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Management of Diabetes Mellitus and Its Complications

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Overview

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I. Glycemic Targets

• 21% reduction in any diabetes-related endpoint
• 14% reduction in MI
• 12% reduction in stroke
• 37% reduction in microvascular disease risk

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II. Non-Pharmacological Management

• Medical nutrition therapy: Reduced caloric intake, low glycaemic-index foods, reduced saturated fats
• Physical activity: At least 150 minutes/week of moderate aerobic exercise
• Weight loss: Even 5-10% weight reduction improves insulin sensitivity significantly
• Smoking cessation: Mandatory for all patients
• Self-monitoring of blood glucose (SMBG)
• Diabetes education: Patient empowerment in self-care

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III. Pharmacological Management

First-line: Metformin (Biguanide)

• Mechanism: Decreases hepatic glucose production; improves insulin sensitivity
• Benefits: No hypoglycemia risk; weight-neutral to modest weight loss; reduces acute cardiovascular events by 38% (UKPDS)
• Caution: Avoid if eGFR < 30 mL/min; monitor renal function and vitamin B12 levels
• Preferred first-line agent for type 2 DM unless contraindicated

Second-line Agents (Summary Table)

Modern Cardio-Renal Priority Framework

• SGLT2 inhibitors: Preferred in diabetic kidney disease (reduce intraglomerular pressure via tubuloglomerular feedback, lower BP, reduce CV events). Discontinue when eGFR < 30 mL/min.
• GLP-1 agonists: Alternative when SGLT2 inhibitors cannot be used; can continue until eGFR falls to 15 mL/min. Semaglutide (weekly), liraglutide (daily), dulaglutide (weekly) are options.

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IV. Insulin Therapy

• Basal insulin (e.g., glargine, detemir): Once-daily; controls fasting glucose
• Bolus (prandial) insulin (e.g., lispro, aspart): Given before meals; controls postprandial glucose
• Premixed insulin: Convenient but less flexible
• Dose titration based on fasting glucose readings
• Risk of hypoglycemia - patient education mandatory

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V. Complications and Their Management

1. Diabetic Retinopathy

• Nonproliferative DR (NPDR): Microaneurysms, retinal hemorrhages, cotton wool spots, venous beading
• Proliferative DR (PDR): Neovascularization, vitreous hemorrhage, retinal detachment
• Diabetic macular edema (DME): Now the leading cause of vision loss in diabetics; increased vascular permeability causes macular swelling

• Type 1 DM: First eye exam within 5 years of diagnosis, then annually
• Type 2 DM: Eye exam at diagnosis, then annually (every 2 years if well controlled with no retinopathy)

• Tight glycemic control: 76% reduced risk of developing DR in type 1 DM; 16-25% reduction in type 2 DM
• Blood pressure control slows progression
• Laser photocoagulation: Indicated for PDR and selected severe NPDR
• Anti-VEGF injections (intravitreal): Improves vision in diabetic macular edema
• Fenofibrate: Evidence supports slowing DR progression (recommended in Australia and Canada for secondary prevention)

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2. Diabetic Neuropathy

• Distal symmetric polyneuropathy (DSPN): "Stocking-glove" distribution; burning pain, paresthesias
• Focal mononeuropathies: CN III or VI (cranial); median nerve most common limb site
• Diabetic amyotrophy: Severe asymmetric muscle weakness/wasting of iliopsoas and quadriceps
• Autonomic neuropathy: Cardiovascular (orthostatic hypotension, fixed HR, resting tachycardia), GI (gastroparesis, diabetic diarrhea, constipation), genitourinary (bladder dysfunction, erectile dysfunction)

• Monofilament testing (5.07/10g Semmes-Weinstein): LR+ = 10.2 for abnormal perception
• Tuning fork (128 Hz) vibration testing: LR+ = 18.5 for timed vibration
• Annual foot exam for all diabetics

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3. Diabetic Nephropathy (Diabetic Kidney Disease)

• Microalbuminuria appears 10-15 years after onset
• 80% progress to macroalbuminuria over the next 10-15 years
• 50% develop ESRD within 10 years of macroalbuminuria; 75% by 20 years

• Normal: < 30 mcg/mg
• Microalbuminuria: 30-299 mcg/mg
• Macroalbuminuria: ≥ 300 mcg/mg

• Glycemic control (HbA1c < 7%)
• BP control (target < 130/80 mmHg)
• RAAS blockade: ACE inhibitors or ARBs - preferred antihypertensives; reduce proteinuria and slow progression
• SGLT2 inhibitors: First-line add-on; reduce intraglomerular pressure, promote natriuresis, lower BP - stop at eGFR < 30
• GLP-1 agonists: Alternative when SGLT2 inhibitors not tolerated; use until eGFR falls to 15 mL/min
• Dietary protein restriction: 0.8 g/kg/day
• Preparation for RRT: Erythropoietin for anemia; manage calcium-phosphate metabolism

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4. Macrovascular Disease (CVD, Stroke, PAD)

• Advanced glycation end-products (AGEs) damage the vascular endothelium
• Pro-oxidative and pro-inflammatory state
• Hypercoagulability: Increased coagulation factors, platelet reactivity, reduced tPA, increased PAI-1
• Atherogenic dyslipidemia: Low HDL, elevated triglycerides, small dense LDL

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5. Diabetic Foot

• Foot ulcers affect up to 25% of diabetics over their lifetime
• Leading cause of non-traumatic lower limb amputation

• Annual comprehensive foot exam
• Monofilament and Doppler ABI (ankle-brachial index) screening
• Patient education: proper footwear, daily inspection
• Multidisciplinary wound care for active ulcers
• Revascularization for significant PAD

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VI. Monitoring Summary

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Recent Evidence Update

1. GLP-1 RAs + SGLT2 inhibitors combo - Circulation 2024 (PMID 39210781): Combined therapy provides additive cardiovascular and kidney protection beyond either drug class alone.
2. GLP-1 RAs in kidney/CV disease - Lancet Diabetes Endocrinol 2025 (PMID 39608381): GLP-1 receptor agonists significantly reduce progression of diabetic kidney disease and major cardiovascular events in RCTs.

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Management of Hyperthyroidism and Hypothyroidism

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PART 1: HYPERTHYROIDISM

Definition and Diagnosis

• Suppressed TSH (< 0.1 mIU/L; often < 0.01 mIU/L in Graves disease)
• Elevated free T4 (FT4) and/or free T3 (FT3)

Common Causes

Clinical Features (Hypermetabolic State)

• Tachycardia, wide pulse pressure, systolic hypertension
• Fever, fine tremor, warm moist skin
• Anxiety, hyperactivity, insomnia
• Diarrhea, weight loss despite increased appetite
• Atrial fibrillation (particularly in elderly and subclinical hyperthyroidism)
• Osteoporosis with prolonged hyperthyroidism
• Exophthalmos, lid lag, lid retraction (Graves ophthalmopathy)

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Management of Hyperthyroidism

1. Antithyroid Drugs (Thionamides)

• Titration regimen: Start high, reduce dose as euthyroidism is achieved (target TSH within normal range)
• Block-and-replace regimen: Full-dose thionamide + low-dose levothyroxine added once euthyroid

• Agranulocytosis (0.2-0.5%) - warn patients to report fever/sore throat; stop drug immediately if suspected
• Rash, urticaria (5-10%)
• Hepatotoxicity (PTU > MMI) - monitor LFTs
• Teratogenicity: avoid MMI in 1st trimester (methimazole embryopathy); switch to PTU; after 1st trimester, switch back to MMI

2. Radioactive Iodine (¹³¹I)

• Most commonly used definitive therapy in the USA
• Destroys thyroid tissue over weeks to months
• Results in hypothyroidism in the majority (then treated with levothyroxine)
• Contraindicated in: pregnancy, breastfeeding, active/severe Graves ophthalmopathy
• May worsen ophthalmopathy (risk mitigated by concurrent glucocorticoids)
• Give antithyroid drugs first to render patient euthyroid before ¹³¹I if severely thyrotoxic; stop thionamide 5-7 days before treatment

3. Surgery (Thyroidectomy)

• Near-total or total thyroidectomy preferred
• Results in permanent hypothyroidism (requires lifelong levothyroxine)
• Indications: Large goiter causing compressive symptoms; suspected malignancy; failed medical therapy; patient preference; severe or active Graves ophthalmopathy; pregnancy in 2nd trimester
• Render patient euthyroid with antithyroid drugs pre-operatively
• Complications: Hypoparathyroidism, recurrent laryngeal nerve injury

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Symptomatic Control: Beta-Blockers

• Propranolol 40-80 mg every 6-8h (preferred - also inhibits T4→T3 conversion; improves tremor, palpitations, anxiety, heat intolerance)
• Atenolol or metoprolol for patients with asthma or COPD (beta-1 selective)
• Do NOT use propranolol in decompensated heart failure

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Special Populations

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Subclinical Hyperthyroidism

• Defined as TSH < 0.1 mIU/L with normal FT4 and FT3
• Associated with 2-3x increased risk of atrial fibrillation (Framingham data)
• Associated with reduced bone mineral density and fracture risk
• AACE recommends treatment for subclinical hyperthyroidism caused by nodular thyroid disease
• ¹³¹I preferred for toxic nodule/TMNG in this setting

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Graves Ophthalmopathy

• Mild: Artificial tears, dark glasses, tape eyelids at night, smoking cessation, selenium 100 mcg bid
• Moderate-to-severe: IV methylprednisolone (500 mg weekly x 6 weeks, then 250 mg weekly x 6 weeks) - preferred over oral steroids
• Refractory: Orbital external beam radiotherapy; orbital decompression surgery
• Teprotumumab (IGF-1 receptor monoclonal antibody): Improves proptosis and diplopia in active moderate-to-severe disease

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THYROID STORM (Thyrotoxic Crisis)

• Cooling (fans, ice packs, cooling blankets) + acetaminophen (avoid aspirin - displaces T4/T3 from binding proteins)
• IV fluids with dextrose (glycogen stores depleted)
• Benzodiazepines for agitation
• Treat precipitating cause (antibiotics empirically if infection suspected)

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PART 2: HYPOTHYROIDISM

Definition and Diagnosis

• Elevated TSH (> 4.5 mIU/L; often > 10 mIU/L in overt hypothyroidism; > 25 mIU/L in severe/prolonged cases)
• Low or low-normal FT4

Causes

Clinical Features (Hypometabolic State)

• Fatigue, cold intolerance, weight gain
• Dry skin, coarse hair, hair loss, brittle nails
• Constipation, bradycardia
• Depression, cognitive slowing, memory impairment
• Periorbital puffiness, non-pitting edema (myxedema)
• Delayed relaxation of deep tendon reflexes
• Menstrual irregularities, infertility
• Dyslipidemia (elevated LDL and total cholesterol)
• Hyponatremia (in severe cases)

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Management of Hypothyroidism

Standard Treatment: Levothyroxine (L-T4)

• Drug of choice for primary hypothyroidism
• Mechanism: Exogenous T4 is peripherally converted to active T3 in tissues
• Standard replacement dose: 1.6 mcg/kg/day (average adult: 75-150 mcg/day)
• Half-life: 7 days - permits once-daily dosing; steady state achieved at 6-8 weeks
• Take on an empty stomach, 30-60 minutes before breakfast (avoid calcium, iron, antacids which impair absorption)

T4 + T3 Combination Therapy

• Considered when patient has normal TSH on T4 alone but persistent hypothyroid symptoms
• Add low-dose liothyronine (L-T3) to T4
• Monitor carefully - T3 is more cardiotoxic and harder to titrate
• Maintain TSH above 1.0 mIU/L
• Not standard first-line; reserve for symptomatic patients who fail T4 monotherapy

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Subclinical Hypothyroidism

• TSH 4.5-10 mIU/L with normal FT4; patient asymptomatic or mildly symptomatic
• 3-5% progress to overt hypothyroidism annually (most represent early Hashimoto disease)
• Check TPO antibodies - positive TPO Ab predicts faster progression
• Treatment considerations (ATA/AACE 2012 guidelines):
  • Treat if: TPO Ab positive, symptoms of hypothyroidism, history of atherosclerotic vascular disease, TSH > 10 mIU/L
  • Observe if: TSH 4.5-10 mIU/L, no antibodies, truly asymptomatic
• Associated with increased risk of CHD events, heart failure, and adverse pregnancy outcomes

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Hypothyroidism in Pregnancy

• Target TSH: 0.1-2.5 mIU/L in 1st trimester; 0.2-3.0 mIU/L in 2nd/3rd trimester
• Levothyroxine dose typically increases 25-30% in first weeks of pregnancy
• Maternal hypothyroidism impairs fetal neurodevelopment - early and aggressive treatment is essential
• Check TSH every 4 weeks in 1st trimester; every 6-8 weeks thereafter

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Hypothyroidism with Coronary Artery Disease

• If coronary revascularization is indicated: perform revascularization BEFORE correcting hypothyroidism
• Use very low starting doses (12.5-25 mcg/day); titrate slowly over months
• Monitor for angina with dose changes

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MYXEDEMA COMA

• Hypothermia (often severe, < 35°C)
• Respiratory depression (CO2 retention)
• Decreased or absent consciousness
• Hyponatremia, hypoglycemia, bradycardia, hypotension

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Summary Comparison Table

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