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.
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.
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.
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.
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.
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.
7B. 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
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.
7C. 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)
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.
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.
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.
7E. 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.
7F. 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
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)
8. 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.
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
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.
10. 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.
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.
~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
Proactive dose escalation during steroid treatment; taper insulin proportionally with steroid taper
12. CLINICAL PEARLS & PHARMACIST WATCHOUTS
12A. Clinical Pearls – Stepwise Mastery
CLINICAL PEARL: 1. 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.
CLINICAL PEARL: 2. 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.
CLINICAL PEARL: 3. 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.
CLINICAL PEARL: 4. 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.
CLINICAL PEARL: 5. 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.
CLINICAL PEARL: 6. 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.
CLINICAL PEARL: 7. 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.
CLINICAL PEARL: 8. 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.
CLINICAL PEARL: 9. 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.
CLINICAL PEARL: 10. 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.
CLINICAL PEARL: 11. 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.
CLINICAL PEARL: 12. 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.
CLINICAL PEARL: 13. 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.
CLINICAL PEARL: 14. 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.
CLINICAL PEARL: 15. 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.
CLINICAL PEARL: 16. 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).
CLINICAL PEARL: 17. GLYBURIDE IN ELDERLY/CKD: AVOID. Active renally-excreted metabolites → prolonged hypoglycemia. Glipizide is preferred (hepatically eliminated). Know the difference when reviewing medication lists.
CLINICAL PEARL: 18. 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.
CLINICAL PEARL: 19. 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.
CLINICAL PEARL: 20. 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.
Rx PHARMACIST WATCHOUT: 1. 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.
Rx PHARMACIST WATCHOUT: 2. 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.
Rx PHARMACIST WATCHOUT: 3. 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.
Rx PHARMACIST WATCHOUT: 4. 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.
Rx PHARMACIST WATCHOUT: 5. 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.
Rx PHARMACIST WATCHOUT: 6. 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.
Rx PHARMACIST WATCHOUT: 7. 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.
Rx PHARMACIST WATCHOUT: 8. 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.
Rx PHARMACIST WATCHOUT: 9. 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.
Rx PHARMACIST WATCHOUT: 10. 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.
Rx PHARMACIST WATCHOUT: 11. 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.
Rx PHARMACIST WATCHOUT: 12. 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.
Rx PHARMACIST WATCHOUT: 13. 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.
Rx PHARMACIST WATCHOUT: 14. 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.
Rx PHARMACIST WATCHOUT: 15. 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.
Rx PHARMACIST WATCHOUT: 16. 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.
Rx PHARMACIST WATCHOUT: 17. 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).
Rx PHARMACIST WATCHOUT: 18. 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.
END OF DOCUMENT
ADA Standards of Care 2024/2025 | ACCP Updates in Therapeutics 2025 | Hem/Onc Pharmacotherapy Specialist Edition