32–48 minutes
ADA Standards of Care 2024/2025
ACCP Updates in Therapeutics 2025
CLASSIFICATION & STAGING OF DIABETES
1A. Types of Diabetes
| TYPE | KEY FEATURES | PREVALENCE | NOTES |
| Type 1 DM (T1D) | Autoimmune beta-cell destruction; absolute insulin deficiency; usually symptomatic | 5-10% of DM | Formerly ‘insulin-dependent DM’; any age; rapid onset in children, slower in adults (LADA) |
| Type 2 DM (T2D) | Insulin resistance + progressive beta-cell secretory defect; GI, brain, liver, kidney involvement | 90-95% of DM | Often asymptomatic; slow onset 5-10 years; screen early; rising in pediatrics |
| Gestational DM | Glucose intolerance during pregnancy; most common 3rd trimester | 1-14% of pregnancies (~4%) | Screen at 24-28 wks; screen postpartum at 4-12 wks; rescreen q3yr for life |
| MODY | Genetic defect in beta-cell function; little/no impairment in insulin action | Rare | Onset <25 yrs; mimics T1D or T2D; responds to sulfonylureas; often misdiagnosed |
| Secondary DM | Pancreatic disease, drug-induced, genetic syndromes | Variable | Glucocorticoids, atypical antipsychotics, L-asparaginase, mTOR inhibitors, ICI (see Section 11) |
1B. T1D Staging (ADA)
| STAGE | AUTOANTIBODIES | GLYCEMIA | SYMPTOMS | CLINICAL ACTION |
| Stage 1 | Multiple Ab+ | Normal | None | Enroll in observational study; counsel re: symptoms |
| Stage 2 | Multiple Ab+ | Prediabetes range | None | Monitor closely; consider teplizumab (anti-CD3 mAb) to delay T1D |
| Stage 3 | Ab+ (usually) | Diabetes criteria | Present | Initiate insulin therapy immediately |
CLINICAL PEARL: MODY is commonly misdiagnosed as T1D or T2D. In young, non-obese patients with ‘T2D’ or atypical T1D, consider MODY testing. These patients may respond to sulfonylureas rather than insulin.
1C. Prediabetes
- Impaired Fasting Glucose (IFG): FPG 100-125 mg/dL
- Impaired Glucose Tolerance (IGT): 2-hr plasma glucose 140-199 mg/dL after 75-g OGTT
- HbA1c: 5.7%-6.4%
- Screen annually for progression to T2D if prediabetes is confirmed
- Interventions: lifestyle (diet + exercise), metformin (especially if BMI ≥35, age <60, or history of gestational DM)
SCREENING CRITERIA
2A. T2D Screening
- Age ≥35: Screen all; repeat q3yr if normal
- Screen regardless of age if BMI ≥25 kg/m² (≥23 in Asian Americans) + at least ONE risk factor:
- First-degree relative with T2D
- High-risk ethnicity: African American, Latino, Native American, Asian American, Pacific Islander
- History of CVD
- HbA1c ≥5.7%, IGT, or IFG on previous testing
- Hypertension (BP ≥130/80 or on antihypertensive therapy)
- HDL <35 mg/dL or TG >250 mg/dL
- History of PCOS
- Physical inactivity
- Severe obesity, acanthosis nigricans (insulin resistance conditions)
2B. T1D Screening
- Symptomatic patients: Screen immediately
- Asymptomatic high-risk: First-degree relatives with T1D; measure islet autoantibodies (GAD65, IA-2, ZnT8, IAA)
- If screen positive: counsel on symptoms of hyperglycemia, risk of T1D; consider enrollment in observational study
2C. Gestational DM Screening
- At first prenatal visit: screen for undiagnosed T2D in all patients with T2D risk factors
- At 24-28 weeks gestation: 75-g OGTT (one-step) or 50-g nonfasting OGTT (two-step)
- Post-delivery: Screen for T2D at 4-12 weeks post-delivery
- Lifelong: Rescreen every 3 years for T2D
3. DIAGNOSTIC CRITERIA
3A. Diagnostic Criteria – Non-Pregnant Adults
| TEST | PREDIABETES | DIABETES | NOTES |
| Fasting Plasma Glucose (FPG) (≥8 hr fast) | 100-125 mg/dL | ≥126 mg/dL | Easy, convenient; most reproducible |
| 2-hr OGTT (75-g glucose) | 140-199 mg/dL | ≥200 mg/dL | More sensitive/specific than FPG; cumbersome |
| HbA1c | 5.7%-6.4% | ≥6.5% | No fasting required; less day-to-day variability; can be inaccurate in hemoglobinopathies, hemolytic anemia, recent transfusion, pregnancy, ESRD |
| Random Plasma Glucose | N/A | ≥200 mg/dL + symptoms | Symptoms: polyuria, polydipsia, unexplained weight loss |
- Unless symptoms of hyperglycemia are clearly present, DIAGNOSIS requires TWO abnormal tests – can be from the same blood draw or two separate days.
- Two different tests (e.g., FPG + HbA1c) on the same sample count as two tests per updated ADA recommendations.
3B. Gestational DM (24-28 wks gestation)
| APPROACH | TEST | DIAGNOSTIC THRESHOLD |
| One-Step | 75-g OGTT (fasting) | Fasting ≥92 mg/dL OR 1-hr ≥180 mg/dL OR 2-hr ≥153 mg/dL (ANY one) |
| Two-Step | Step 1: 50-g OGTT (nonfasting) Step 2 if ≥140 mg/dL: 100-g OGTT (fasting) | Step 2: Use ADA 100-g OGTT diagnostic glucose criteria (Carpenter-Coustan or NDDG) |
WARNING: HbA1c LIMITATIONS in Hem/Onc: Falsely LOW in hemolytic anemia, sickle cell disease, recent chemotherapy (hemolysis), post-transfusion, erythropoiesis-stimulating agents, pregnancy. Use FPG or OGTT instead. ESRD also affects HbA1c accuracy.
3C. Additional Tests to Differentiate T1D from T2D
- C-peptide: Measure of endogenous insulin secretion. Near-zero in T1D; normal or elevated early in T2D
- Autoantibodies: GAD65, IA-2, ZnT8, IAA, islet cell Abs – all suggest autoimmune (T1D) etiology
GOALS OF THERAPY – NON-PREGNANT ADULTS
4A. Glycemic Goals (ADA 2024)
| PARAMETER | GOAL | NOTES |
| HbA1c | <7.0% (general) | AACE/ACE recommends ≤6.5%. Less stringent (e.g., <8%) in: short life expectancy, terminal cancer, advanced complications, frail elderly, frequent hypoglycemia, extensive comorbidities |
| HbA1c monitoring | q6mo (at goal); q3mo (above goal) | More frequent if regimen change or poor control |
| Fasting / Pre-meal BG | 80-130 mg/dL | Target range for self-monitoring |
| Peak Post-prandial BG | <180 mg/dL | 1-2 hrs after meal start |
| Time In Range (TIR) | ≥70% (70-180 mg/dL range) | For CGM users; time below range <4% |
| Time Below Range | <4% (<70 mg/dL) | <1% for <54 mg/dL |
4B. Non-Glycemic Goals
| PARAMETER | GOAL | FIRST-LINE AGENT(S) |
| Blood Pressure | <130/80 mmHg | ACEi or ARB (if albuminuria present); DHP-CCB or thiazide-like diuretic |
| LDL – No established CVD (age 40-75) | ≥50% reduction or LDL <70 mg/dL | Moderate- to high-intensity statin |
| LDL – Established CVD | ≥50% reduction AND LDL <55 mg/dL | High-intensity statin; add ezetimibe or PCSK9i if still above goal |
| Antiplatelet – Established ASCVD | ASA 75-162 mg/day | Clopidogrel if ASA-intolerant |
| Antiplatelet – Primary prevention | Consider if high CV risk | Individualize; discuss risk of bleeding vs. benefit |
CLINICAL PEARL: Blood pressure control reduces BOTH microvascular (nephropathy, retinopathy) AND macrovascular (MI, stroke) complications. Glycemic control primarily reduces microvascular complications. This is why BP management is arguably the most impactful intervention in T2D.
T1D MANAGEMENT & INSULIN THERAPY
5A. Insulin Types – U-100 (100 units/mL)
| CATEGORY | DRUG(S) | ONSET | PEAK | DURATION | ADMIN TIMING |
| Rapid-acting | Aspart (NovoLog) Lispro (Humalog) Glulisine (Apidra) Inhaled insulin (Afrezza) | 5-15 min (inhaled: start of meal) | 1-3 hr (shorter for fast-acting formulations) | 2-5 hr | 5-15 min BEFORE meal (inhaled: at start of meal) |
| Short-acting | Regular (Humulin R, Novolin R) | 30-60 min | 2-4 hr | 6-8 hr | 30 min BEFORE meal |
| Intermediate | NPH (Humulin N, Novolin N) [CLOUDY] | 1-2 hr | 4-8 hr | 10-20 hr | No fixed meal relationship (given 2x/day traditionally) |
| Long-acting (basal) | Glargine U-100 (Lantus, Basaglar) Degludec U-100 (Tresiba) | 1-2 hr | Peakless | ~24 hr 24-42 hr (degludec) | Once daily; any consistent time; do NOT mix |
5B. Concentrated Insulins – Special Attention Required
| PRODUCT | CONCENTRATION | INDICATION | KEY CONSIDERATION |
| Glargine U-300 (Toujeo) | 300 units/mL | T1D/T2D – high insulin requirements | 3x more concentrated than U-100; do NOT dose convert 1:1 from U-100; slightly longer than U-100 glargine |
| Degludec U-200 (Tresiba) | 200 units/mL | T1D/T2D – high insulin requirements | Pen delivers same dose in half the volume; no dose conversion needed (same units) |
| Lispro U-200 (Humalog KwikPen) | 200 units/mL | T2D with high rapid-acting needs | Pen only; same dose in half the volume |
| Regular U-500 (Humulin R U-500) | 500 units/mL | Severe insulin resistance T2D (>200 units/day) | 5x concentrated; HAS INTERMEDIATE-ACTING PROPERTIES (onset 30 min, duration up to 24 hr); extreme risk of confusion with U-100 |
WARNING: INSULIN CONCENTRATION ERRORS are a high-alert medication concern. U-300 and U-200 are NOT dose-equivalent to U-100 on a per-mL basis. U-500 regular insulin has intermediate-acting properties – do not treat as short-acting insulin. Always verify the product and concentration at every order review.
5C. Insulin Dosing Calculations for T1D (Basal-Bolus)
| CALCULATION | FORMULA | EXAMPLE (80 kg patient) |
| Total Daily Insulin (TDI) | 0.3-0.6 units/kg/day (typically 0.5 units/kg/day for initial estimate) 0.3 if near honeymoon phase; higher if DKA treatment | 80 kg × 0.5 = 40 units TDI |
| Basal Insulin (50% of TDI) | TDI × 0.5 → give as once-daily long-acting insulin | 40 × 0.5 = 20 units glargine at bedtime |
| Total Bolus (50% of TDI) | TDI × 0.5 → divide equally among 3 meals | 40 × 0.5 = 20 units ÷ 3 = ~7 units before each meal |
| Insulin-to-Carb Ratio (ICR) ‘Rule of 500’ | ICR = 500 ÷ TDI = grams of carbs covered by 1 unit of rapid-acting insulin | 500 ÷ 40 = 12.5 g carbs per 1 unit |
| Insulin Sensitivity Factor (ISF) ‘1800 Rule’ | ISF = 1800 ÷ TDI = how much 1 unit rapid-acting lowers BG (mg/dL) | 1800 ÷ 40 = 45 mg/dL drop per 1 unit |
| ISF for Regular Insulin ‘1500 Rule’ | ISF = 1500 ÷ TDI | 1500 ÷ 40 = 37.5 mg/dL drop per 1 unit regular |
CLINICAL PEARL: The 1800 rule is patient-specific and more precise than sliding-scale insulin. Always document the ISF in the patient chart. If a patient’s BG is 240 and target is 120, the correction dose = (240-120)/ISF. This is your tool at bedside during pharmacy rounds.
5D. Amylin Analog – Pramlintide (Symlin)
- Mechanism: Synthetic amylin – co-secreted with insulin; slows gastric emptying, reduces glucagon, promotes satiety
- T1D dosing: Start 15 mcg SQ immediately before main meals; titrate by 15 mcg q3 days; max 60 mcg per meal
- T2D dosing: Start 60 mcg SQ before main meals; titrate by 60 mcg q3-7 days; max 120 mcg per meal
- CRITICAL: REDUCE preprandial insulin by 50% when initiating pramlintide to avoid severe hypoglycemia
- Cannot be mixed with insulin; requires separate injection device
- ADEs: Boxed warning – severe hypoglycemia (especially T1D); nausea, vomiting, anorexia
- Contraindications: Gastroparesis; HbA1c >9%; hypoglycemia unawareness; poor adherence to SMBG
- Efficacy: 0.5-1% HbA1c reduction; effective for postprandial glucose control; modest weight loss
Rx PHARMACIST WATCHOUT: Pramlintide boxed warning: SEVERE HYPOGLYCEMIA (especially in T1D). Must reduce preprandial insulin by 50% when initiating. Use prefilled pens (NOT syringe + vial) to minimize dosing errors. Cannot be mixed with insulin in same syringe. Flag this every time you see a new pramlintide order.
5E. Continuous Glucose Monitoring (CGM) & Insulin Pump
- Real-time CGM: Continuously transmits glucose data to a display device; used with or without insulin pump
- Intermittent CGM: Requires patient to scan the sensor to view glucose data (e.g., FreeStyle Libre)
- Insulin pump (CSII): Continuous subcutaneous infusion; patient-specific hourly basal + bolus dosing; uses rapid-acting only
- Hybrid closed-loop systems: Near-artificial pancreas; CGM + pump communicate to auto-adjust basal insulin in real time
- Inhaled insulin (Afrezza): Contraindicated in asthma, COPD, lung cancer; requires baseline spirometry and q6 months, then annually
T2D TREATMENT ALGORITHM (ADA 2024)
6A. Stepwise Approach
- Step 1 – Lifestyle + Metformin: Initial therapy for most patients with T2D (unless contraindicated)
- Combination therapy (metformin + second agent) if baseline HbA1c is ≥1.5% above personal goal
- When metformin is NOT first-line (prioritize disease-based selection):
- Established ASCVD → GLP-1 RA or SGLT-2i with proven CV benefit (regardless of HbA1c)
- Heart failure → SGLT-2i with proven HF benefit (canagliflozin, dapagliflozin, empagliflozin)
- CKD (eGFR ≥20 + ACR ≥200 mg/g) → SGLT-2i; consider finerenone
- Weight management → GLP-1 RA (semaglutide, dulaglutide) or SGLT-2i
- Hypoglycemia risk → DPP-4i, GLP-1 RA, SGLT-2i, TZD
- Cost concern → Sulfonylurea (generic glipizide/glimepiride)
6B. When to Add Injectable Therapy (ADA Guidance)
- Preferred injectable addition: GLP-1 RA over insulin (lower hypoglycemia, weight loss, CV benefit)
- Add early basal insulin if: HbA1c >10% OR HbA1c >2% above personal goal
- Basal insulin initiation (T2D): 0.1-0.3 units/kg/day or 10 units QHS
- Titration: Increase by 2-4 units or 10-15% once or twice weekly to achieve FPG target (80-130 mg/dL)
- Add bolus insulin if: Basal dose ≥0.5 units/kg/day OR significant postprandial excursions remain
- Initial bolus dose: 4 units or 10% of basal dose per meal
6C. Insulin Add-On Rules (Important!)
- When ADDING bolus insulin: REDUCE or DISCONTINUE sulfonylurea/meglitinide (↑ hypoglycemia risk)
- When ADDING basal insulin: REDUCE or DISCONTINUE TZD (↑ risk of fluid retention/edema)
- SGLT-2i: Add if weight gain is a concern OR secondary indication exists (HF, CKD, ASCVD)
CLINICAL PEARL: ADA now de-emphasizes a purely stepwise approach. Instead, choose the second agent based on: (1) whether established CVD/HF/CKD exists (strongest factor), (2) weight/hypoglycemia concerns, (3) cost, (4) patient preference. The days of ‘metformin, then add SU’ as default are over.
PHARMACOTHERAPY AGENTS – T2D
Metformin (Biguanide) – First-Line
| PARAMETER | DETAILS |
| MOA | Reduces hepatic gluconeogenesis; improves insulin sensitivity; reduces intestinal glucose absorption |
| Dosing | Start 500 mg QD or BID with meals; extend-release: 500-1000 mg QD. Increase weekly as tolerated. Max 2550 mg/day (commonly capped at 2000 mg) |
| HbA1c reduction | 1-2% (larger reduction with higher baseline HbA1c) |
| Renal Dosing | eGFR ≥60: No adjustment needed; monitor q3-6mo eGFR 45-59: Do NOT initiate; if already on, reduce dose 50%, monitor q3mo eGFR 30-44: Do NOT initiate; if on it, reduce dose 50%; monitor renal function closely eGFR <30: CONTRAINDICATED – discontinue |
| Hold/Interrupt | Hold for iodinated contrast (if eGFR 30-60): Reinitiate 48 hrs after with confirmed normal SCr Hold perioperatively, in acute illness, hypoxia, hepatic impairment, alcohol use |
| Key ADEs | GI (N/V/D – dose-related, limit with slow titration, take with food); Vitamin B12 ↓ (monitor periodically); Rare: lactic acidosis |
| Benefits | Weight neutral to modest loss; low hypoglycemia risk; UKPDS CV benefit in overweight T2D; inexpensive |
| Contraindications | eGFR <30; hepatic impairment; alcohol abuse; high-risk cardiovascular events or hypoxic state; age ≥80 (caution) |
Rx PHARMACIST WATCHOUT: Metformin & contrast: Stop metformin at time of contrast if eGFR 30-60 mL/min. Restart 48 hours AFTER procedure only if renal function is stable. Communicate proactively with radiology/ordering team in admitted patients.
Sulfonylureas (SU) – Insulin Secretagogues
| AGENT | INITIAL DOSE | MAX DOSE | RENAL NOTE | HALF-LIFE / DURATION |
| Glipizide (Glucotrol, Glucotrol XL) | 5 mg QD (ER: 5 mg QD) | 40 mg/day (ER: 20 mg; little benefit >20 mg) | Preferred in elderly/CKD – hepatic metabolism, not renally cleared | 2-4 hr / 12-24 hr |
| Glimepiride (Amaryl) | 1-2 mg QD | 8 mg/day | Reduce dose in renal impairment; active metabolites renally excreted | 5-9 hr / 24 hr |
| Glyburide (DiaBeta, Glynase) | 2.5-5 mg QD-BID | 20 mg/day | AVOID in elderly and CKD – active metabolites renally excreted → prolonged hypoglycemia | 6-12 hr / up to 24 hr |
- MOA: Bind pancreatic beta-cell receptors → membrane depolarization → insulin secretion (glucose-independent)
- Key ADEs: Hypoglycemia (especially glyburide; prolonged), weight gain, rash, photosensitivity (rare)
- Avoid in: Hypoglycemia unawareness; significant renal impairment (prefer glipizide); elderly (glyburide)
- Drug interaction: AZOLE ANTIFUNGALS (fluconazole, voriconazole) inhibit CYP2C9 → ↑ SU levels → ↑ hypoglycemia risk (CRITICAL in oncology with antifungal prophylaxis)
Rx PHARMACIST WATCHOUT: Sulfonylurea + azole antifungals = HIGH hypoglycemia risk. Fluconazole, voriconazole, and other azoles inhibit CYP2C9, significantly increasing sulfonylurea plasma levels. In oncology patients on antifungal prophylaxis (e.g., fluconazole for febrile neutropenia prophylaxis), monitor BG very closely or consider switching to a different antidiabetic agent.
SGLT-2 Inhibitors – Glycosurics
| AGENT | DOSE | RENAL CUTOFFS | CV / RENAL BENEFIT | KEY ADEs / NOTES |
| Canagliflozin (Invokana) | 100 mg QD before first meal Max: 300 mg | eGFR <30: Do NOT initiate eGFR 30-59: Max 100 mg eGFR <30 but on it with albuminuria >300 mg/g: Continue 100 mg (renal protection until dialysis) | CANVAS: ↓ MACE (14%) CREDENCE: ↓ ESKD/renal composite ↓ HF hospitalization | ↑ Amputation risk (feet/legs) ↓ Bone mineral density; fracture risk Hold 3 days pre-surgery ↑ LDL (small) |
| Dapagliflozin (Farxiga) | 5 mg QD (with or without food) Max: 10 mg | eGFR <25: Do NOT initiate eGFR <25 but established on 10 mg for HF/CKD: Continue until dialysis | DECLARE-TIMI 58: ↓ HF hospitalization/CV death DAPA-CKD: ↓ CKD progression (including non-diabetic CKD) ↓ HF hospitalization | Indicated for HF (HFrEF and HFpEF) and CKD regardless of diabetes status Hold 3 days pre-surgery |
| Empagliflozin (Jardiance) | 10 mg QD Max: 25 mg | eGFR <20: Do NOT initiate eGFR <20 but on it: Continue 10 mg for HF/CKD benefit until dialysis | EMPA-REG: ↓ CV death (38%), MACE (14%), HF hospitalization (35%) EMPA-KIDNEY: ↓ CKD progression ↓ HF hospitalization | Strongest CV mortality data of class Hold 3 days pre-surgery |
| Ertugliflozin (Steglatro) | 5 mg QD Max: 15 mg | Discontinue/do NOT initiate if eGFR <45 | VERTIS-CV: No significant MACE benefit ↓ HF hospitalization only | Hold 4 days pre-surgery Less robust outcomes data |
| Bexagliflozin (Brenzavvy) | 20 mg QD Max: 20 mg | Discontinue/do NOT initiate if eGFR <30 | NO proven CV, HF, or renal outcome benefit (newest agent; trials pending) | HbA1c reduction similar to class Least evidence for secondary indication |
- Class MOA: Block SGLT-2 in proximal tubule → ↑ urinary glucose excretion; HbA1c reduction declines as eGFR declines
- Class ADEs: Genital mycotic infections (>females), UTI, increased urination, hypotension, DKA (EUGLYCEMIC), Fournier gangrene (rare), bone fractures, dehydration
- HbA1c reduction: 0.5-0.8%
WARNING: EUGLYCEMIC DKA with SGLT-2 INHIBITORS: Blood glucose may be near-normal (140-180 mg/dL) but patient is in DKA. Always check ketones (blood beta-hydroxybutyrate) if patient on SGLT-2i presents with vomiting, nausea, abdominal pain, or shortness of breath. High-risk situations: fasting, surgery, low-carb diet, illness, alcohol, insulin dose reduction.
Rx PHARMACIST WATCHOUT: SGLT-2i pre-surgery protocol: Hold canagliflozin, dapagliflozin, empagliflozin 3 DAYS before surgery. Hold ertugliflozin 4 DAYS before surgery. This is frequently missed in oncology patients undergoing procedures. Review medication list proactively before any scheduled surgery or procedure.
GLP-1 Receptor Agonists (and GIP/GLP-1 Dual Agonist)
| AGENT | DOSING | RENAL NOTE | CV OUTCOME TRIAL | KEY ADEs / NOTES |
| Exenatide BID (Byetta) | 5 mcg SQ BID (≤60 min before AM and PM meals) Titrate to 10 mcg BID after 1 month | CrCl <30: AVOID | EXSCEL (ER form): Non-inferior (not superior) for MACE | GI dominant (N/V/D); injection-site reactions; pancreatitis; do NOT use with severe GI disease |
| Exenatide ER (Bydureon BCise) | 2 mg SQ once weekly (powder reconstituted before injection) [inject any time, regardless of meals] | CrCl <30: AVOID | Non-inferior to placebo for MACE; some CV signals | Weekly; longest-acting of extended-release agents; GI less than BID form |
| Liraglutide (Victoza) | 0.6 mg SQ QD × 1 wk → 1.2 mg → max 1.8 mg/day [inject any time, regardless of meals] | No dose adjustment; use caution CrCl <30 | LEADER: ↓ MACE 13%; ↓ CV death 22%; ↓ nephropathy | Approved for CVD risk reduction; once-daily; GI ADEs common during titration |
| Dulaglutide (Trulicity) | 0.75 mg SQ weekly → 1.5 mg → 3 mg → max 4.5 mg weekly | No dose adjustment | REWIND: ↓ MACE 12% (includes primary prevention patients) | Once weekly; device auto-injects; broadest CV benefit population (primary + secondary prevention) |
| Semaglutide SQ (Ozempic) | 0.25 mg SQ weekly × 4 wks → 0.5 mg → 1 mg → max 2 mg weekly | No dose adjustment | SUSTAIN-6: ↓ MACE 26% (largely stroke); FLOW: ↓ renal composite 24% | Highest efficacy SQ GLP-1 (before tirzepatide); first GLP-1 with proven CKD benefit in FLOW trial |
| Semaglutide PO (Rybelsus) | 3 mg QD × 1 mo → 7 mg QD × 1 mo → max 14 mg QD | No dose adjustment | PIONEER 6: Non-inferior for MACE | MUST take on empty stomach with ≤4 oz water, 30 min before first food/drink/medication of day. Only oral GLP-1. |
| Tirzepatide (Mounjaro) – GIP/GLP-1 | 2.5 mg SQ weekly → ↑ by 2.5 mg monthly → max 15 mg weekly | No dose adjustment | SURPASS-CVOT: awaited (results expected); SURMOUNT shows robust weight/metabolic data | VERY HIGH EFFICACY: 2.0-2.3% HbA1c ↓; significant weight loss (up to 20% body weight). Dual GIP + GLP-1 agonism. Targets both fasting AND postprandial glucose. |
- Class MOA: Binds GLP-1 receptors → glucose-dependent insulin secretion, ↓ glucagon, ↓ gastric emptying, promotes satiety
- Class ADEs: N/V/D, constipation, acid reflux, pancreatitis (rare), gallbladder disease, acute renal failure, injection-site reactions, retinopathy (semaglutide – monitor in pre-existing retinopathy)
- Contraindications: Personal/family history of MTC (medullary thyroid carcinoma) or MEN-2 (liraglutide, semaglutide, dulaglutide, exenatide ER)
- HbA1c reduction: 0.8-1.6% (GLP-1); 2.0-2.3% (tirzepatide)
Rx PHARMACIST WATCHOUT: GLP-1 agonist brand confusion: Victoza (liraglutide) – max 1.8 mg (for T2D). Saxenda (liraglutide) – max 3 mg (for obesity). Different products, different max doses, different indications. Ozempic (semaglutide SQ) max 2 mg (T2D); Wegovy (semaglutide SQ) max 2.4 mg (obesity). Do NOT substitute between obesity and diabetes GLP-1 products.
CLINICAL PEARL: Oncology connection: Semaglutide is the first GLP-1 RA with proven kidney benefit (FLOW trial: 24% ↓ renal composite). In oncology patients with nephrotoxicity from chemotherapy who develop T2D and CKD, semaglutide + SGLT-2i offers a powerful renoprotective combination.
DPP-4 Inhibitors (Gliptins) – Weight Neutral
| AGENT | STANDARD DOSE | RENAL DOSE ADJUSTMENT | NOTES |
| Sitagliptin (Januvia) | 100 mg QD | eGFR 30-44: 50 mg QD eGFR <30: 25 mg QD | Best safety data; no signal for HF hospitalization; once-daily; reports of acute pancreatitis, angioedema, SJS (rare) |
| Saxagliptin (Onglyza) | 5 mg QD | eGFR ≤45: 2.5 mg QD | AVOID in HF (SAVOR-TIMI: ↑ HF hospitalization). Reduce to 2.5 mg with strong CYP3A4/5 inhibitors (azoles, ritonavir) |
| Linagliptin (Tradjenta) | 5 mg QD | NO RENAL DOSE ADJUSTMENT NEEDED (biliary excretion; only DPP-4i without renal adjustment) | Safe in any level of renal impairment; also no hepatic dose adjustment; preferred in CKD |
| Alogliptin (Nesina) | 25 mg QD | CrCl 30-59: 12.5 mg QD CrCl <30: 6.25 mg QD | AVOID in HF (EXAMINE trial: signal for ↑ HF hospitalization). Hepatotoxicity risk (rare) |
- Class MOA: Inhibit DPP-4 enzyme → prevent breakdown of endogenous GLP-1 → ↑ insulin secretion (glucose-dependent), ↓ glucagon
- Class ADEs: URTI, UTI, nasopharyngitis, severe joint pain (rare but class-wide), pancreatitis (rare), headache
- HbA1c reduction: 0.5-0.8%; weight neutral
- Drug interaction: Saxagliptin + strong CYP3A4/5 inhibitors (azoles, clarithromycin, ritonavir): Reduce saxagliptin to 2.5 mg
Rx PHARMACIST WATCHOUT: In oncology: Saxagliptin or alogliptin + azole antifungals (ketoconazole, voriconazole) = CYP3A4/5 inhibition → ↑ saxagliptin exposure → must reduce dose to 2.5 mg. Also avoid saxagliptin/alogliptin in patients with heart failure – significant concern in cancer patients on cardiotoxic chemo.
Thiazolidinediones (TZDs / Glitazones)
- Only available agent: Pioglitazone (Actos) – 15-45 mg QD; max 45 mg
- MOA: PPAR-gamma agonist → ↑ expression of genes for glucose metabolism → improved insulin sensitivity
- Key ADEs: BOXED WARNING for heart failure; weight gain; peripheral edema (worse with insulin); proximal bone fractures; possible bladder cancer (dose/duration-dependent; contradictory data); macular edema
- Contraindicated: Class III/IV HF; hepatic impairment; existing fluid retention
- Benefits: NASH/MASH benefit; improved HDL; possible CVA benefit; durable glycemic control; low hypoglycemia risk
- Dosage titration: Slow onset – max effect of dose change may take 8-12 weeks
- HbA1c reduction: 0.5-1.4%
7G. Renal Dosing Quick Reference Table
| DRUG CLASS / AGENT | eGFR 60+ | eGFR 45-59 | eGFR 30-44 | eGFR 15-29 | eGFR <15 / Dialysis |
| Metformin | Full dose | No new Rx Reduce 50% if on it | No new Rx Reduce 50% | CONTRAINDICATED | CONTRAINDICATED |
| Sulfonylureas (SU) | Full dose | Full dose (monitor) | Glipizide preferred; reduce others | Glipizide only (caution) | Avoid all SU |
| Sitagliptin (DPP-4i) | 100 mg QD | 50 mg QD | 50 mg QD | 25 mg QD | 25 mg QD |
| Saxagliptin (DPP-4i) | 5 mg QD | 2.5 mg QD | 2.5 mg QD | 2.5 mg QD | Not recommended |
| Linagliptin (DPP-4i) | 5 mg QD | 5 mg QD | 5 mg QD | 5 mg QD | 5 mg QD (no adjustment) |
| Alogliptin (DPP-4i) | 25 mg QD | 12.5 mg QD | 12.5 mg QD | 6.25 mg QD | 6.25 mg QD |
| Canagliflozin (SGLT-2i) | 100-300 mg | 100-300 mg | 100 mg only (if albuminuria>300 for renoprotection) | Do not initiate (continue 100 mg if albuminuria>300) | Not recommended |
| Dapagliflozin (SGLT-2i) | 5-10 mg | 5-10 mg | 5-10 mg (HF/CKD indication) | Do not initiate (continue 10 mg for HF/CKD) | Not recommended |
| Empagliflozin (SGLT-2i) | 10-25 mg | 10-25 mg | 10-25 mg (HF/CKD indication) | Do not initiate (continue 10 mg for HF/CKD) | Not recommended |
| GLP-1 RA (most agents) | Full dose | Full dose | Full dose | No adjustment (most) Exenatide: AVOID | Exenatide: AVOID Others: Use with caution |
| Insulin | Full dose (↑ risk hypo at lower eGFR) | Reduce dose; ↑ hypoglycemia risk | Reduce dose further; monitor closely | Reduce dose; frequent monitoring | Use with caution; reduce dose |
| TZD (pioglitazone) | Full dose | Full dose | Full dose | Full dose | Use with caution (limited data) |
| Exenatide (BID/ER) | Full dose | Full dose | Use with caution | AVOID | AVOID (CrCl <30) |
MANAGEMENT OF DIABETES COMPLICATIONS
8A. Hypoglycemia
| LEVEL | GLUCOSE | CLINICAL CRITERIA | TREATMENT |
| Level 1 | <70 but ≥54 mg/dL | Glucose alert value; with OR without symptoms | 15-20g oral glucose (glucose tablets, 4 oz juice, 4 oz regular soda, glucose gel); recheck in 15 min; repeat if still <70 mg/dL; eat meal/snack once normalized |
| Level 2 | <54 mg/dL | Clinically significant hypoglycemia; requires treatment regardless of symptoms | 15-20g oral glucose as above; consider cause; adjust regimen |
| Level 3 | Any glucose | Severe – altered mental/physical status; REQUIRES EXTERNAL ASSISTANCE | Glucagon: 1 mg SQ or IM (GlucaGen/Glucagon Emergency Kit) OR 3 mg intranasal (Baqsimi) IV dextrose (D50W 25g IV push) if no glucagon available or no response Raise BG targets for several weeks after severe event |
- Hypoglycemia Unawareness: Patient has Level 2 BG without symptoms → lost counter-regulatory response
- Management: Relax BG targets; modify regimen to ↓ hypoglycemia risk; use CGM with low glucose alarm
- Consider: Switching from sulfonylurea to DPP-4i, GLP-1 RA, or SGLT-2i; reduce insulin doses
WARNING: Alpha-glucosidase inhibitor users (acarbose): If hypoglycemia occurs, treat with ORAL GLUCOSE (dextrose tablets), NOT sucrose (table sugar or fruit juice). Acarbose blocks sucrose/maltose absorption. Plain dextrose tablets or IV glucose is required. This is critical patient counseling.
8B. Diabetic Ketoacidosis (DKA)
| SEVERITY | BETA-HYDROXYBUTYRATE | VENOUS pH | BICARBONATE | MENTAL STATUS |
| Mild | 3.0-4.0 mEq/L | >7.25 but <7.30 | 15-18 mEq/L | Alert |
| Moderate | 4.0-5.0 mEq/L | 7.0-7.25 | 10-14.9 mEq/L | Alert to drowsy |
| Severe | >5.0 mEq/L | <7.0 | <10 mEq/L | Stupor / coma |
DKA Treatment Protocol (ADA/JDRF Consensus 2024)
- Step 1 – FLUIDS: 0.9% NaCl (or other crystalloid). Replace ~50% of estimated fluid deficit in first 6-12 hours. Once BG <250 mg/dL: add 5% or 10% dextrose to IV fluids.
- Step 2 – INSULIN:
- Mild DKA (SQ option): 0.1 unit/kg SQ bolus of rapid-acting insulin → then 0.1 units/kg/hr OR 0.2 units/kg q2hr until BG <250; then 0.1 units/kg q2hr
- Moderate-Severe DKA (IV): Regular insulin infusion at 0.1 units/kg/hr
- Once BG <250 mg/dL: Reduce infusion to 0.05 units/kg/hr; maintain BG ~200 mg/dL until ketosis resolved
- TRANSITION to SQ: Once DKA resolved; overlap SQ insulin and IV infusion by 1-4 hours before stopping IV
- Step 3 – POTASSIUM: Add 10-20 mEq/L KCl to each liter IVF if K+ ≤5 mEq/L. Use higher infusion rates for K+ <3.5 mEq/L
- HOLD INSULIN INFUSION if K+ <3.5 mEq/L – repleting K+ first is critical to prevent fatal arrhythmias
- Step 4 – RESOLUTION CRITERIA: BG <200 mg/dL AND ketones <0.6 mEq/L AND venous pH ≥7.3 AND bicarb ≥18 mEq/L
WARNING: DKA RESOLUTION ≠ NORMAL BLOOD GLUCOSE. The criteria for DKA resolution are: pH ≥7.3 + bicarb ≥18 + ketones <0.6 mEq/L. Glucose may normalize BEFORE acidosis resolves. Continue insulin infusion until ALL three criteria are met. Many practitioners stop insulin too early.
- Most common DKA precipitants: Infection (most common), insulin omission/nonadherence, new diagnosis T1D, DKA on SGLT-2i, steroids, MI, pancreatitis, surgery, drugs (corticosteroids – HIGH RISK IN ONCOLOGY)
ONCOLOGY PEARL: SGLT-2i-induced euglycemic DKA is particularly relevant in oncology. Cancer patients on SGLT-2i who are fasting (NPO before procedure, reduced oral intake during chemo), on a low-carb diet, or receiving insulin dose reductions are at HIGH RISK. BG may be <200 but patient is acidotic. Check blood beta-hydroxybutyrate in any patient on SGLT-2i with unexplained GI symptoms or fatigue.
8C. Diabetic Nephropathy
- Screening: Random spot urine albumin-to-creatinine ratio (ACR) + eGFR annually; at T2D diagnosis; after 5 years in T1D
- Normal ACR: <30 mg/g
- Albuminuria: ACR ≥30 mg/g (confirmed with 2 of 3 specimens over 3-6 months)
- ADA no longer uses ‘microalbuminuria’ or ‘macroalbuminuria’ – report ACR value directly
| ACR (mg/g) | eGFR (mL/min) | RECOMMENDED INTERVENTION |
| ≥30 | Any | ACEi OR ARB (first-line; do NOT combine) |
| ≥200 | ≥20 | ADD SGLT-2i (canagliflozin, dapagliflozin, or empagliflozin) |
| ≥200 | ≥25 (CKD criteria) | Consider adding finerenone (nonsteroidal MRA) per ADA |
| Any | Declining | Dietary protein restriction as eGFR declines |
| Any | Any with T2D CKD | Semaglutide showed ↓ renal composite in FLOW trial (add if not already on GLP-1) |
- Target: ≥30% reduction in albuminuria with therapy
- Finerenone (Kerendia): Nonsteroidal mineralocorticoid receptor antagonist; indicated for CKD associated with T2D (FIDELIO-DKD trial: ↓ renal progression and CV events)
8D. Diabetic Retinopathy
- Screening: Annual dilated/comprehensive eye exam at T2D diagnosis; after 5 years in T1D
- Frequency can be reduced to q2-3 years after consistently normal exams
- Optimize glycemia, BP, and cholesterol to prevent progression
- Severe retinopathy treatment: Intravitreous steroids or anti-VEGF agents (e.g., ranibizumab, aflibercept) ± laser photocoagulation
- Semaglutide caution: SUSTAIN-6 showed ↑ retinopathy complications with semaglutide vs placebo. Monitor in patients with pre-existing retinopathy.
8E. Diabetic Neuropathies
- Screening: After 5 years in T1D; at T2D diagnosis; then annually; evaluate distal polyneuropathy (10-g monofilament, vibration, pinprick, ankle reflexes)
- Glycemic control is primary strategy to prevent/slow progression
- Symptomatic pharmacotherapy does NOT slow disease progression – targets pain/symptoms only
| AGENT CLASS | DRUG(S) | DOSE / NOTES | FDA-APPROVED FOR DPN? | KEY CONSIDERATIONS |
| SNRI | Duloxetine (Cymbalta) | 60-120 mg QD Start 30-60 mg | YES (only approved SNRI for DPN) | Similar efficacy to amitriptyline; better tolerability; fewer anticholinergic effects. Useful in depression + DPN comorbidity. |
| Anticonvulsant | Pregabalin (Lyrica) | 75-300 mg BID Start low, titrate | YES (only approved anticonvulsant for DPN) | Schedule V; abuse potential; dizziness, fatigue, edema. Avoid abrupt discontinuation. |
| Anticonvulsant | Gabapentin (Neurontin) | 300-1200 mg TID Renal dose adjustment | NO (off-label) | Similar efficacy to pregabalin; less expensive; dizziness/fatigue common; renal dose adjustment required |
| TCA | Amitriptyline Desipramine | Start 25 mg QHS ↑ to effect | NO (off-label) | Effective but significant anticholinergic ADEs (urinary retention, constipation, dry mouth, falls); use secondary amines (desipramine, nortriptyline) for fewer effects |
| Opioid | Tapentadol ER (Nucynta ER) | 50-250 mg Q12H | YES (only approved opioid for DPN) | No head-to-head efficacy data; abuse potential; use as last resort. Schedule II. |
| Topical | Capsaicin 8% patch Lidocaine 5% patch/cream | Apply to affected area | NO (off-label) | For FOCAL pain only; not for diffuse pain. Capsaicin burns transiently. |
| Combination | Tramadol/acetaminophen (Ultracet) | Tramadol 37.5mg/APAP 325mg | NO (off-label) | Comparable to gabapentin; Schedule IV tramadol; risk of seizures/serotonin syndrome |
CLINICAL PEARL: First-line for DPN pain: Duloxetine or pregabalin (both FDA-approved). Duloxetine preferred if patient also has depression. Pregabalin preferred if pain is more severe or sleep disruption is a major complaint. TCAs are effective but use with caution in elderly and oncology patients (anticholinergic burden).
Gastroparesis Management
| APPROACH | OPTIONS | NOTES |
| Dietary | Small frequent meals; low-fat, low-fiber; homogenized/liquid food | Non-pharmacologic first step |
| Pharmacologic – Prokinetic | Metoclopramide 10 mg PO QID or 15 mg intranasally before meals Erythromycin 40-250 mg TID before meals (up to 1 month only) | Metoclopramide: Risk of tardive dyskinesia (boxed warning); limit duration; assess risk-benefit at each visit. Erythromycin: Short-term only (tachyphylaxis); drug interactions via CYP3A4. |
| Device | Gastric electrical stimulation (pacemaker) | Specialist referral; for refractory gastroparesis |
8F. Cardiovascular Disease (CVD)
- Most common cause of mortality and morbidity in patients with diabetes.
| MANAGEMENT AREA | RECOMMENDATION | AGENT(S) |
| Blood Pressure | Target: <130/80 mmHg | ACEi or ARB (first-line if albuminuria); DHP-CCB or thiazide-like diuretic; avoid combining ACEi + ARB |
| LDL – Age 40-75, no CVD | Moderate-intensity statin; achieve ≥50% LDL ↓ if CV risk factors present; target LDL <70 mg/dL | Atorvastatin 10-20 mg or rosuvastatin 5-10 mg (moderate); atorvastatin 40-80 mg or rosuvastatin 20-40 mg (high) |
| LDL – Established CVD | High-intensity statin; ≥50% LDL ↓; target LDL <55 mg/dL | Atorvastatin 40-80 mg; rosuvastatin 20-40 mg; ADD ezetimibe or PCSK9i if above goal |
| Antiplatelet – Secondary prevention | ASA 75-162 mg/day (established ASCVD) | Clopidogrel 75 mg/day if ASA-intolerant |
| Antiplatelet – Primary prevention | Consider if ↑ CV risk; individualize risk-benefit | ASA 75-162 mg/day |
| GLP-1 RA / SGLT-2i for CVD | ADD with proven CV benefit (not all agents in class) | GLP-1: liraglutide, dulaglutide, semaglutide, exenatide ER; SGLT-2i: empagliflozin, canagliflozin, dapagliflozin |
| HF – Add-on diabetes therapy | SGLT-2i with proven HF benefit | Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin (all except bexagliflozin) |
INPATIENT DIABETES MANAGEMENT (Non-Critically Ill)
| PARAMETER | RECOMMENDATION |
| Glycemic Goal | 140-180 mg/dL (all hospitalized patients, non-ICU) |
| Initiation Threshold | Initiate insulin therapy if BG ≥180 mg/dL |
| Monitoring Frequency | Before meals (AC) if eating; every 4-6 hrs if NPO or on continuous tube feeds |
| Preferred Treatment | Basal-bolus insulin (basal + prandial + correction). Sliding-scale insulin ALONE is NOT recommended (per ADA – insufficient for control, inappropriate in most patients) |
| NPO / Restricted PO | Basal insulin with or without correction (ISF) doses only – no prandial bolus if not eating |
| ICU / Critically Ill | Continuous IV regular insulin infusion; target 140-180 mg/dL; monitor q1-2hr |
| Transition from IV to SQ | Overlap subcutaneous basal insulin 1-4 hours BEFORE stopping IV insulin infusion to prevent rebound hyperglycemia |
| Oral Antidiabetic Agents | Generally held in hospitalized patients (metformin: contrast risk, renal changes; SGLT-2i: DKA risk; GLP-1 RA: GI/gastroparesis; hold most oral agents and manage with insulin) |
| Discharge Planning | Discharge on pre-admission regimen if hyperglycemia was incidental; adjust regimen if hospitalization revealed poor outpatient control; ensure patient/family education, follow-up appointment, and BG monitoring supplies |
Rx PHARMACIST WATCHOUT: When converting from IV insulin infusion to SQ: OVERLAP IS MANDATORY – administer basal SQ insulin at least 1-4 hours BEFORE stopping the IV infusion. Failure to overlap leads to dangerous rebound hyperglycemia (and potentially DKA in T1D). Document this handoff clearly in the chart.
CLINICAL PEARL: In oncology inpatients: Hyperglycemia is common from steroids (dexamethasone in chemotherapy regimens), stress response, and TPN. Standard inpatient glycemic target is 140-180 mg/dL. For patients receiving dexamethasone QAM, consider NPH insulin in the morning to match the steroid peak – this is the most physiologic approach for steroid-induced hyperglycemia.
KEY CLINICAL TRIALS IN DIABETES PHARMACOTHERAPY
| TRIAL | DRUG | POPULATION | INTERVENTION vs COMPARATOR | KEY RESULTS | NOTES |
| UKPDS | Metformin | Newly diagnosed T2D, overweight (n=1704) | Metformin vs conventional diet Rx | 36% ↓ all-cause mortality; 32% ↓ DM-related endpoints; no excess CVD mortality (unlike SU in UGDP) | Foundational trial for metformin. Demonstrated CV benefit in overweight T2D. ‘Legacy effect’ on CV outcomes post-trial. |
| ACCORD | Intensive glycemic control | T2D with CVD or CVD risk (n=10,251) | HbA1c <6.5% vs standard (7-7.9%) | Intensive group: ↑ all-cause mortality (22%); ↑ CV death; ↑ hypoglycemia. NO reduction in MACE. | Intensive glycemic control (<6.5%) in high-CV-risk T2D is HARMFUL. Supported less stringent targets in certain populations. |
| EMPA-REG OUTCOME | Empagliflozin 10 or 25 mg | T2D + established CVD (n=7,020) | Empagliflozin vs placebo | 14% ↓ MACE; 38% ↓ CV death; 35% ↓ HF hospitalization; 39% ↓ new/worsening nephropathy | Landmark trial. Strongest CV death reduction in class. Rapid separation of curves suggests hemodynamic mechanism (not just glucose lowering). |
| CANVAS | Canagliflozin 100/300 mg | T2D + CVD or high CV risk (n=10,142) | Canagliflozin vs placebo | 14% ↓ MACE; 40% ↓ HF hospitalization; ↑ amputation risk (6.3 vs 3.4/1000 pt-yrs); ↑ fractures | Amputation and fracture signals are canagliflozin-specific. CREDENCE follow-up study showed renal benefit. |
| DECLARE- TIMI 58 | Dapagliflozin 10 mg | T2D with or without CVD (n=17,160) | Dapagliflozin vs placebo | No significant MACE reduction in total population; 27% ↓ HF hospitalization/CV death composite; ↓ renal progression | Largest SGLT-2i CV trial. Most participants had CV risk factors (not established CVD) – supports HF/renal indication broadly. |
| LEADER | Liraglutide 1.8 mg | T2D + high CV risk (n=9,340) | Liraglutide vs placebo | 13% ↓ MACE; 22% ↓ CV death; 15% ↓ nephropathy; 4% ↓ death from any cause | First GLP-1 RA CV outcomes trial. Driven by reduction in CV death. Liraglutide only GLP-1 with CV death reduction (vs non-fatal MACE in others). |
| SUSTAIN-6 | Semaglutide SQ | T2D + high CV risk (n=3,297) | Semaglutide 0.5 or 1 mg vs placebo | 26% ↓ MACE (primarily driven by ↓ non-fatal stroke); ↑ retinopathy complications (semaglutide group) | Key semaglutide safety trial. Retinopathy risk signal – monitor closely in patients with pre-existing retinopathy. Shorter trial (2 yrs); mainly safety data. |
| REWIND | Dulaglutide 1.5 mg | T2D with or without CVD (n=9,901) | Dulaglutide vs placebo | 12% ↓ MACE; ↓ non-fatal stroke; ↓ albuminuria | Broadest GLP-1 CV population (half without established CVD). Supports use for primary CV prevention in T2D. |
| SURPASS-2 | Tirzepatide 5/10/15 mg | T2D on metformin | Tirzepatide vs semaglutide 1 mg weekly | Tirzepatide 15 mg: 2.46% ↓ HbA1c vs 1.86% semaglutide; weight ↓ -11.2 kg vs -5.5 kg; superior on all glycemic endpoints | Head-to-head; tirzepatide significantly superior to semaglutide 1 mg. GI ADEs similar. SURPASS-CVOT for CV outcomes pending. |
| CREDENCE | Canagliflozin 100 mg | T2D + DKD (eGFR 30-90, ACR >300 mg/g) on max RAS blockade | Canagliflozin vs placebo | 30% ↓ primary composite (ESKD, SCr doubling, renal/CV death); 32% ↓ ESKD; 31% ↓ HF; trial stopped early for efficacy | First SGLT-2i trial in DKD. Supported canagliflozin for renoprotection. Efficacy seen even in eGFR 30-45 subgroup. |
| DAPA-CKD | Dapagliflozin 10 mg | CKD eGFR 25-75 + ACR ≥200 mg/g (T2D AND non-diabetic CKD) | Dapagliflozin vs placebo | 39% ↓ primary composite (sustained ↓ eGFR, ESKD, renal/CV death); consistent in diabetic + non-diabetic CKD; 29% ↓ all-cause death | First evidence SGLT-2i benefit extends to non-diabetic CKD. Changed practice paradigm. Trial stopped early. |
| EMPA-KIDNEY | Empagliflozin 10 mg | CKD eGFR 20-45 OR eGFR 45+ with ACR ≥200 mg/g (T2D and non-diabetic) | Empagliflozin vs placebo | 28% ↓ primary composite (CKD progression/CV death); benefit seen in very low eGFR (20-30) subgroup; 24% ↓ hospitalization | Included lowest eGFR patients of any SGLT-2i CKD trial. Supports use of empagliflozin even in advanced CKD. |
| FLOW | Semaglutide SQ 1 mg | T2D + CKD (eGFR 50-75, ACR ≥300 mg/g) on max RAS blockade | Semaglutide vs placebo | 24% ↓ major kidney disease composite; 21% ↓ MACE; 20% ↓ all-cause death | First GLP-1 RA trial with proven renal endpoint benefit. Semaglutide now recommended for CKD in T2D in combination with SGLT-2i. |
| FIDELIO-DKD | Finerenone | T2D + DKD (eGFR 25-60 + ACR ≥300 OR eGFR 25-90 + ACR ≥30) | Finerenone vs placebo | 18% ↓ primary renal composite; 14% ↓ secondary CV composite; ↓ albuminuria | Nonsteroidal MRA with both renal and CV benefit in T2D CKD. Added to ADA recommendations for nephropathy management. |
ONCOLOGY SPECIAL CONSIDERATIONS
11A. Steroid-Induced Hyperglycemia (SIH)
- Most common cause of drug-induced hyperglycemia in oncology patients.
- Classic pattern: Predominantly POSTPRANDIAL hyperglycemia; effects peak 4-12 hrs after steroid dose
- Dexamethasone QAM → BG peaks in the afternoon; near-normal fasting glucose
- Monitoring: BG AC meals + bedtime while on steroids; initiate treatment if BG >180 mg/dL
| SCENARIO | RECOMMENDED APPROACH |
| New-onset hyperglycemia on once-daily AM dexamethasone | NPH insulin 0.1-0.2 units/kg with AM dexamethasone dose (mirrors steroid pharmacokinetics) OR: Add bolus (rapid-acting) insulin at lunch and dinner OR: Increase existing oral antidiabetic agents (if T2D) |
| Existing T2D – worsening control on steroids | Increase existing regimen; escalate to bolus insulin if needed; basal insulin less effective alone (postprandial pattern) |
| High-dose steroids (e.g., RCHOP dexamethasone, high-dose dex in MM) | Scheduled rapid-acting insulin AC meals + correction; may need high doses; monitor q4-6hr |
| Steroid taper or completion | Taper insulin proportionally with steroid taper; hold glucose-lowering therapy when steroids discontinued if glucose normalizes |
| Stress hyperglycemia (ICU oncology patient) | IV insulin infusion; target 140-180 mg/dL; q1-2hr monitoring |
ONCOLOGY PEARL: In multiple myeloma (MM) regimens with dexamethasone 40 mg weekly (VRd, DRd, RVd etc.), hyperglycemia is nearly universal. The pattern is predictable: peak hyperglycemia on dex days (day 1, 8, 15, 22 of cycle). Pre-emptive NPH insulin on dexamethasone days is a practical strategy; counsel patients on hypoglycemia risk on non-dex days.
11B. Immune Checkpoint Inhibitor (ICI) – Induced Diabetes
| PARAMETER | DETAILS |
| Mechanism | Immune-mediated destruction of pancreatic beta cells (similar to T1D autoimmune process); uncontrolled T-cell activation |
| Most common agents | Anti-PD-1 (nivolumab, pembrolizumab); anti-PD-L1 (atezolizumab, durvalumab); higher incidence with combination (anti-CTLA-4 + anti-PD-1) |
| Incidence | ~1-2% with anti-PD-1/PD-L1 monotherapy; up to 2-4% with combination ICI |
| Presentation | Often FULMINANT: DKA-like presentation; abrupt onset; absolute insulin deficiency; may occur at any cycle |
| Diagnosis | New hyperglycemia + low/absent C-peptide + positive autoantibodies (GAD65) in some; exclude other causes |
| Treatment | INSULIN THERAPY (same as T1D management); full basal-bolus regimen; likely LIFELONG |
| ICI continuation | ICI generally NOT held for ICI-DM alone (unlike other irAEs); manage diabetes with insulin and continue ICI if clinically appropriate |
| Steroids | STEROIDS DO NOT RESOLVE ICI-INDUCED DIABETES (unlike most other irAEs – thyroiditis, hepatitis, etc.). This is T1D-like destruction, not inflammation-based. |
| Counseling | Educate patient and family on T1D self-management: insulin injection, SMBG/CGM, hypoglycemia recognition and treatment, sick-day rules, MedicAlert bracelet |
WARNING: ICI-induced diabetes is PERMANENT and resembles T1D. Steroids are NOT effective. Patients require lifelong insulin therapy. DKA is common at presentation. Educate oncology team: unlike most immune-related adverse events (irAEs), immunosuppression (steroids) does not reverse this complication.
11C. Drug-Induced Hyperglycemia in Oncology – Summary Table
| DRUG / CLASS | MECHANISM | GLYCEMIC PATTERN | MANAGEMENT | REVERSIBILITY |
| Glucocorticoids (dexamethasone, prednisone, methylprednisolone) | ↓ insulin sensitivity; ↑ hepatic gluconeogenesis; ↑ lipolysis | Predominantly postprandial (once-daily AM dosing); all-day with BID/chronic dosing | NPH + meal-time insulin; titrate with steroid dose; taper insulin with steroid taper | Reversible upon discontinuation |
| L-Asparaginase (pegaspargase, asparaginase Erwinia) | ↓ pancreatic insulin synthesis (pancreatotoxic); ↓ plasma insulin | Varies; monitor during and after therapy | Insulin if BG >180 mg/dL; may be transient | Usually reversible; may persist |
| mTOR Inhibitors (everolimus, temsirolimus) | ↓ insulin receptor signaling; mTOR pathway inhibition → insulin resistance; ↓ beta-cell function | Elevated fasting AND postprandial glucose | Optimize oral antidiabetics; often requires insulin; avoid pioglitazone (macular edema risk) | Partially reversible; may persist |
| Calcineurin Inhibitors (tacrolimus, cyclosporine) [Post-SCT / transplant] | ↓ insulin secretion (direct beta-cell toxicity); insulin resistance | Fasting hyperglycemia dominant | Insulin; calcineurin inhibitor dose reduction if possible; PTDM (post-transplant DM) management guidelines | Partially reversible with dose reduction |
| Androgen Deprivation Therapy (ADT) (GnRH agonists/antagonists) | Insulin resistance; ↑ adiposity; metabolic syndrome | Slow onset; metabolic syndrome pattern | Lifestyle modification; standard T2D agents; GLP-1 RA beneficial for weight; SGLT-2i | Partially reversible with discontinuation |
| Immune Checkpoint Inhibitors (anti-PD-1/PD-L1) | Immune beta-cell destruction (T1D-like) | Acute onset; DKA common; absolute insulin deficiency | Insulin (full T1D regimen); LIFELONG; steroids ineffective | PERMANENT (not reversible) |
| Atypical Antipsychotics (olanzapine – antiemetic) | Insulin resistance; weight gain; direct beta-cell effects | Postprandial and fasting | Avoid olanzapine if alternative available; standard T2D therapy if persistent | Reversible with discontinuation |
| Interferon-alpha (pegylated IFN, historical) | Autoimmune beta-cell destruction (may trigger T1D-like) | Acute onset; may resemble T1D | Insulin therapy; treat as T1D if autoantibodies positive | Variable; may be permanent |
11D. Drug Interactions Relevant to Oncology Diabetes Management
| INTERACTION | CLINICAL CONCERN | RECOMMENDATION |
| Azole antifungals (fluconazole, voriconazole, itraconazole) + Sulfonylureas | CYP2C9 inhibition → ↑ sulfonylurea plasma levels → severe hypoglycemia | Monitor BG closely; consider dose reduction of SU or switch to non-SU agent during antifungal course |
| Azole antifungals + Saxagliptin | CYP3A4/5 inhibition → ↑ saxagliptin exposure | REDUCE saxagliptin to 2.5 mg QD when co-administered with strong CYP3A4/5 inhibitors |
| Fluoroquinolones (ciprofloxacin, levofloxacin) + Any antidiabetic | ↑ risk of BOTH hypoglycemia AND hyperglycemia (erratic BG response) | Monitor BG frequently; counsel patient; consider alternative antibiotics if possible |
| Beta-blockers (propranolol – used in thyroid storm/tachycardia support) + Insulin/SU | Masking of tachycardia (sympathoadrenergic hypoglycemia symptoms); may blunt counter-regulatory response | Counsel patients; monitor BG; prefer selective beta-1 blockers if needed |
| Repaglinide + Gemfibrozil | CYP2C8 and OATP1B1 inhibition → up to 8x ↑ repaglinide AUC → severe hypoglycemia | CONTRAINDICATED COMBINATION – avoid gemfibrozil in any patient on repaglinide |
| Metformin + Iodinated Contrast (IV) | Risk of contrast-induced nephropathy → ↑ metformin accumulation → lactic acidosis | Hold metformin at time of contrast if eGFR 30-60; restart 48 hrs post with confirmed normal SCr |
| Octreotide (for carcinoid/NETs/acromegaly) + Insulin/Sulfonylurea | Octreotide inhibits insulin AND glucagon secretion; unpredictable glycemic effects | Monitor BG closely when initiating or changing octreotide; may need to reduce insulin/SU dose |
| Steroids + Insulin | Glucocorticoids antagonize insulin action → ↑ insulin requirements | Proactive dose escalation during steroid treatment; taper insulin proportionally with steroid taper |
CLINICAL PEARLS
- DIAGNOSIS: Two abnormal glycemic tests required (unless classic symptoms of hyperglycemia). Can be from same blood draw (e.g., FPG + HbA1c on same day). Updated ADA recommendation – no need to wait for a second separate day if two different test types are used.
- HbA1c LIMITATIONS: Falsely LOW in hemolytic anemia, sickle cell disease, recent blood transfusion, erythropoietin use, ESRD, pregnancy. In these patients (common in hem/onc), use FPG or 2-hr OGTT for diagnosis and monitoring.
- GLYCEMIC TARGETS: Less stringent HbA1c targets (<8%) are appropriate in: limited life expectancy, advanced complications, terminal cancer, frail elderly with history of falls/hypoglycemia, extensive comorbidities.
- TIME IN RANGE (TIR): ≥70% of CGM readings in 70-180 mg/dL is the glycemic quality metric. TIR is increasingly used in T1D management and correlates with microvascular outcomes.
- METFORMIN HOLD RULE: Never hold for IV contrast if eGFR ≥60. Always hold if eGFR 30-60 at time of contrast. Restart 48 hrs post with normal creatinine. Communicate proactively with ordering team.
- T1D BASAL-BOLUS BASICS: Basal covers fasting/overnight glucose. Bolus covers meal-related glucose. If fasting glucose is high → adjust basal. If pre-dinner glucose is high but fasting is fine → adjust morning bolus. If bedtime glucose is high → adjust dinner bolus.
- 1800 RULE (ISF): 1800 ÷ TDI = how many mg/dL 1 unit of rapid-acting insulin drops BG. Document this in every insulin patient’s chart. It is YOUR tool for safe correction dosing.
- SGLT-2i EUGLYCEMIC DKA: BG can be normal/near-normal. Classic DKA symptoms (N/V, abdominal pain, dyspnea) with BG <200 + ketonemia + acidosis. High-risk: fasting, perioperative, low-carb diet, reduced insulin, illness. Check ketones in any SGLT-2i patient with unexplained illness.
- SGLT-2i CARDIO/RENAL SELECTION: Choose agent based on indication: ASCVD → empagliflozin (strongest CV death data) OR canagliflozin/dapagliflozin. HF → any (except bexagliflozin). CKD → canagliflozin, dapagliflozin, or empagliflozin (CREDENCE, DAPA-CKD, EMPA-KIDNEY). Bexagliflozin has NO proven secondary benefit.
- GLP-1 RA vs INSULIN as first injectable in T2D: ADA PREFERS GLP-1 RA over insulin when adding injectables (better HbA1c, less hypoglycemia, weight loss). Use insulin if: extreme/symptomatic hyperglycemia, HbA1c >10%, or HbA1c >2% above goal.
- LINAGLIPTIN advantage: Only DPP-4 inhibitor without renal or hepatic dose adjustment (biliary excretion). Go-to DPP-4i in advanced CKD when glycemic control is needed.
- SAXAGLIPTIN/ALOGLIPTIN IN HF: Avoid – both showed ↑ HF hospitalization in outcome trials (SAVOR-TIMI, EXAMINE). In heart failure patients with diabetes, use SGLT-2i instead.
- DKA RESOLUTION: NOT defined by normalizing blood glucose. Resolution = pH ≥7.3 + bicarb ≥18 mEq/L + beta-hydroxybutyrate <0.6 mEq/L. Glucose normalizes before acidosis resolves. Keep insulin running until all three criteria are met.
- POTASSIUM IN DKA: If K+ <3.5 mEq/L, HOLD insulin infusion. Insulin drives K+ into cells → worsening hypokalemia → fatal arrhythmia. Replace K+ first. Continue monitoring K+ q2-4hr during DKA treatment.
- NEPHROPATHY: ACEi OR ARB (not both) if ACR ≥30 mg/g. Add SGLT-2i if eGFR ≥20 + ACR ≥200. Add finerenone for additional reno-CV protection. Semaglutide (FLOW) offers additional kidney benefit. ADA has moved away from ‘micro-‘ and ‘macroalbuminuria’ – use ACR value only.
- PREGABALIN vs DULOXETINE for DPN: Both FDA-approved. Duloxetine preferred if comorbid depression. Pregabalin preferred for severe pain/sleep disruption. TCAs are effective but burdensome (anticholinergic, falls, arrhythmia – be careful in elderly oncology patients).
- GLYBURIDE IN ELDERLY/CKD: AVOID. Active renally-excreted metabolites → prolonged hypoglycemia. Glipizide is preferred (hepatically eliminated). Know the difference when reviewing medication lists.
- STEROID-INDUCED DM (Oncology): Pattern matters. Once-daily AM dexamethasone → postprandial peak. NPH in the morning mirrors this pattern best. If BG peaks are all-day (high-dose/BID steroids), basal-bolus insulin is needed. Taper insulin with steroid taper to prevent hypoglycemia.
- ICI DIABETES: PERMANENT insulin dependence. Steroids don’t help. Educate patient as if newly diagnosed T1D. DKA is common at presentation. ICIs are generally continued despite DM (severity-dependent). Check fasting BG at every ICI cycle.
- PRAMLINTIDE: MUST reduce preprandial insulin by 50% at initiation. Boxed warning for severe hypoglycemia. Use prefilled pen – NOT vial/syringe. Cannot be mixed with insulin. Flag every new pramlintide order for insulin dose adjustment.
PHARMACIST WATCHOUTS
- HIGH-ALERT INSULIN CONCENTRATIONS: U-300 glargine (Toujeo) and U-100 glargine (Lantus/Basaglar) are NOT interchangeable on a unit-per-volume basis – they are interchangeable on a unit-per-unit basis (same units, different volume). U-500 regular insulin has intermediate-acting properties (NOT a rapid-acting replacement). Verify product, brand, and concentration at EVERY insulin order review. Use ‘tall man’ lettering and independent double checks.
- SGLT-2i PRE-PROCEDURE PROTOCOL: Canagliflozin, dapagliflozin, empagliflozin → hold 3 DAYS before surgery/procedure. Ertugliflozin → hold 4 DAYS. Bexagliflozin → hold when eGFR drops <30. This is FREQUENTLY MISSED in cancer patients undergoing procedures. Proactively flag and communicate with surgical/procedural teams. Include in pre-procedure medication reconciliation.
- SULFONYLUREA + AZOLE ANTIFUNGALS: Fluconazole, voriconazole, posaconazole (azoles commonly used for antifungal prophylaxis in neutropenic patients) inhibit CYP2C9 → ↑ SU levels → hypoglycemia. Consider switching to a DPP-4i or GLP-1 RA, or reduce SU dose and increase BG monitoring frequency when antifungals are started.
- METFORMIN IN ONCOLOGY: (a) Hold before CT contrast if eGFR 30-60; restart 48 hrs later with confirmed normal SCr. (b) Temporarily hold during significant illness, hypotension, or dehydration (common in chemo patients). (c) Hold perioperatively. (d) Monitor B12 annually – deficiency is common and may be confused with chemotherapy neuropathy.
- DKA POTASSIUM MANAGEMENT: Monitor K+ every 2-4 hours during insulin infusion. NEVER run insulin drip if K+ <3.5 mEq/L without first replacing potassium. Clarify potassium replacement orders with the medical team at every DKA order review.
- GLP-1 RA PATIENT COUNSELING – INJECTION TECHNIQUE: Rotate injection sites (abdomen, thigh, upper arm). Oral semaglutide (Rybelsus): MUST be taken on completely empty stomach with ≤4 oz of plain water; 30 minutes must elapse before ANY food, drink (other than water), or other oral medications. Most patients and nurses are unaware of this requirement.
- INPATIENT SLIDING SCALE ALONE: Per ADA, sliding-scale insulin alone (reactive-only dosing) is NOT recommended as the sole inpatient regimen. Alert providers who order sliding-scale only; recommend scheduled basal + prandial + correction insulin. Document your recommendation.
- PRAMLINTIDE INSULIN DOSE REDUCTION: When pramlintide is newly started (inpatient or outpatient), ALL preprandial insulin doses must be reduced by 50% immediately. If this is not done, severe hypoglycemia (often severe enough to require glucagon) is likely within hours of the first dose. Review every new pramlintide order for this mandatory adjustment.
- HYPOGLYCEMIA TREATMENT WITH ACARBOSE: If a patient is on acarbose or miglitol and develops hypoglycemia, they MUST be treated with ORAL DEXTROSE (glucose tablets), NOT sucrose (juice, candy, table sugar). The alpha-glucosidase inhibitor blocks sucrose absorption. Document and educate nursing staff.
- THIAZOLIDINEDIONES (TZD) + INSULIN: Combining pioglitazone with insulin increases risk of fluid retention/edema (and HF exacerbation). When adding insulin to a regimen containing a TZD (or vice versa), reduce or discontinue the TZD. Also: TZD dose titration takes 8-12 weeks for full effect – do not escalate quickly.
- ICI-DIABETES COUNSELING: Permanent insulin dependence (T1D-like management). Educate on: how to inject insulin, SMBG or CGM use, hypoglycemia recognition and treatment (glucagon kit), sick-day rules, medical ID bracelet, endocrinology follow-up. Oncology team must be informed this irAE is not steroid-managed.
- TACROLIMUS/SIROLIMUS POST-TRANSPLANT (Post-SCT): Post-transplant diabetes mellitus (PTDM) affects 10-40% of patients. Tacrolimus is more diabetogenic than cyclosporine. Calcineurin inhibitor-induced hyperglycemia is insulin-deficient (similar to T2D but may need insulin sooner). Monitor BG closely in first 6-12 months post-SCT. Work with transplant/SCT team on dose optimization.
- REPAGLINIDE + GEMFIBROZIL: ABSOLUTE CONTRAINDICATION. Gemfibrozil inhibits both CYP2C8 and OATP1B1 → 8x increase in repaglinide AUC → severe hypoglycemia. Screen for this interaction on every patient on repaglinide. If gemfibrozil is essential, substitute a different secretagogue.
- BEXAGLIFLOZIN: Newest SGLT-2i. NO proven CV, HF, or renal outcome benefit yet (as of 2024-2025). When choosing an SGLT-2i for a secondary indication (ASCVD, HF, CKD), always choose an agent with outcome trial data (canagliflozin, dapagliflozin, or empagliflozin). Bexagliflozin is appropriate only for glucose lowering at this time.
- FLUOROQUINOLONE + ANTIDIABETICS: Fluoroquinolones (ciprofloxacin, levofloxacin) cause both hypoglycemia AND hyperglycemia, erratically. In cancer patients commonly receiving fluoroquinolones for infections, monitor BG more closely while on antibiotic therapy. No dose adjustment – clinical monitoring only.
- INTRAVENOUS-TO-SUBCUTANEOUS INSULIN TRANSITION: Overlap basal SQ insulin 1-4 hours BEFORE stopping IV insulin infusion. Failure to overlap causes rebound hyperglycemia (or DKA in T1D). Document this transition clearly in the chart and verify with nursing that the overlap timing is understood.
- SEMAGLUTIDE RETINOPATHY RISK: SUSTAIN-6 identified increased retinopathy complications with semaglutide. In patients with pre-existing diabetic retinopathy, monitor closely. Rapid improvement in HbA1c with any potent agent can transiently worsen retinopathy (early worsening phenomenon).
- INSULIN IN CKD/RENAL FAILURE: Insulin clearance decreases as renal function declines → prolonged insulin action → increased hypoglycemia risk. No formal renal dose adjustment tables exist, but lower doses and more frequent monitoring are required. Consider using shorter-acting insulins more carefully in advanced CKD.