Note: Davidson's Principles and Practice of Medicine is not directly in the library, but the content below is drawn from Harrison's Principles of Internal Medicine 22E (2025), which follows the identical framework and is the gold-standard equivalent for exam purposes. The approach, drug classes, targets, and complication management are completely interchangeable with Davidson's coverage.

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MANAGEMENT OF DIABETES MELLITUS

(Davidson's / Harrison's Framework - Long Answer for Marks)

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I. OVERALL GOALS OF THERAPY

1. Eliminate symptoms related to hyperglycemia (polyuria, polydipsia, weight loss, blurred vision)
2. Reduce or eliminate long-term microvascular and macrovascular complications
3. Allow the patient to achieve as normal a lifestyle as possible

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II. MULTIDISCIPLINARY TEAM APPROACH

• Primary care physician / endocrinologist / diabetologist
• Advanced practice provider (APP)
• Pharmacist
• Certified diabetes educator
• Nutritionist / dietitian
• Behavioral health professional / social worker
• Subspecialists when complications arise: ophthalmologist, nephrologist, neurologist, cardiologist, podiatrist

• Proactive, team-based delivery
• Self-management education and support
• Evidence-based guidelines
• Community resources supporting healthy lifestyles

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III. COMPREHENSIVE DIABETES CARE - KEY ELEMENTS (Table 416-1, Harrison's)

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IV. GLYCEMIC TARGETS

HbA1c Targets:

• General target: <7.0% (53 mmol/mol) for most non-pregnant adults
• <6.5% - appropriate in younger patients, short disease duration, no CVD, no hypoglycemia risk, high motivation
• <8.0% - appropriate in elderly, limited life expectancy, extensive comorbidities, hypoglycemia unawareness, long-standing poorly-controlled DM

Other Glycemic Targets (ADA):

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V. LIFESTYLE MANAGEMENT

A. Nutrition Therapy

• No single "diabetic diet" is universally mandated
• Carbohydrate restriction (low-carb or Mediterranean diet) - most effective at lowering postprandial glucose
• Reduce refined carbohydrates, added sugars, and saturated fats
• Increase dietary fiber, whole grains, vegetables
• Caloric restriction for overweight/obese Type 2 DM patients (target 5-10% weight loss)
• Avoid sugar-sweetened beverages
• Moderate alcohol (1 drink/day women, 2/day men) - always with food to prevent hypoglycemia
• Medical nutrition therapy (MNT) by a registered dietitian reduces HbA1c by 1-2%

B. Physical Activity

• 150 minutes/week of moderate-intensity aerobic activity (brisk walking, cycling, swimming)
• Resistance/strength training 2-3 times per week
• Break prolonged sitting (>90 min) with brief activity
• Benefits: improves insulin sensitivity, reduces HbA1c by ~0.6%, reduces cardiovascular risk
• Precautions in Type 1 DM: adjust insulin/carbohydrate intake around exercise; monitor for hypoglycemia

C. Diabetes Self-Management Education and Support (DSMES)

• Structured education at diagnosis, annually, and when complications arise
• Improves glycemic control, quality of life, and reduces complications

D. Smoking Cessation

• Smoking worsens insulin resistance and accelerates all vascular complications
• All diabetic patients should be counselled and offered cessation support

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VI. PHARMACOLOGICAL MANAGEMENT

TYPE 1 DIABETES MELLITUS

Basal-Bolus Insulin Regimen (preferred):

• Basal insulin (once or twice daily): covers fasting glucose
  • Long-acting: Glargine (U-100 or U-300), Detemir, Degludec (U-100 or U-200)
• Bolus/prandial insulin (before each meal): covers post-meal glucose
  • Rapid-acting: Lispro, Aspart, Glulisine
  • Ultra-rapid: Faster Aspart, Lispro-aabc
• Correction boluses for hyperglycemia using an insulin sensitivity factor

Continuous Subcutaneous Insulin Infusion (CSII / Insulin Pump):

• Delivers basal and bolus insulin continuously via a subcutaneous catheter
• Used in motivated, well-educated T1DM patients
• Reduces HbA1c and hypoglycemia compared to MDI in many patients
• Automated insulin delivery (AID/closed-loop) systems: CGM-integrated pump adjusts insulin automatically

Adjunctive therapy in Type 1 DM:

• Pramlintide (amylin analogue): reduces post-meal glucose, weight; used as adjunct with mealtime insulin
• SGLT2 inhibitors (off-label, with caution): may reduce HbA1c and weight but increased risk of diabetic ketoacidosis (euglycemic DKA)
• Metformin (off-label): sometimes used to reduce insulin dose in overweight T1DM

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TYPE 2 DIABETES MELLITUS

• Baseline HbA1c and degree of hyperglycemia
• Presence of ASCVD, heart failure, CKD
• Hypoglycemia risk
• Weight considerations
• Cost and access

Step 1: Lifestyle modification + METFORMIN

• Mechanism: reduces hepatic glucose output (activates AMPK), improves peripheral insulin sensitivity
• HbA1c reduction: 1-1.5%
• Advantages: weight-neutral or modest weight loss, no hypoglycemia, proven CV safety, low cost
• Contraindications: eGFR <30 mL/min/1.73m², active liver disease, excess alcohol, iodinated contrast (temporarily hold)
• Adverse effects: GI (nausea, diarrhea) - start low, titrate slowly; long-term: B12 deficiency
• Start: 500 mg OD or BD with meals; titrate to 1000 mg BD (max 2550 mg/day)

Step 2: Add second agent based on patient characteristics

Drug Classes Summary:

• Drugs: Semaglutide (SC weekly or oral daily), Liraglutide, Dulaglutide, Exenatide, Albiglutide
• Mechanism: Enhance glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, reduce appetite
• HbA1c reduction: 1-1.5%
• Benefits: Weight loss (3-5 kg), CV risk reduction (LEADER, SUSTAIN-6 trials), BP reduction
• Adverse effects: Nausea, vomiting, diarrhea (common initially), pancreatitis risk (rare), contraindicated in personal/family history of medullary thyroid cancer or MEN2
• No hypoglycemia when used alone

• Drugs: Empagliflozin, Dapagliflozin, Canagliflozin, Ertugliflozin
• Mechanism: Block SGLT2 in proximal tubule - glycosuria regardless of insulin
• HbA1c reduction: 0.5-1%
• Benefits: Weight loss (2-3 kg), BP reduction, HF hospitalization reduction (EMPA-REG, DAPA-HF), renal protection
• Adverse effects: Urinary tract infections, genital mycotic infections, polyuria, euglycemic DKA (rare), volume depletion, Fournier's gangrene (rare)
• Contraindicated: eGFR <20-45 (varies by agent)

• Drugs: Sitagliptin, Saxagliptin, Vildagliptin, Alogliptin, Linagliptin
• Mechanism: Inhibit DPP-4 enzyme which degrades GLP-1 - prolong endogenous GLP-1 action
• HbA1c reduction: 0.5-0.8%
• Advantages: Weight-neutral, low hypoglycemia risk, well tolerated, oral, once daily, dose-adjusted in CKD (except Linagliptin)
• Adverse effects: Nasopharyngitis, urinary tract infections, possible pancreatitis (rare), joint pain

• Drugs: Glimepiride, Glipizide, Glibenclamide (Glyburide), Gliclazide MR
• Mechanism: Bind SUR1 on pancreatic beta cells - stimulate insulin secretion (insulin secretagogues)
• HbA1c reduction: 1-1.5%
• Advantages: Very effective, cheap, widely available, oral
• Disadvantages: Hypoglycemia (major risk especially with Glibenclamide), weight gain (1-2 kg), secondary failure over time
• Preferred: Gliclazide MR (lower hypoglycemia risk vs. Glibenclamide)
• Use with caution in elderly, CKD, irregular meals

• Drugs: Pioglitazone (Rosiglitazone now rarely used)
• Mechanism: PPAR-gamma agonist - improve peripheral insulin sensitivity
• HbA1c reduction: 0.5-1.4%
• Advantages: Durable glycemic control, no hypoglycemia, modest TG reduction, HDL increase
• Disadvantages: Weight gain (2-4 kg), fluid retention, contraindicated in heart failure, increased fracture risk, rare bladder cancer risk (Pioglitazone long-term)
• CV benefit: Pioglitazone reduced stroke and MI (PROactive trial)

• Drugs: Acarbose, Miglitol, Voglibose
• Mechanism: Inhibit intestinal alpha-glucosidase - delay/reduce carbohydrate absorption - blunt post-meal glucose spikes
• HbA1c reduction: 0.5-0.8%
• Adverse effects: Flatulence, diarrhea, abdominal discomfort - limit use
• Useful for: Isolated postprandial hyperglycemia

• Drugs: Repaglinide, Nateglinide
• Mechanism: Short-acting insulin secretagogues, taken before meals
• Useful when meals are irregular, or in patients with renal impairment (Repaglinide safer in CKD)
• Risk: Hypoglycemia (less than SUs)

• Tirzepatide (Mounjaro) - weekly SC injection
• Dual agonist at GIP and GLP-1 receptors
• Greatest HbA1c reduction of any non-insulin agent (~2%)
• Significant weight loss (15-20% body weight)
• CV and renal benefits emerging

Step 3: Add insulin when oral/injectable agents are insufficient

• HbA1c >10% or symptomatic severe hyperglycemia at diagnosis
• Failure of 2-3 oral agents to achieve target
• Acute illness, surgery, hospitalization
• Pregnancy
• Renal/hepatic failure contraindicating oral agents
• Weight loss suggesting insulin deficiency

• Start with basal insulin (Glargine/Detemir/Degludec) 10 units at bedtime or 0.1-0.2 units/kg
• Titrate by 2 units every 3 days until fasting glucose is at target (4.4-7.2 mmol/L)
• If HbA1c still not at target despite optimal basal: add prandial insulin (basal-plus) or switch to premixed
• Continue metformin with insulin (reduces dose requirements and weight gain)
• Discontinue sulfonylureas when insulin is added (risk of hypoglycemia)

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VII. MONITORING AND SELF-MANAGEMENT

HbA1c Monitoring:

• 3-monthly until target achieved, then every 6 months
• Reflects average glucose over preceding 8-12 weeks (weighted toward recent weeks)
• Limitations: Falsely low in hemolytic anemia, hemoglobinopathies; falsely high in iron deficiency

Continuous Glucose Monitoring (CGM):

• Real-time or intermittently-scanned glucose readings via subcutaneous sensor
• Recommended for all T1DM patients, and T2DM on insulin
• Time-in-Range (TIR 70-180 mg/dL) is the key CGM metric - target >70%
• Flash glucose monitoring (FreeStyle Libre): factory calibrated, cost-effective option

Self-Monitoring of Blood Glucose (SMBG):

• T1DM: minimum 4 tests/day (before meals + bedtime) if not on CGM
• T2DM on insulin: as directed by physician
• T2DM on non-insulin therapy: periodic checks - not routinely needed

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VIII. MANAGEMENT OF SPECIFIC SITUATIONS

A. Hypertension in DM

• Target BP: <130/80 mmHg (ADA 2024)
• First-line: ACE inhibitor or ARB (renoprotective, antiproteinuric) - mandatory if proteinuria or CKD present
• Add thiazide, calcium channel blocker, or beta-blocker as needed
• Avoid: high-dose thiazides (worsen insulin resistance), non-selective beta-blockers (mask hypoglycemia)

B. Dyslipidemia in DM

• Statin therapy for all diabetic patients aged >40 years (primary prevention) or with ASCVD (any age)
• Target LDL: <2.6 mmol/L (no ASCVD); <1.8 mmol/L (established ASCVD)
• Very high risk (ASCVD + DM): target LDL <1.4 mmol/L
• Add Ezetimibe or PCSK9 inhibitor if statin alone insufficient
• Triglycerides: target <1.7 mmol/L; fibrates if >5.6 mmol/L (pancreatitis risk)

C. Antiplatelet Therapy

• Aspirin 75-100 mg/day: Recommended for all T2DM patients with established ASCVD
• Primary prevention (no prior CVD): Aspirin only if >50 years with additional CVD risk factors (discuss risk-benefit)

D. Diabetic Nephropathy (Diabetic Kidney Disease)

• Screen: Annual urine albumin-to-creatinine ratio (ACR) + eGFR
• Microalbuminuria: ACR 30-300 mg/g; Macroalbuminuria: ACR >300 mg/g
• Treatment: ACE inhibitor or ARB (first-line, even if normotensive); SGLT2 inhibitor (Dapagliflozin, Empagliflozin); Finerenone (new non-steroidal MRA) - reduces CKD progression in T2DM with CKD
• Dietary protein restriction: 0.8 g/kg/day (avoid excess protein)
• BP control <130/80

E. Diabetic Retinopathy

• Screen: Dilated fundus examination at diagnosis (T2DM), 5 years after diagnosis (T1DM), then annually
• Non-proliferative (NPDR): Optimize glycemic + BP control
• Proliferative (PDR): Panretinal photocoagulation (PRP) laser therapy; intravitreal anti-VEGF agents (Ranibizumab, Bevacizumab)
• Macular oedema: Anti-VEGF injections first-line; focal laser second-line

F. Diabetic Neuropathy

• Symmetric distal polyneuropathy (most common):
  • Pain: Duloxetine (first-line), Pregabalin, Gabapentin, Tricyclic antidepressants (Amitriptyline), Tapentadol
  • Topical: Capsaicin cream, Lidocaine patches
• Autonomic neuropathy:
  • Gastroparesis: small frequent meals, Metoclopramide, Domperidone, Erythromycin
  • Orthostatic hypotension: Fludrocortisone, Midodrine
  • Erectile dysfunction: PDE-5 inhibitors (Sildenafil)
• Foot care: Regular inspection, podiatry, protective footwear, early treatment of ulcers

G. Cardiovascular Disease

• Strongest predictor of mortality in T2DM
• Aggressively treat all modifiable CV risk factors: glycemia, BP, lipids, smoking, weight, physical activity
• GLP-1 RA (Semaglutide, Liraglutide) and SGLT2 inhibitors (Empagliflozin, Canagliflozin) have proven CV mortality benefit in T2DM patients with ASCVD

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IX. SPECIAL CIRCUMSTANCES

Diabetic Ketoacidosis (DKA) - T1DM emergency

• Insulin deficiency + stress hormones → lipolysis → ketogenesis → metabolic acidosis
• Precipitants: missed insulin, infection, new diagnosis T1DM
• Management: IV fluids (0.9% NaCl), IV insulin infusion, Potassium replacement, treat precipitant
• Hold SGLT2 inhibitors; restart insulin when patient eating and glucose <11 mmol/L

Hyperglycaemic Hyperosmolar State (HHS) - T2DM emergency

• Extreme hyperglycemia (>30 mmol/L), severe dehydration, no/minimal ketosis
• Management: Aggressive IV fluid resuscitation (2-3L in first hour), low-dose insulin, electrolyte monitoring, anticoagulation (high DVT risk)

Inpatient / Perioperative Management

• Target glucose: 7.8-10.0 mmol/L in hospital (general ward)
• ICU target: 7.8-10.0 mmol/L (tighter targets increase hypoglycemia risk)
• Preferred: Basal-bolus insulin regimen in hospital (not sliding scale alone)
• Hold: Metformin (contrast, surgery, renal impairment), SGLT2i (DKA risk), GLP-1 RA (gastroparesis, poor oral intake)

Diabetes in Pregnancy (Gestational DM / Pre-existing DM)

• Target HbA1c: <6.5% pre-conception; <6.0% first trimester; <6.5% second and third trimester
• Safe in pregnancy: Insulin (all types), Metformin (some guidelines), Glibenclamide (some guidelines)
• Avoid: All other OHAs, ACE inhibitors, ARBs (teratogenic), statins
• GDM: Screen all at 24-28 weeks (75g OGTT); treat with dietary modification first, then insulin if targets not met

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X. EVIDENCE BASE FOR INTENSIVE GLYCEMIC CONTROL

Type 1 DM - DCCT/EDIC Trial:

• Intensive therapy (HbA1c 7.3%) vs. Conventional (HbA1c 9.1%)
• Intensive therapy reduced:
  • Retinopathy: 47% reduction
  • Nephropathy (clinical): 54% reduction
  • Neuropathy: 60% reduction
  • Albuminuria: 39% reduction
  • CV events (30yr follow-up): 57% reduction in MI/stroke/CV death
  • Mortality: 33% reduction
• Legacy effect: Benefits persisted for decades even after glycemic separation disappeared

Type 2 DM - UKPDS:

• Intensive glycemic control reduced microvascular complications by 25%
• Post-trial monitoring: 10-year legacy effect - continued reduction in MI and death

CV Outcome Trials (CVOTs):

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XI. PREVENTION OF TYPE 2 DIABETES

At-risk individuals (Prediabetes: IFG or IGT):

• Lifestyle modification (primary intervention): 5-10% weight loss + 150 min/week exercise reduces T2DM risk by 58% (Diabetes Prevention Program, DPP)
• Metformin: Reduces risk by 31% in DPP; especially effective in BMI >35, age <60, women with prior GDM
• Screen annually for progression to T2DM

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XII. SYSTEMATIC APPROACH SUMMARY TABLE

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