Pharmacologic Treatment Intensification Strategies Beyond Basal Insulin

Generic (Brand)Favorable EffectsUnfavorable Effects/CautionsClinical Pearls for Drug Selection and Management Beyond Basal Insulin
Metformin (Glucophage)
  • • High efficacy

  • • Low hypoglycemia risk

  • • Weight neutral/modest loss

  • • Low cost

  • • Long-term use associated with vitamin B12 deficiency (monitor if peripheral neuropathy, anemia)

  • • Contraindicated when eGFR <30 mL/min/1.73 m2

  • • Rare/serious safety concerns: lactic acidosis

  • • Should be continued, if tolerated and not contraindicated

  • • May require basal insulin dose reduction upon initiation

  • • Consider metformin XR if previous GI intolerance to metformin IR

Thiazolidinediones Pioglitazone (Actos)Rosiglitazone (Avandia)
  • • High efficacy

  • • Low hypoglycemia risk

  • • Low cost

  • • Benefit in NASH

  • • Weight gain

  • • Fluid retention/edema (among those with heart failure)

  • • Bone fractures (among postmenopausal females and elderly males)

  • • Bladder cancer (pioglitazone)

  • • Increased LDL-C (rosiglitazone)

  • • May require basal insulin dose reduction upon initiation

  • • May cause weight gain when used in combination with insulin

Sulfonylureas Glipizide (Glucotrol) Glimepiride (Amaryl) Glyburide (Diabeta)
  • • High efficacy

  • • Low cost

  • • High risk of hypoglycemia

  • • Weight gain

  • • May cause weight gain when used in combination with insulin

  • • Consider discontinuing when initiating combination injectable therapy

GLP-1 receptor agonists Liraglutide (Victoza) Exenatide ER (Bydureon) Dulaglutide (Trulicity) Semaglutide injection (Ozempic) Semaglutide oral (Rybelsus) Lixisenatide (Adlyxin)
  • • High efficacy

  • • Low hypoglycemia risk

  • • Weight loss (semaglutide> liraglutide>dulaglutide>exenatide>lixisenatide)

  • • CV benefits (liraglutide>dulaglutide>semaglutide injection)

  • • Renal benefits seen with liraglutide (LEADER) and injectable semaglutide (SUSTAIN-6)

  • • High cost

  • • Avoid in setting of gastroparesis

  • • GI intolerance (nausea, vomiting, diarrhea)

  • • Rare/serious safety concerns: MEN2 or thyroid C-cell tumors, acute pancreatitis, worsening of diabetic retinopathy complications (semaglutide oral and injection)

  • • Consider prior to basal insulin in most patients

  • • May require a lower insulin dose when initiating a GLP-1 receptor agonist

  • • Shorter-acting agents have greater PPG reduction vs. longer-acting agents

SGLT2 inhibitors Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Ertugliflozin (Steglatro)
  • • Intermediate efficacy

  • • Low hypoglycemia risk

  • • Weight loss

  • • CV benefits (empagliflozin and canagliflozin)

  • • Renal benefits seen with canagliflozin in CREDENCE; ongoing trials with dapagliflozin (DAPA-CKD) and empagliflozin (EMPA-KIDNEY)

  • • Modest decrease in blood pressure

  • • High cost

  • • Genitourinary infections

  • • Volume depletion/hypotension

  • • Rare/serious safety concerns: amputation risk (canagliflzin and ertugliflozin), eDKA, bone fractures (canagliflozin), urinary tract infections, Fournier’s gangrene

  • • May require basal insulin dose reduction upon initiation

DPP-4 inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Tradjenta) Alogliptin (Nesina)
  • • Intermediate efficacy

  • • Low hypoglycemia risk

  • • Weight neutral

  • • High cost

  • • Joint pain

  • • Potential risk for heart failure exacerbation (saxagliptin, alogliptin)

  • • Rare/serious safety concerns: acute pancreatitis, joint pain

  • • Consider discontinuing DPP-4 inhibitor when initiating a GLP-1 receptor agonist

Fixed-ratio combinations (basal insulin plus GLP-1 receptor agonist) Insulin degludec plus liraglutide (Xultophy) Insulin glargine plus lixisenatide (Soliqua)
  • •Once-daily regimen

  • •Less hypoglycemia and weight gain compared with intensive insulin regimens

  • • Greater reduction in BeAM differential glucose as compared with insulin glargine monotherapy

  • • Reduced GI side effects vs. GLP-1 receptor agonist alone

  • • High cost

  • • Less flexibility in dosing

  • • GI side effects

  • • For initiation, if currently on GLP-1 receptor agonist, use 10–16 dose steps (Xultophy) or 10–15 units (Soliqua)

  • • Dose adjustments should be made based on target FBG every 3–4 days

Prandial insulin (rapid-acting analogs) Insulin lispro (Humalog) Insulin glulisine (Apidra) Insulin aspart (Novolog) Ultra-rapid-acting insulin aspart (Fiasp) Inhaled human insulin (Afrezza)
  • • Highest efficacy

  • • Greater flexibility in dosing vs. premixed insulin

  • • Inhaled option available for select patients desiring less injections

  • • High cost

  • • Weight gain

  • • Multiple daily injections

  • • Mimics physiological meal-stimulated insulin release

  • • Consider rapid-acting over short-acting insulin for less risk of hypoglycemia

  • • Fiasp has a quicker onset of action and faster offset of exposure and can be dosed at mealtime or within 20 minutes after starting a meal

  • • Initial dose of lispro, glulisine, or aspart should be 4 units or 10% of the basal dose with the largest meal

  • • Titrate lispro, glulisine, or aspart by 1–2 units or 10–15% twice weekly

  • • Afrezza is available in three cartridge strengths (4, 8, and 12 units) and is contraindicated in patients with chronic lung disease (asthma, COPD) and is not recommended in patients who smoke or recently quit smoking

Premixed insulin NPH/regular 70/30 (Humulin 70/30) Lispro 50/50 (Humalog 50/50) Lispro 75/25 (Humalog 75/25) Lispro 75/25 (Humalog 75/25) Aspart 70/30 (Novolog 70/30)
  • • Lower costs compared with basal insulin analogs

  • • Fewer injections compared with basal-bolus regimens

  • • Simplified regimen vs. basal-bolus

  • • High incidence of nocturnal hypoglycemia and glycemic variability

  • • Less flexibility in dosing

  • • May be initiated in insulin-naive patients and those already receiving insulin requiring treatment intensification

  • COPD, chronic obstructive pulmonary disease; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA-CKD, A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease; eDKA, euglycemic diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; EMPA-KIDNEY, The Study of Heart and Kidney Protection With Empagliflozin; FBG, fasting blood glucose; GI, gastrointestinal; IR, immediate release; LDL-C, LDL cholesterol; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcomes; MEN2, multiple endocrine neoplasia syndrome type 2; NASH, nonalcoholic steatohepatitis, PPG, postprandial glucose; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects with Type 2 Diabetes; XR, extended release.