condition of abnormal blood glucose (BG) that is not high enough to meet DM diagnostic thresholds
• Prediabetes often progresses to DM

Screening for Diabetes

• Screening for type 1 DM in asymptomatic individuals is not recommended due to low disease prevalence and acute onset of symptoms
• Screening for type 2 DM is recommended for asymptomatic adults who are overweight (BMI ≥25 kg/m2) and have at least one other risk factor for developing type 2 DM
• All adults should be screened every 3 years starting at 45 years old, regardless of risk factors
• Children at risk for developing type 2 DM should undergo screening every 3 years starting at age 10 years

Treatment of Diabetes

• The primary goal of treatment is to prevent or delay the progression of long-term microvascular and macrovascular complications.

Goals of Treatment

• Alleviate symptoms of hyperglycemia
• Minimize hypoglycemia and other adverse effects
• Individualize glycemic targets, with more or less stringent goals depending on the patient

Nonpharmacologic Therapy

Medical Nutrition Therapy (MNT)

• Implement a healthy meal plan that is:
  • Moderate in calories and carbohydrates
  • Low in saturated fat
  • Rich in essential vitamins and minerals
• Target an initial weight loss goal of at least 5% in type 2 DM patients who are overweight or obese through calorie restriction

Physical Activity

• Aerobic exercise goals:
  • At least 150 minutes/week of moderate-intensity exercise
  • Spread over at least 3 days/week
  • No more than 2 days between activity
• Resistance/strength training:
  • Recommended at least 2 times/week
  • Except for patients with proliferative diabetic retinopathy

Patient Involvement and Education

• Patients must be involved in decision-making and have strong knowledge of the disease and associated complications

Insulin Therapy

• Insulin has the advantage of individualized dosing based on glycemic levels, making it a more personalized treatment option.

Advantages and Disadvantages

• Disadvantages of insulin include the risk of hypoglycemia, need for injections, and weight gain.

Administration of Insulin

• Most insulin products are administered subcutaneously (SC) for chronic diabetes management.
• Inhaled human insulin is an exception, which is a dry powder of regular insulin that is inhaled and absorbed through pulmonary tissue.

Pharmacokinetics of Insulin

• The pharmacokinetics of insulin products are characterized by their onset, peak, and duration of action.

Basal Insulin

• Basal insulin (or background insulin) refers to longer-acting insulins that regulate BG levels in between meals.
• Options for basal insulin include:
  • NPH (not ideal due to distinct peak and twice daily dosing requirement)
  • Detemir (has a peak and often lasts)

Insulin Options

• Bolus insulin options include Aspart, lispro, and glulisine, which are rapid-onset, short-duration insulins
• Other options include inhaled human insulin, fast-acting insulin aspart (Fiasp®), and insulin lispro (Lyumjev®), which are ultrarapid onset insulins

Characteristics of Rapid-Acting Insulins

• Offer a faster onset and shorter duration of action compared to regular insulin
• Ultra-rapid acting insulins have an even faster onset, mimicking prandial endogenous insulin release more closely

Insulin Types and Characteristics

• Rapid-acting insulins have a lower risk of hypoglycemia compared to regular insulin.

Premixed Insulin Products

• Premixed insulin products contain both basal and prandial components.
• These products are limited by fixed mixed formulations, making it challenging to tailor the dosing regimen.

Insulin Dosage

• The average daily insulin requirement for type 1 DM is 0.5–0.6 units/kg.
• The daily insulin dose is typically divided into two components: 50% as basal insulin and 50% for meal coverage.

Adverse Effects of Insulin Therapy

• Hypoglycemia is the most common adverse effect of insulin therapy.
• Insulin therapy also causes dose-dependent weight gain.

Subcutaneous Insulin Administration

• SC administration can result in lipoatrophy or lipohypertrophy.
• Rotating injection sites can prevent lipoatrophy or lipohypertrophy.

Metformin Mechanism of Action

• Decreases hepatic glucose production and enhances insulin sensitivity in peripheral (muscle) tissues
• Increases glucose uptake into muscle cells

Metformin Recommendations

• Recommended as first-line pharmacotherapy in patients with type 2 DM (unless a contraindication or intolerability exists)

Effects on Body Weight and Glucose Regulation

• Does not cause weight gain
• May lead to a modest (2–3 kg) weight loss
• Does not directly increase pancreatic insulin secretion, resulting in a low risk of hypoglycemia

Effects on Lipid Profile

• Decreases plasma triglycerides and low-density lipoprotein cholesterol (LDL-C)
• Modestly increases high-density lipoprotein cholesterol (HDL-C)

Adverse Effects

• Frequently causes GI side effects (diarrhea, abdominal discomfort, stomach upset)
• GI side effects are usually dose-dependent, transient, mild, and can be minimized with slow dose titration and taking metformin with or immediately after meals
• May cause a metallic taste
• May lower vitamin B12 concentrations, requiring annual measurement or supplementation if indicated

Rare but Serious Adverse Effects

• Lactic acidosis occurs rarely, usually in the setting of severe illness or acute kidney injury
• Diagnosis must be confirmed by laboratory measurement of high lactic acid levels and acidosis

Renal Considerations

• Metformin is renally excreted and accumulates in renal insufficiency
• Withhold metformin therapy starting the day of IV contrast dye procedure and resume it 2–3 days later if normal renal function has been documented

Combination Therapy

• Can be used in combination with any other antihyperglycemic therapy
• Often continued when insulin therapy is initiated

Mechanism of Action

• SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) reduce plasma glucose by preventing the kidneys from reabsorbing glucose back into the bloodstream, leading to increased glucose excretion in the urine.

Efficacy

• SGLT-2 inhibitors lower both FPG (Fasting Plasma Glucose) and postprandial glucose (PPG).

Indications and Contraindications

• Can be added to metformin or other second-line agents.
• Can be used as monotherapy in patients who cannot tolerate or take metformin.
• Recommended for patients at high risk for or with established ASCVD (Atherosclerotic Cardiovascular Disease), heart failure, or CKD (Chronic Kidney Disease).

Adverse Effects

• Unlikely to cause hypoglycemia unless combined with medications such as sulfonylureas, meglitinides, or insulin.
• Most common adverse effect is genital mycotic infections, more common in women and uncircumcised men.
• Slightly increased risk of urinary tract infections.
• May cause polyuria, dehydration, dizziness, or hypotension due to osmotic diuresis effects.

Mechanism of Action

• GLP1-RAs stimulate insulin secretion and suppress inappropriately high postprandial glucagon secretion, decreasing hepatic glucose output
• They also slow gastric emptying, increase satiety, and cause weight loss (average 1–3 kg)

Classification of GLP1-RAs

• Short-acting agents: exenatide, lixisenatide (predominantly lower PPG levels)
• Long-acting agents: dulaglutide, liraglutide, exenatide XR, semaglutide (lower both FPG and PPG, with larger effects on FPG)

FDA Approval

• Dulaglutide, liraglutide, and semaglutide are FDA approved to reduce the risk of major adverse CV events in adults with type 2 DM and established ASCVD

Clinical Use

• GLP1RAs can be used as monotherapy in patients who cannot tolerate or take first line therapy
• Six GLP1RAs are administered SC (subcutaneously)
• Semaglutide is available as SC and oral preparations

DPP-4 Inhibitors Mechanism of Action

• Prolong half-life of endogenously produced GLP-1 and GIP, increasing glucose-dependent insulin secretion from the pancreas.
• Reduce inappropriate postprandial glucagon secretion, resulting in lower glucose levels.

Effects on Body

• Do not alter gastric emptying.
• Do not cause weight gain or loss.

Clinical Usage

• Considered second- or third-line therapy.

Advantages

• Once-daily dosing.
• Oral administration.
• Weight neutrality.
• Low risk of hypoglycemia.
• Good tolerability.

Mechanism of Action

• TZDs bind to PPAR-γ receptors, primarily located on fat and vascular cells, to enhance insulin sensitivity in muscle, liver, and fat tissues.

Efficacy

• Maximum effects of TZDs may not be seen until 3-4 months of therapy.

Clinical Use

• TZDs are considered second- or third-line agents for type 2 DM.
• They can be used in combination with metformin and other commonly prescribed medications.

Adverse Effects

• Fluid retention may occur, leading to peripheral edema, HF, hemodilution of hemoglobin and hematocrit, and weight gain.
• Weight gain is dose-related and results from both fluid retention and fat accumulation.

Contraindications

• TZDs are contraindicated in patients with New York Heart Association Class III or IV HF.
• They should be used with caution in patients with Class I or II HF.

Mechanism of Action

• Sulfonylureas enhance insulin secretion by binding to the sulfonylurea receptor SUR1 on pancreatic β-cells.

Advantages and Limitations

• Sulfonylureas have an extensive record of safety and effectiveness.
• They are administered orally.
• They are inexpensive.
• However, they are discouraged or used with caution due to the risk of hypoglycemia and weight gain.
• Tachyphylaxis to the insulin secretion effect occurs, leading to poor long-term durability of response in most patients.

Side Effects

• The most common side effect is hypoglycemia.
• Weight gain is common, typically 1–2 kg.

Allergy Concerns

• Patients with sulfa allergy rarely experience cross-reactivity with sulfonylureas.

α-Glucosidase Inhibitors

• Acarbose and miglitol delay the breakdown of sucrose and complex carbohydrates in the small intestine, prolonging carbohydrate absorption.
• Suitable for patients who are near target A1C levels with near-normal FPG but high PPG levels.
• Common side effects include flatulence, abdominal pain, and diarrhea, which can be reduced by slow dosage titration.

Meglitinides

• Nateglinide and repaglinide stimulate insulin secretion from pancreatic β-cells by binding to a site adjacent to the sulfonylurea receptor.
• They have a faster onset and shorter duration of action compared to sulfonylureas.
• Main side effects are hypoglycemia and weight gain, similar to sulfonylureas.
• Suitable for patients with erratic meal schedules, but may require multiple daily dosing, which can decrease adherence.
• Must be taken by mouth with each meal.

Bile Acid Sequestrants

• Colesevelam's mechanism to lower plasma glucose levels is unknown.
• Its role in therapy is unclear.

Dopamine Agonists

• 1-Bromocriptine mesylate is FDA-approved for treating type 2 diabetes mellitus (DM).
• The mechanisms by which it improves glycemic control are unknown.
• Its role in treating type 2 DM is unclear.

Amylin Analogs

• Pramlintide is a synthetic amylin analog that reduces glucagon secretion, slows gastric emptying, and increases satiety.
• It was the first non-insulin agent approved for patients with type 1 diabetes mellitus (DM).
• It is used primarily in type 1 DM as adjunctive therapy for patients who are not achieving postprandial glucose (PPG) goals despite maximizing mealtime insulin doses.
• It can also decrease weight and may allow for lower mealtime insulin doses.

Treatment of Type 2 Diabetes

• Upon diagnosis, set a patient-specific A1C target and implement comprehensive lifestyle modifications.
• Initial treatment typically begins with metformin, unless there is a comorbidity that requires a different agent.
• Comorbidity-specific recommendations include:

  Cardiovascular Disease

  • Use of SGLT2 inhibitors or GLP1RA in high-risk or established ASCVD patients.

  Heart Failure

  • Use of SGLT2 inhibitors in Heart Failure patients, avoiding TZDs.

  Chronic Kidney Disease

  • Use of SGLT2 inhibitors in CKD patients, with or without ASCVD.
• If the initial A1C is close to goal (≤7.5%), consider treating with lifestyle modifications alone if the patient is motivated.
• Consider starting two medications (e.g., metformin plus a second agent) if the initial A1C is >1.5% higher than the target A1C.
• Consider early introduction of basal insulin in patients with very high A1C levels (>10%) or symptoms of hyperglycemia.
• Patients who are not meeting their goals should be seen at least every 3 months, and those meeting goals should be seen at least every 6 months, with additional therapy added if glucose targets have not been met.

Managing Type 2 Diabetes Mellitus

• Most patients with type 2 DM eventually require combination therapy.
• If the A1C target is not achieved after 3 months of dual therapy or if the patient cannot tolerate the selected drug(s), triple therapy is recommended, adding a drug from another class.
• Oral medications can often manage type 2 DM for years before injectable medications are needed.
• Insulin is recommended for extreme (A1C >10%) or symptomatic hyperglycemia.
• GLP-1 RAs are preferred over basal insulin due to equal or superior A1C lowering efficacy, weight loss, and low risk of hypoglycemia.
• Basal insulin can be initiated if additional glucose lowering is needed after maximizing GLP-1 RA dose.
• If A1C target is not reached by maximally titrating basal insulin, consider a GLP-1 RA or SGLT-2 inhibitor if the patient is not already taking one, as PPG levels are likely elevated.
• Prandial insulin is also an option, with dose titration over time to achieve target PPG levels.

Insulin Regimens for Type 1 Diabetes

• All patients with type 1 diabetes require exogenous insulin.
• Adequate glycemic control is achieved through intensive insulin regimens that mimic normal physiologic insulin secretion.

Components of Insulin Regimens

• Basal insulin: consistent secretion of insulin throughout the day to manage glucose levels overnight and in between meals.
• Prandial insulin: bursts of insulin in response to glucose rises after ingestion of carbohydrates.

Methods of Insulin Delivery

• Multiple daily injections (MDI)
• Continuous subcutaneous insulin infusion (CSII) via an insulin pump.

Common Insulin Regimens

• One injection of long-acting insulin (e.g., insulin glargine) for the basal component.
• Three injections of rapid-acting insulin (e.g., insulin lispro) for the prandial component.
• Alternative option: two injections of intermediate-acting insulin (e.g., NPH insulin) and two injections of short-acting insulin (e.g., regular insulin).

Recommendations

• The ADA Standards of Care recommend using rapid-acting insulins rather than regular insulin to reduce the risk of hypoglycemia.

Insulin Pump Therapy (CSII)

• Infuses rapid-acting insulin to cover both basal and prandial insulin needs
• Provides a constant basal rate throughout the day
• Allows for bolus doses based on current glucose levels, carbohydrate intake, and insulin on board

Insulin Dosing

• Total daily insulin dose is divided into 50% basal insulin and 50% prandial insulin
• Prandial insulin is distributed across meals
• Insulin doses are adjusted based on self-monitoring of blood glucose (SMBG) data

Carbohydrate Counting and Bolus Doses

• Patients should learn to count carbohydrates to match prandial insulin doses to their intake
• Carbohydrate-to-insulin ratios (C:I ratios) and correction factors (CF) help individualize bolus insulin doses

Pramlintide Therapy

• Indicated as adjunctive treatment in patients with type 1 DM who are not achieving glycemic targets despite optimization of mealtime insulin

Monitoring and Follow-up

• Patients should SMBG before each meal or use continuous glucose monitoring (CGM) to evaluate the insulin regimen and make treatment decisions
• Assess patients every 3 months if uncontrolled and every 6 months if controlled
• Intensive insulin therapy patients should SMBG at least four times daily, before meals and at bedtime
• SMBG is crucial during times of intercurrent illness or stresses for early detection and prevention of DKA

Continuous Glucose Monitoring (CGM)

• Recommended in patients with type 1 DM who are not meeting glycemic goals
• Recommended in patients with hypoglycemia unawareness to better detect and prevent hypoglycemic events

Insulin Regimens

• Multiple-component insulin regimen consists of one injection of long-acting insulin (detemir, glargine, degludec) for basal glycemic coverage and three injections of rapid-acting insulin (aspart, lispro, glulisine) for glycemic coverage for each meal.
• Alternative insulin regimen consists of two injections of intermediate-acting insulin (NPH) and rapid-acting insulin (aspart, lispro, glulisine), or short-acting regular insulin.

Insulin Administration by Insulin Infusion Device

• The basal insulin rate is decreased during the evening and increased slightly prior to the patient awakening in the morning.
• Rapid-acting insulin (aspart, lispro, or glulisine) is used in the insulin pump.

Hypoglycemia

• Hypoglycemia is a common complication of some diabetes medications.
• Hypoglycemia severity levels:
  • Level 1: Hypoglycemia alert value (≤70 mg/dL); may not cause symptoms, but treatment with fast-acting carbohydrate and medication dose adjustment may be necessary.
  • Level 2: Clinically significant hypoglycemia.

Initial Autonomic Symptoms of Hypoglycemia

• Tachycardia is a common initial autonomic symptom of hypoglycemia, characterized by a rapid heart rate.
• Palpitations, a feeling of irregular heartbeat or fluttering, are also a typical initial autonomic symptom.
• Sweating is a classic autonomic symptom of hypoglycemia, indicating the body's "fight or flight" response.
• Tremors, or involuntary muscle tremors, are another initial autonomic symptom of hypoglycemia.
• Hunger, or Shakiness, is a initial autonomic symptom of hypoglycemia, which may be accompanied by other symptoms.

Neuroglycopenic Symptoms

• Neuroglycopenic symptoms often occur when blood glucose (BG) levels are low.
• These symptoms are related to the brain's response to low glucose levels.

Management of Hypoglycemia

• If the patient is unconscious, administer IV glucose or glucagon injection to increase glycogenolysis in the liver.
• Glucagon kits should be prescribed and readily available to patients on insulin at risk of severe hypoglycemia.
• It takes 10-15 minutes for glucose levels to rise after glucagon administration, and patients often experience vomiting.
• Position the patient on their side with the head tilted downward to prevent aspiration.

Monitoring and Prevention of Hypoglycemia

• Clinicians should monitor hypoglycemia at every visit to minimize future episodes.
• Reevaluate the treatment regimen of patients with frequent or severe hypoglycemia to prevent future episodes.

Macrovascular Complications

• Macrovascular complications, such as CHD and stroke, are the leading causes of death in people with diabetes.
• The ADA recommends low-dose aspirin therapy (75-162 mg daily) for all patients with established ASCVD.
• Clopidogrel may be used in patients allergic to aspirin as an alternative to aspirin therapy.

Cardiovascular Prevention

• The role of antiplatelet therapy for primary cardiovascular (CV) prevention is unclear due to the potential risk of bleeding, but may be recommended if the 10-year risk of a CV event is >20%.

Management of Established ASCVD

• In patients with established ASCVD, consider using a GLP1-RA (Glucagon-Like Peptide-1 Receptor Agonist) or an SGLT-2 inhibitor.

Blood Pressure Management

• For patients with BP > 120/80 mm Hg, recommend lifestyle changes, including:
  • Dietary changes
  • Physical activity
  • Weight loss in overweight or obese patients
• For patients with BP > 140/90 mm Hg, start drug therapy using agents proven to reduce CV events.
• For patients with BP > 160/100 mm Hg, use a combination of two medications.

Statin Therapy

• Initiate high-intensity statin therapy in all patients with:
  • Diabetes
  • Preexisting ASCVD
  • Regardless of baseline lipid levels
• Prescribe moderate-intensity statin to all patients with:
  • Type 1 or type 2 DM
  • Over the age of 40
  • Without ASCVD

Microvascular Complications

• Improving glucose control reduces the risk of developing microvascular complications and slows their progression.

Nephropathy

• Albuminuria is a marker of renal damage.
• Screening for albuminuria should begin: • At diagnosis and annually thereafter in persons with type 2 DM. • At puberty and after 5-years’ disease duration in persons with type 1 DM.
• Glucose and BP control are crucial for preventing and slowing nephropathy progression.
• SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) reduce the decline in kidney function in patients with CKD, with or without diabetes.
• ACE inhibitors and ARBs slow the progression of renal disease in patients with diabetes.
• Diuretics are often necessary due to volume expanded states and are recommended as second-line therapy.
• The ADA recommends a BP goal (no specific value mentioned in the text).

Retinopathy

• Patients with diabetes require routine eye examinations to thoroughly evaluate the retina.
• Early retinopathy can be reversed with improved glycemic control and optimal blood pressure control.
• Advanced retinopathy will not fully regress with improved glycemic control.
• Laser photocoagulation has significantly improved sight preservation.
• Intravitreal antivascular endothelial growth factor (VEGF) therapy is highly effective for sight preservation.

Anti-VEGF Medications

• Bevacizumab (used off-label) is an anti-VEGF monoclonal antibody.
• Ranibizumab is an anti-VEGF monoclonal antibody.
• Aflibercept is a VEGF decoy receptor.

Neuropathy

• Peripheral neuropathy is the most common complication in patients with type 2 diabetes mellitus.
• Predominant symptoms of peripheral neuropathy include paresthesias, numbness, and pain.
• The feet are more commonly affected than the hands.
• Improved glycemic control is the primary treatment for peripheral neuropathy and may alleviate some symptoms.
• Pharmacologic therapy for peripheral neuropathy is symptomatic and includes:
  • Low-dose tricyclic antidepressants (nortriptyline or desipramine)
  • Duloxetine
  • Gabapentin
  • Pregabalin
  • Venlafaxine
  • Topical capsaicin
  • Tramadol

Diabetic Complications and Management

• Gastroparesis can be improved with good glycemic control and medication such as metoclopramide or low-dose erythromycin.
• Diabetic diarrhea often occurs at night and can be treated with a 10-14 day course of antibiotics like doxycycline or metronidazole.
• Octreotide may be used in cases of diarrhea that do not respond to antibiotics.
• Orthostatic hypotension may be treated with mineralocorticoids like fludrocortisone or adrenergic agonists like midodrine.
• Erectile dysfunction is a common complication, and initial treatment often involves a trial of oral phosphodiesterase-5 inhibitors like sildenafil, vardenafil, or tadalafil.

Monitoring and Evaluation

• Measure A1C every 3-6 months to monitor long-term glycemic control.
• For patients with type 1 DM, SMBG should be performed 4-6 times a day, including before meals, physical activity, and at bedtime.
• The optimal frequency of SMBG for patients with type 2 DM on oral agents is still unclear.
• Healthcare providers should ask patients with type 1 DM about hypoglycemia frequency and severity at each visit.
• Screen for complications, including:
  • Eye exams
  • Blood pressure assessment
  • Foot examination
  • Albuminuria screening
  • Fasting lipid panel check

Preventive Care

• Administer an annual influenza vaccine to patients with diabetes.
• Assess for administration of pneumococcal and hepatitis B vaccine series.
• Manage other cardiovascular risk factors, such as smoking.

Definition and Characteristics of Asthma

• Asthma is a heterogeneous disease characterized by chronic airway inflammation.
• It is defined by a history of respiratory symptoms that vary over time and in intensity.
• Symptoms include wheezing, shortness of breath, chest tightness, and cough.

Pathophysiology of Asthma

• The disease involves a variable degree of airflow obstruction.
• In allergic patients, inhaled allergens activate inflammatory cells (mast cells, neutrophils, and macrophages).
• These cells release proinflammatory mediators, such as histamine and eicosanoids, which induce:
  • Contraction of airway smooth muscle (bronchospasm)
  • Mucus secretion
  • Edema
  • Exudation of plasma in the airways

Clinical Presentation of Asthma

Chronic Asthma

• Signs and symptoms include:
  • Episodes of shortness of breath
  • Chest tightness
  • Dry coughing (particularly at night)
  • Wheezing or a whistling sound when breathing
• These symptoms can occur:
  • With exercise
  • Spontaneously
  • In association with known allergens

Acute Severe Asthma

• Uncontrolled asthma can progress to an acute state, characterized by anxiety, severe dyspnea, shortness of breath, chest tightness, or burning, and limited ability to speak.
• Symptoms are unresponsive to usual measures, such as SABAs (short-acting beta2-agonists).

Signs of Acute Severe Asthma

• Dry, hacking cough
• Tachypnea (rapid breathing rate)
• Tachycardia (rapid heart rate)
• Pallor or cyanosis (pale or blue-tinged skin)
• Hyperinflated chest with intercostal and supraclavicular retractions (visible chest deformity)

Diagnosis of Chronic Asthma

• Diagnosis is primarily made through history and confirmatory spirometry.
• Spirometry demonstrates obstruction, indicated by a low FEV1/FVC ratio (forced expiratory volume in 1 second / forced vital capacity).

Goals of Asthma Treatment

• Achieve good control of symptoms and maintain normal activity levels.
• Minimize future risk of exacerbations and side effects.

Nonpharmacologic Therapy

Patient Education

• Mandatory to improve medication adherence, self-management skills, and use of healthcare services.

Monitoring and Triggers

• Routine PEF monitoring is recommended for patients with severe asthma or poor symptom perception.
• Avoidance of known allergenic triggers can improve symptoms and reduce medication use.

Smoking and Dehydration

• Smokers should be encouraged to quit.
• Correct dehydration if present in acute asthma exacerbations.

Oxygen Therapy

• Initiate oxygen therapy in acute asthma exacerbations.

Preferred Treatment for Adults and Adolescents

• GINA track 1 with as-needed ICS-formoterol remains the preferred treatment for adults and adolescents.
• ICS-formoterol reduces the risk of severe exacerbation compared to SABA reliever, with similar symptom control.

Add-on Treatment for Severe Asthma

• Add-on treatment for severe asthma includes long-acting muscarinic antagonist (LAMA), leukotriene receptor antagonists (LTRA), and biologic agents.
• Choice of add-on treatment depends on inflammatory phenotype (e.g. allergic asthma, eosinophilic asthma) and other clinical features.

Maintenance Oral Corticosteroid (OCS)

• Low-dose maintenance oral corticosteroid (OCS) should be considered only as a last resort due to long-term side effects.

Stepping Down Treatment

• Once good asthma control is achieved and maintained for 2-3 months, consider stepping down treatment gradually to find the patient's lowest treatment that controls both symptoms and exacerbations.

Primary Therapy for Acute Exacerbations

• Inhaled SABAs and systemic corticosteroids are primary therapies for acute exacerbations.
• Additional treatments may include inhaled ipratropium, intravenous (IV) magnesium sulfate, and oxygen.
• Treatments are typically administered concurrently to facilitate rapid improvement.

β2-Agonists

• SABAs (e.g., albuterol) are the first-choice treatment for acute severe asthma management and intermittent episodes of bronchospasm (e.g., exercise-induced bronchospasm).
• Aerosol administration of SABAs enhances bronchoselectivity and provides a more rapid response compared to systemic administration.

Long-Acting β2-Agonists (LABAs)

• Two LABAs, formoterol and salmeterol, provide bronchodilation for 12 hours or longer and are dosed twice daily.
• When combined with an inhaled corticosteroid (ICS), formoterol can be dosed daily and as needed (more frequently than twice daily).

Corticosteroids in Asthma Management

• ICS are the preferred long-term control therapy for persistent asthma due to their potency and consistent effectiveness.
• ICS are the only therapy shown to reduce the risk of mortality from asthma.
• Response to ICS is delayed, requiring patience and consistent use.

Systemic Toxicity of ICS

• Systemic toxicity of ICS is minimal with low-to-moderate doses.
• However, high doses of ICS increase the risk of systemic effects, including:
  • Growth suppression in children
  • Osteoporosis
  • Cataracts
  • Dermal thinning
  • Adrenal insufficiency

Local Adverse Effects of ICS

• Local adverse effects of ICS include:
  • Dose-dependent oropharyngeal candidiasis
  • Dysphonia
• These effects can be reduced by using a spacer device.

Systemic Corticosteroids in Acute Severe Asthma

• Systemic corticosteroids are indicated in all patients with acute severe asthma not responding completely to initial inhaled β2-agonist administration.
• Systemic corticosteroids should be administered within 1 hour of presentation.

IV vs Oral Administration

• IV therapy offers no advantage over oral administration except in patients unable to take oral medications.

Anticholinergics in Asthma

• Anticholinergics reverse cholinergic mediated bronchoconstriction and are effective bronchodilators in asthma.

Ipratropium Bromide in Asthma

• Ipratropium bromide is useful as adjunctive therapy in acute severe asthma not completely responsive to SABA alone.
• Patients with persistent asthma who are intolerant to short-acting β2-agonists may be prescribed ipratropium for rescue inhaler use.

Tiotropium Bromide in Asthma

• Tiotropium bromide is a long-acting inhaled anticholinergics with a duration of 24 hours.
• Tiotropium may be considered an add-on therapy in patients whose asthma is not well controlled with ICS and LABA combination therapy.

Leukotriene Modifiers

• Zafirlukast and montelukast are oral leukotriene receptor antagonists (LTRA) that reduce the proinflammatory and bronchoconstriction effects of leukotriene D4.
• Less effective than Inhaled Corticosteroids (ICS) and Long-Acting Beta-Agonists (LABAs) when added to ICS.
• Not used to treat acute exacerbations, must be taken regularly, even during symptom-free periods.

Adverse Effects

• Unusual adverse effects observed, including:
  • Irritability
  • Aggressiveness
  • Sleep disturbances
  • Rarely, suicidality
• Monitor patients for signs of these effects, especially within a few weeks of starting therapy.

Zileuton

• 5-lipoxygenase inhibitor
• Limited use due to:
  • Potential for elevated hepatic enzymes
  • Inhibition of metabolism of drugs metabolized by CYP3A4 (e.g., theophylline, warfarin)

Safety Concerns

• Fatal hepatic failure associated with zafirlukast reported.

Methylxanthines

• Rarely used today due to high risk of severe life-threatening toxicity, numerous drug interactions, and decreased efficacy compared to ICS, LABAs, and biologics.
• Theophylline is available for oral and IV administration.

Theophylline Dosing and Monitoring

• Dosing requires monitoring of serum concentrations for both efficacy and toxicity.
• Monitoring is necessary to prevent seizures and death.
• Theophylline is metabolized primarily by the hepatic CYP P450 microsomal enzymes.

Drug Interactions and Metabolism

• Drug interactions affect theophylline metabolism, significantly impacting blood concentrations.
• Hepatic CYP P450 microsomal enzymes play a crucial role in theophylline metabolism.

Evaluating Therapeutic Outcomes

• Inhalation technique should be evaluated monthly initially and then every 3–6 months for patients on inhaled drugs.
• Most patients should experience decreased symptoms within 1–2 weeks and achieve maximum improvement within 4–8 weeks after initiation of anti-inflammatory therapy or dosage increase.

Definition and Characteristics of COPD

• COPD is a heterogeneous lung condition characterized by chronic respiratory symptoms, including dyspnea, cough, sputum production, and/or exacerbations.
• These symptoms are caused by abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that lead to persistent, often progressive, airflow obstruction.

Component Conditions of COPD

• Chronic bronchitis: characterized by chronic or recurrent excess mucus secretion with cough that occurs on most days for at least 3 months of the year for at least 2 consecutive years.
• Emphysema: characterized by abnormal, permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls, without fibrosis.

Pathophysiology of COPD

• The most common cause of COPD is exposure to tobacco smoke.
• Inhalation of noxious particles and gases activates inflammatory cells to release inflammatory mediators.
• Inflammatory cells and mediators lead to widespread destructive changes in airways, resulting in chronic airflow limitation.
• Chronic hypoxemia and changes in pulmonary vasculature lead to increases in pulmonary pressures.
• Sustained elevated pulmonary pressures can lead to right-sided heart failure (cor pulmonale) characterized by right ventricle hypertrophy in response to increased pulmonary vascular resistance.

Clinical Presentation of COPD

• Initial symptoms include chronic cough and sputum production, which may persist for several years before dyspnea develops.
• Dyspnea is characterized as "increased effort to breathe" or "air hunger", worsens with exercise, and progresses over time, leading to decreased exercise tolerance or decline in physical activity.
• Additional symptoms may include chest tightness, wheezing, shallow breathing, increased resting respiratory rate, "barrel chest" due to lung hyperinflation, pursed lips during expiration, use of accessory respiratory muscles, and cyanosis of mucosal membranes.

Diagnosis of COPD

• Diagnosis is based on patient symptoms, history of exposure to risk factors (e.g., tobacco smoke and occupational substances), and confirmation by pulmonary function testing (spirometry).
• Spirometry assesses lung volumes and capacities, including Forced Vital Capacity (FVC) and Forced Expiratory Volume (FEV1).
• The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines classify airflow limitation into four grades: mild (GOLD 1), moderate (GOLD 2), severe (GOLD 3), and very severe (GOLD 4).

Goals of Treatment for COPD

• Prevent or slow disease progression
• Relieve symptoms
• Improve exercise tolerance
• Improve overall health status
• Prevent and treat exacerbations
• Prevent and treat complications
• Reduce morbidity and mortality

Nonpharmacologic Therapy for COPD

• Smoking cessation is the most important intervention to prevent development and progression of COPD
• Reducing exposure to occupational dust and fumes as well as other environmental toxins is crucial
• Pulmonary rehabilitation programs include:
  • Exercise training
  • Breathing exercises
  • Psychosocial support
• Annual influenza vaccination is recommended during each influenza season
• Vaccination against pneumococcal infection is recommended for all adults with COPD
• Long-term O2 therapy (by nasal cannula) is required for some patients with severe COPD

Pharmacologic Therapy for COPD

• Bronchodilators are the mainstay of drug therapy
• Classes of bronchodilators include:
  • Short- and long-acting β2-agonists
  • Short- and long-acting muscarinic antagonists (anticholinergics)
  • Methylxanthines
• Short-acting inhaled bronchodilators relieve symptoms (e.g., dyspnea)
• Long-acting inhaled bronchodilators relieve symptoms and reduce exacerbation frequency

Patient Assessment and Selection of Therapy

• GOLD guidelines combine symptoms (by questionnaires) and frequency of exacerbations in the previous 12 months to determine patient risk group and recommend initial treatment