Newer oral and noninsulin therapies to treat type 2 diabetes mellitus

Article Figures & Data

TABLE 1

Noninsulin drugs for type 2 diabetes approved by the US Food and Drug Administration since 2005

Drug	Year approved
DPP-4 inhibitors
Sitagliptin (Januvia)	2006
Saxagliptin (Onglyza)	2009
Linagliptin (Tradjenta)	2011
Alogliptin (Nesina)	2013
GLP-1 receptor agonists
Short-acting (4–6 hrs)
Exenatide (Byetta)	2005
Lixisenatide (Lyxumia)	NDA submitted
Intermediate-acting (24 hrs)
Liraglutide (Victoza)	2010
Long-acting (7 days)
Exenatide extended-release (Bydureon)	2012
Albiglutide (Tanzeum)	2014
Dulaglutide (Trulicity)	2014
SGLT-2 inhibitors
Canagliflozin (Invokana)	2013
Dapagliflozin (Farxiga)	2014
Empagliflozin (Jardiance)	2014
Bile acid sequestrant
Colesevelam (Welchol)	2008
Dopamine-receptor agonist
Bromocriptine quick-release (Cycloset)	2009

DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; NDA = new drug application; SGLT-2 = sodium-glucose cotransporter-2.

TABLE 2

Incretins: DPP-4 inhibitors marketed in the United States

Dosing	Sitagliptin (Januvia)	Saxagliptin (Onglyza)	Linagliptin (Tradjenta)	Alogliptin (Nesina)
With or without food	100 mg/day; oral	2.5–5 mg/day; oral	5 mg/day; oral	25 mg/day; oral
Renal dose adjustment	Reduce to 50 mg/day if CrCl 30–50 mL/min; reduce to 25 mg/day if < 30 mL/min or ESRD	Reduce to 2.5 mg/day if CrCl < 50 mL/min or ESRD	Fecal elimination route; no renal adjustment needed	Reduce to 12.5 mg/day if CrCl 30–59 mL/min; reduce to 6.25 mg/day if < 30 mL/min or ESRD
Hepatic dose adjustment	No clinical experience with severe hepatic insufficiency (Child-Pugh score ≥ 9)	None	None	No clinical trials in severe hepatic insufficiency (Child-Pugh grade C)
Elimination half-life	12.4 hours	2.5 hours	> 24 hours	12.5–21.1 hours
Comments	Low risk of hypoglycemia		Long half-life; good choice for patients with chronic kidney disease	Long half-life
	Similar glycemic efficacy as a class: Agents cause modest improvements in glycated hemoglobin levels Overall, well tolerated; insufficient data regarding association with acute pancreatitis

CrCl = creatinine clearance; DPP-4 = dipeptidyl peptidase-4; ESRD = end-stage renal disease.
Based on information in Tran L, Zielinski A, Roach AH, et al. Pharmacologic treatment of type 2 diabetes: oral medications. Ann Pharmacother 2015; 49:540–556.

TABLE 3

Incretins: GLP-1 receptor agonists marketed in the United States

	Dosing (subcutaneous)	Renal dosing	Half-life; peak	Side effects
Short-acting (4–6 hours)
Exenatide (Byetta)	5 μg twice daily; may increase to 10 μg twice daily after 4 weeks; take within 60 minutes of morning and evening meals; at least 6 hours apart	Not recommended if CrCl < 30 mL/min	2.4 hours Peak: 2.1 hours	Weight loss, GI upset
Intermediate-acting (24 hours)
Liraglutide (Victoza)	Initial: 0.6 mg/day for 7 days Maintenance: 1.2 mg/day; may increase to 1.8 mg/day, if needed Body weight affects dosing: 1.2 mg and 1.8 mg doses provide adequate exposure for body weight ranges between 40–160 kg; has not been studied in body weight > 160 kg	No dose adjustment required but caution needed in patients with renal impairment	~13 hours Peak: 8–12 hours	Weight loss, nausea
Long-acting (7 days)
Exenatide extended- release (Bydureon)	2 mg once/week	Not recommended if CrCl < 30 mL/min	Not available Peaks: week 2 and week 6–7 (~10 weeks after discontinuation, plasma concentrations fall below minimal detectable levels)	Weight loss, nausea
Albiglutide (Tanzeum)	Initial: 30 mg once/week; may increase to 50 mg once/week, if response inadequate	Not recommended if eGFR < 15 mL/min/1.73 m²; use with caution in patients with renal impairment	~5 days Peak: 3–5 days	Weight loss, nausea
Dulaglutide (Trulicity)	0.75 mg once/week; may increase to 1.5 mg once/week, if needed Available as prefilled pen or syringe	No dose adjustment required	~5 days Peak: 24–72 hours	Weight loss, nausea

CrCl = creatinine clearance; eGFR = estimated glomerular filtration rate; GI = gastrointestinal; GLP-1 = glucagon-like peptide-1.
Based on information in Tran L, Zielinski A, Roach AH, et al. Pharmacologic treatment of type 2 diabetes: injectable medications. Ann Pharmacother 2015; 49:700–714.

TABLE 4

Oral pharmacologic agents for treatment of type 2 diabetes mellitus

Medication	Dosing	Renal dose adjustment	HbA1c reduction; monotherapy	HbA1c reduction; add-on	Hypoglycemia risk; monotherapy	Added benefits	Side effects/ disadvantages
SGLT-2 inhibitors
Canagliflozin	100 mg once/day; can titrate to 300 mg/day	eGFR 45–60, ≤ 100 mg/day; eGFR < 45, avoid	0.91%–116%	0.37%–0.92%	Low	Weight loss, decreased blood pressure, works at all stages of type 2 diabetes mellitus	Genitourinary infections, mild increase LDL, volume depletion/ dizziness, transient increase in creatinine, less effective with decreased eGFR, euglycemic DKA
Dapagliflozin	5 mg once/day; can titrate to 10 mg/day	eGFR < 60, avoid	0.54%–0.66%	0.4%–0.69%	Low
Empagliflozin	10 mg once/day; can titrate to 25 mg/day	eGFR < 45, avoid	0.74%–0.85%	0.38%–0.64%	Low
Bile acid sequestrants
Colesevelam	3.75 g once/day 1.875 g twice/day	No	0%–0.5%	0.3%–0.5%	Low	Decreased LDL, weight neutral	Increased triglycerides, constipation, decreased absorption of other medications
Dopamine-receptor agonists
Bromocriptine quick release	0.8 mg once/day; titrate by 0.8 mg weekly until 1.6–4.8 mg/day achieved	No	0.55% (single study)	0.4%–0.7%	Low	Possible decreased CV events, weight neutral	Nausea, headache, diarrhea, fatigue

CV = cardiovascular; DKA = diabetic ketoacidosis; eGFR = estimated glomerular filtration rate with units as mL/min/1.72m²; HbA1c = hemoglobin A1c; LDL = low-density lipoprotein; SGLT-2 = sodium-glucose cotransporter-2.
Based on information in Tran L, Zielinski A, Roach AH, et al. Pharmacologic treatment of type 2 diabetes: oral medications. Ann Pharmacother 2015; 49:540–556.