Introduction
Indications | Contraindications | Warnings and precautions* | Most common adverse reactions†
| Dosing | Dose adjustment in renal impairment
‡
| |
---|---|---|---|---|---|---|
GLP-1RAs | ||||||
Exenatide
| Use as monotherapy, in combination with OADs and insulin | Serious hypersensitivity to exenatide or product components | Pancreatitis, hypoglycemia (with insulin and sulfonylurea), use with severe renal impairment and ESRD, severe GI disease, hypersensitivity to exenatide | Nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, asthenia | Starting dose 5 mcg twice daily; titrate to 10 mcg twice daily after 1 month; exenatide is administered twice daily, 1 h before morning and evening meals | None; exenatide should not be used in severe renal impairment or ESRD |
Exenatide Extended Release (EQW) | Use as monotherapy and in combination with OADs | Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 or serious hypersensitivity to exenatide or product components | Thyroid C-cell tumors, pancreatitis, hypoglycemia (with insulin and sulfonylurea), use in severe renal impairment and ESRD, severe GI disease, hypersensitivity to exenatide | Nausea, diarrhea, headache, vomiting, constipation, injection site pruritus, injection site nodule, and dyspepsia | 2 mg once weekly without regard to meals | None; should not be used in severe renal impairment or ESRD |
Liraglutide | Use as monotherapy, in combination with OADs and insulin | Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 or serious hypersensitivity to liraglutide or product components | Thyroid C-cell tumors, pancreatitis, serious hypoglycemia (with insulin and sulfonylurea), use in renal impairment, hypersensitivity to liraglutide | Headache, nausea, diarrhea, and anti-liraglutide antibody formation | Starting dose 0.6 mg/day for 1 week; 1.2 mg/day thereafter; if acceptable glycemic control is not reached, dose can be increased to 1.8 mg/day; Liraglutide is administered once daily independently of meals | None |
DPP-4 inhibitors | ||||||
Sitagliptin | Use as monotherapy, in combination with OADs and insulin | Serious hypersensitivity to sitagliptin | Acute pancreatitis, acute renal failure, hypoglycemia (with insulin and a sulfonylurea), allergy/hypersensitivity | Upper respiratory tract infection (URI), nasopharyngitis, and headache; hypoglycemia when used with insulin/sulfonylurea | 100 mg once daily, with or without food | 50 mg once daily in moderate renal impairment; 25 mg once daily in severe renal impairment and ESRD |
Saxagliptin | Use as monotherapy, in combination with OADs and insulin | Serious hypersensitivity to saxagliptin | Acute pancreatitis, hypoglycemia (with insulin and a sulfonylurea), hypersensitivity to saxagliptin | URI, urinary tract infection (UTI), and headache; hypoglycemia when used with insulin/sulfonylurea; peripheral edema when used with a TZD | N/A | 2.5 mg once daily in moderate or severe renal impairment or ESRD |
Linagliptin | Use as monotherapy, in combination with OADs and insulin | Serious hypersensitivity to linagliptin | Hypoglycemia (with sulfonylurea/insulin) | Nasopharyngitis; hypoglycemia when used with sulfonylurea | N/A | None |
Alogliptin | Use as monotherapy, in combination with OADs and insulin | Serious hypersensitivity to alogliptin | Acute pancreatitis, hypersensitivity, hepatic effects, hypoglycemia (with insulin and a sulfonylurea) | Nasopharyngitis, headache, URI | N/A | 12.5 mg once daily in moderate renal impairment; 6.25 mg once daily in severe impairment and ESRD |
Drug comparison/study design and duration | Patient population | Background medication (s) | ∆ A1C (%) | ∆ FPG (mmol/L unless otherwise noted) | ∆ 2-h PPG (mmol/L) (mg/dL) | Hypoglycemic episodes (%) (event/person/year) | ||||
---|---|---|---|---|---|---|---|---|---|---|
Treatment | GLP-1RA | DPP-4 inhibitor | GLP-1RA | DPP-4 inhibitor | GLP-1RA | DPP-4 inhibitor | GLP-1RA | DPP-4 inhibitor | ||
Liraglutide (1.2 or 1.8 mg/day) vs sitagliptin 26-week open-label study [12] | Patients with inadequate glycemic control on metformin | Metformin | −1.24* −1.50* | −0.9 | −1.87* −2.14* | −0.83 | NR | 5% (0.370) | 5% (0.106) | |
At 26 weeks; *P < 0.0001 for comparison of each dose of liraglutide to sitagliptin | ||||||||||
26-week extension study of liraglutide (1.2 or 1.8 mg/day) vs. sitagliptin [13] | Patients with inadequate glycemic control on metformin | Metformin | −1.29* −1.51* | −0.88 | −1.71* −2.04* | −0.59 | NR | 8.1% (0.143) 8.3% (0.154) | 6.4% (0.170) | |
At 52 weeks; *P < 0.0001 for comparison of each dose of liraglutide to sitagliptin | ||||||||||
Second 26-week extension in which patients on sitagliptin were switched to liraglutide [14] | Patients with inadequate glycemic control on metformin | Metformin | −0.9* −1.3* | −0.2 −0.5 after switch to liraglutide†
| −1.3* −1.7* | −0.8 −1.4 after switch to liraglutide†
| NR | (0.156)‡
(0.130)‡
| (0.031)§
(0.060)§
| |
*Change from baseline (week 0)
†Change after switch to liraglutide at week 52
‡Rates of minor hypoglycemia from week 0 to week 72; 1 patient on liraglutide 1.2 mg/day experienced 2 major episodes
§Rates of minor hypoglycemia after switch to liraglutide; no episodes of major hypoglycemia were reported | ||||||||||
Exenatide vs sitagliptin vs background medication alone; 4-week open-label study [15] | −1.8*†
| −1.5* | NR | NR | NR | |||||
*P < 0.0001 for comparison with baseline; †
P = 0.0154 for comparison with metformin + insulin glargine (−1.23%) | ||||||||||
Exenatide vs sitagliptin plus exenatide; 20-week, double-blind, parallel-group study [16] | Patients with inadequate glycemic control on metformin + sitagliptin | Metformin | −0.38* | −0.68 | 0.06* | −0.55 | −1.55* | −2.10 | 0.8% | 1.6% |
*P < 0.05 for comparison of exenatide BID with exenatide BID + sitagliptin | ||||||||||
Exenatide vs sitagliptin; 2-week, double-blind crossover [17] | Patients on a stable regimen of metformin | Metformin | NR | −15 | −19 | 112 mg/dL* | 37 mg/dL | 1 minor episode | NR | |
*P < 0.0001 for comparison of exenatide BID to sitagliptin | ||||||||||
Exenatide vs sitagliptin; 8-week, double-blind crossover [18] | Patients on a stable regimen of metformin or TZD | Metformin or TZD | NR | −1.6* | −1.6 | −6.0 | −2.5 | NR | ||
*P < 0.01 for comparison of exenatide BID to sitagliptin | ||||||||||
EQW vs sitagliptin vs pioglitazone; 26-week, double-blind, superiority study [19] | Patients on a stable regimen of metformin | Metformin | −1.5* | −0.9 | −1.8†
| −0.9 | NR | 1% | 3% | |
At 26 weeks; *P < 0.0001, †
P = 0.038 for comparison of EQW to sitagliptin | ||||||||||
26-week open-label extension in which patients previously on sitagliptin or pioglitazone switched to exenatide [20] | None: all oral medications, including metformin, were stopped in the extension | −0.06 | −0.31* after switch to exenatide ER | −0.2 | −0.7* after switch to EQW | NR | 1% | 2% after switch to EQW | ||
*At 52 weeks, P < 0.05 for comparison with blinded period (weeks 0–26) | ||||||||||
EQW vs sitagliptin vs metformin vs pioglitazone; 26-week noninferiority [21] | Drug-naive patients | None | −1.53* | −1.15 | −2.3* | −1.1 | NR | Minor: 5.2% Major: 2.0% | 3.1% | |
*P < 0.001 for comparison of exenatide BID to sitagliptin; NS for comparison with metformin or pioglitazone |
Drug comparison/study design and duration | Patient population | Background medication(s) | ∆ A1C (%) | ∆ FPG (mmol/L unless otherwise noted) | ∆ 2-h PPG (mmol/L) (mg/dL) | Hypoglycemic episodes (%) (event/person/year) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Treatment | EQW | EBID | LQD | EQW | EBID | LQD | EQW | EBID | LQD | EQW | EBID | LQD | ||
Liraglutide vs exenatide; 26-week, open-label, parallel group (LEAD-6) [22] | Patients not adequately controlled on maximally tolerated doses of metformin, sulfonylurea, or both | Metformin, sulfonylurea, or both | – | −0.79 | −1.12* | – | −0.6 | −1.61 | – | Favored exenatide* | – | 2.6 EPY | 1.93 EPY†
| |
At 26 weeks; *P < 0.0001 compared with exenatide; †
P = 0.0131 compared with exenatide | ||||||||||||||
14-week, open-label extension in which patients on exenatide BID switched to liraglutide (LEAD-6) [23] | – | −0.32* after switch to liraglutide | −0.06 | – | −0.9* after switch to liraglutide | −0.2 | – | – after switch to liraglutide | – | – | −0.9* after switch to liraglutide | −0.4†
| ||
At 40 weeks; *P < 0.0001 vs exenatide BID for weeks 0–26; †
P = 0.0089 vs liraglutide for weeks 0–26 | ||||||||||||||
Liraglutide vs. EQW; 26-week, open-label, parallel group (DURATION-6) [24] | Patients on oral antidiabetic agents | Metformin, sulfonylurea, and/or pioglitazone | −1.28 | – | −1.48 | NR | – | NR | NR | – | NR | 10.8% | – | 8.9% |
Exenatide vs. EQW; 30-week, open-label noninferiority (DURATION-1) [25] | Patients who were drug naive or on 1 or more antidiabetic agents | None or metformin, sulfonylurea, TZD, or any 2 agents | −1.9* | −1.5 | – | −2.3†
| −1.4 | – | −5.3§
| −6.9 | – | 14.5% | 15.4% | – |
At 30 weeks *P = 0.0023, †
P < 0.001, §
P = 0.0124 for comparison of exenatide BID to once-weekly exenatide | ||||||||||||||
22-week extension in which patients on exenatide BID switched to EQW (DURATION-1) [26] | Patients who were drug naive or on one or more antidiabetic agents | None or metformin, sulfonylurea, TZD, or any two agents | −2.0% | −2.0% after change to EW | – | −47 mg/dL | −43 mg/dL after change to EW | – | NR | NR | – | NR | NR | – |
Exenatide vs. EQW; 24-week open-label (DURATION-5) [27] | Patients who were drug naive or on one or more antidiabetic agents | None or metformin, sulfonylurea, TZD, or any combination | −1.6* | −0.9 | – | −1.9†
−35 | −0.7 −12 | – | NR | NR | – | 6.8% | 5.4% | – |
*P < 0.0001, †
P = 0.0008 compared with exenatide BID |
Drug comparison/study design and duration | Patient population | Background medication(s) | ∆ A1C (%) | ∆ FPG (mmol/L unless otherwise noted) | ∆ 2-h PPG (mmol/L) (mg/dL) | Hypoglycemic episodes (%) (event/person/year) | ||||
---|---|---|---|---|---|---|---|---|---|---|
Treatment | GLP-1RA | GLP-1RA + Insulin | GLP-1RA | GLP-1RA + Insulin | GLP-1RA | GLP-1RA + Insulin | GLP-1RA | GLP-1RA + Insulin | ||
Liraglutide vs liraglutide + insulin Liraglutide; 12-week lead, in which liraglutide was added to metformin[28] | Insulin-naive patients on metformin or metformin/sulfonylurea combination | Metformin | −1.3 (O) −0.7 (RC) −0.6 (RT) | – | −2.0 (O) −1.5 (RC) −1.0 (RT) | – | NR | – | 6.2% (O) (0.38) 0% (RC) (0) 4.3% (RT) (0.21) | – |
At 12 weeks, controlled patients were included in an observational group (O) and continued in the extension. Inadequately controlled patients were randomized to continued therapy (randomized control, RC) or to additional treatment with insulin detemir (randomized treatment, RT) | ||||||||||
26-week, open-label extension in which patients controlled by liraglutide/metformin combination continued same treatment; inadequately controlled patients were randomized to continue same treatment or to receive insulin in addition to combination [28] | −1.1 (O) −0.8 (RC) | −1.1* (RT) | −2.1 (O) −2.3 (RC) | −3.1† (RT) | NR | NR | 4.2% (O) (0.13) 1.3% (RC) (0.03) | 9.2%‡ (RT) (0.29) | ||
*P < 0.0001; †
P = 0.03; ‡
P = 0.004 for RC vs RT comparisons at end of 26-week extension | ||||||||||
Exenatide BID vs placebo; 30-week, double-masked, placebo- controlled [29] | Patients on insulin alone or in combination with metformin or pioglitazone or both | Insulin, alone or in combination with metformin or pioglitazone or both | – | −1.74* | – | −1.6 NS | – | NR | – | 1.4 EPY |
*P < 0.001 for comparison with placebo (−1.04); NS not significantly different from placebo (−1.5) |
Drug comparison/study design and duration | Patient population | Background medication(s) | ∆ A1C (%) | ∆ FPG (mmol/L unless otherwise noted) | ∆ 2-h PPG (mmol/L) (mg/dL) | Hypoglycemic episodes (%) (event/person/year) | ||||
---|---|---|---|---|---|---|---|---|---|---|
Treatment | DPP-4 inhibitor | DPP-4 inhibitor + Insulin | DPP-4 inhibitor | DPP-4 inhibitor + Insulin | DPP-4 inhibitor | DPP-4 inhibitor + Insulin | DPP-4 inhibitor | DPP-4 inhibitor + Insulin | ||
Linagliptin vs placebo; 1-year, randomized, double-blind study [30] | Patients with T2D and severe renal impairment | Insulin, sulfonylurea, glitazone, alpha-glucosidase inhibitor + glinide | – | −0.72* | NR | NR | NR | NR | – | 83.7% |
*P < 0.0001 for treatment with linagliptin + background meds compared with placebo + background meds | ||||||||||
Sitagliptin vs increasing dose of insulin; 24-week, parallel group [31] | Patients uncontrolled on insulin alone | Insulin | – | −0.63* | – | NS | – | −74.5 mg/dL†
| – | 7.0§ EPY |
*P = 0.01 for comparison with increasing dose of insulin (−0.22); †
P < 0.001 for comparison with increasing dose of insulin (−21.7); NS not significantly different between treatments (values not reported); §
P < 0.05 vs increasing dose of insulin (14.3 EPY) | ||||||||||
Sitagliptin vs placebo; 24-week, double-blind, placebo-controlled, parallel group [32] | Patients uncontrolled on insulin alone or in combination with metformin | Insulin, alone or in combination with metformin | – | −0.6* | – | −18.5†
| – | −30.9 mg/dL | – | 16%§
|
*P < 0.001 for comparison with placebo (0); †
P ≤ 0.001 for comparison with placebo (−3.5 for FSG and +5.2 for PPG); §
P < 0.003 compared with placebo | ||||||||||
Saxagliptin vs placebo; 24-week, double-blind, placebo-controlled, parallel group [33] | Patients uncontrolled on insulin alone or in combination with metformin | Insulin, alone or in combination with metformin | – | −0.73* | – | −0.22 | – | −1.3†
| – | Minor: 5.3% Major: 1.0% |
At week 24, *P < 0.0001 compared with placebo; †
P = 0.0016 compared with placebo |
Drug comparison/study design and duration | ∆ BW (kg) | ∆ β-cell function (HOMA-B) (%) | ∆ SBP (mmHg) | |||
---|---|---|---|---|---|---|
Treatment | GLP-1RA | DPP-4 inhibitor | GLP-1RA | DPP-4 inhibitor | GLP-1RA | DPP-4 inhibitor |
Liraglutide (1.2 or 1.8 mg/day) vs sitagliptin; 26-week, open-label study with 26-week extension [12] | −2.86* −3.38* | −0.96 | 27.23* 28.70* | 4.18 | −0.55 −0.72 | −0.94 |
At 26 weeks; *P < 0.0001 for comparison of each dose of liraglutide to sitagliptin | ||||||
First 26-week extension [13] | −2.78* −3.68* | −1.16 | 22.58†
25.76†
| 3.98 | −0.37 −2.55 | −1.03 |
At 52 weeks; *P < 0.0001, †
P < 0.001 for comparison of each dose of liraglutide to sitagliptin | ||||||
Second 26-week extension in which patients on sitagliptin were switched to liraglutide [14] | −2.6 −3.1 | −1.6* −2.5* after switch to liraglutide | Improvements observed with both doses | Significant increases observed with both doses after switch to liraglutide | No notable changes observed | No significant changes observed after switch to liraglutide |
At 78 weeks; *P < 0.0001 for comparison of each dose of liraglutide to sitagliptin | ||||||
Exenatide vs sitagliptin vs background medication alone; 4-week, open-label study [15] | −0.9 | 0.4 | NR | NR | NR | NR |
*P < 0.037 for comparison with metformin + insulin glargine (0.4) | ||||||
Exenatide vs sitagliptin plus exenatide; 20-week, double-blind, parallel-group study [16] | −2.58 | −2.20 | NR | NR | −2.3 | −0.8 |
Exenatide vs sitagliptin; 2-week, double-blind crossover [17] | −0.8* | −0.3 | NR | NR | NR | NR |
*P = 0.0056 for comparison of exenatide BID to sitagliptin | ||||||
Exenatide vs sitagliptin; 8-week, double-blind crossover [18] | −1.37* | −0.89 | 32.9 | 20.8 | −2.5 | −2.0 |
*P < 0.05 for comparison of exenatide BID to sitagliptin | ||||||
EQW vs sitagliptin vs pioglitazone; 26-week, double-blind, superiority study [19] | −2.3* | −0.8 | NR | NR | Decreased†
| No change |
At 26 weeks; *P = 0.0002 for comparison of exenatide BID to sitagliptin; †
P = 0.0055 for difference in SBP (−4 mmHg) | ||||||
26-week, open-label extension in which patients previously on sitagliptin or pioglitazone switched to exenatide [20] | 0.7* | −1.1* after switch to EQW | NR | NR | −0.9 | −2.7* after switch to EQW |
At 52 weeks, *P < 0.05 comparison with blinded period (weeks 0–26) | ||||||
EQW vs sitagliptin vs metformin vs pioglitazone; 26-week noninferiority [21] | −2.0* | −0.8 | Ratio (baseline to endpoint): +1.8†
| Ratio (baseline to endpoint): +1.3 | NR | NR |
*P < 0.001 for comparison of EQW to sitagliptin or pioglitazone; NS for comparison with metformin; †
P < 0.001 for comparison of EQW to sitagliptin, pioglitazone, or metformin |
Drug comparison/study design and duration | ∆ BW (kg) | ∆ β-cell function(HOMA-B) (%) | ∆ SBP (mmHg) | ||||||
---|---|---|---|---|---|---|---|---|---|
Treatment | EQW | EBID | LQD | EQW | EBID | LQD | EQW | EBID | LQD |
Liraglutide vs exenatide; 26-week, open-label, parallel group (LEAD-6) [22] | – | −2.87 | −3.24 | – | 2.74 | 32.12* | – | −2.00 | −2.51 |
At 26 weeks; *P < 0.0001 compared with exenatide | |||||||||
14-week, open-label extension in which patients on exenatide BID switched to liraglutide (LEAD-6) [23] | – | −0.9* after switch to liraglutide | −0.4†
| – | 14.5‡ after switch to liraglutide | NR | – | −3.8* after switch to liraglutide | −2.2 |
At 40 weeks; *P < 0.0001 compared with exenatide at 26 weeks; †
P = 0.0089 compared with liraglutide at 26 weeks; ‡
P = 0.001 compared with exenatide at 26 weeks; §
P = 0.0128 compared with exenatide at 26 weeks | |||||||||
Liraglutide vs. EQW; 26-week, open-label, parallel group (DURATION-6) [24] | −2.68 | – | −3.58 | NR | – | NR | −2.5 | – | −3.5 |
Exenatide BID vs. EQW; 30-week, open-label noninferiority (DURATION-1) [25] | −3.7 | −3.6 | – | NR | NR | – | −4.7 | −3.4 | – |
22-week extension in which patients on exenatide BID switched to exenatide ER (DURATION-1) [26] | −4.1 | −4.5 after switch to exenatide ER | – | NR | NR | – | −6.2 | −3.8 after switch to exenatide ER | – |
Exenatide BID vs. EQW; 24-week, open-label (DURATION-5)[27] | −2.3 | −1.4 | – | NR | NR | – | −2.9 | −1.2 | – |
Drug comparison/study design and duration | ∆ BW (kg) | ∆ β-cell Function (HOMA-B) (%) | ∆ SBP (mmHg) | |||
---|---|---|---|---|---|---|
Treatment | GLP-1RA | GLP-1RA + Insulin | GLP-1RA | GLP-1RA + Insulin | GLP-1RA | GLP-1RA + Insulin |
Liraglutide vs liraglutide + insulin; 12-week lead-in which liraglutide was added to metformin [28] | −4.4 (O) −3.5 (RC) −3.5 (RT) | – | NR | – | NR | – |
At 12 weeks, controlled patients were included in an observational group (O) and continued in the extension. Inadequately controlled patients were randomized to continued therapy (randomized control, RC) or to additional treatment with insulin detemir (randomized treatment, RT) | ||||||
26-week, open-label extension in which patients controlled by liraglutide/metformin combination continued same treatment; patients not adequately controlled by liraglutide/metformin combination were randomized to continue same treatment or to receive insulin in addition to combination [28] | −4.8 (O) −4.7 (RC) | −4.0* (RT) | NR | NR | −3.3 (O) −3.1 (RC) | −1.7 (RT) |
*P = 0.03; ‡
P = 0.004 for RC vs RT comparisons at end of 26-week extension | ||||||
Exenatide BID vs placebo; 30-week, double-masked, placebo-controlled trial in patients on background therapy with insulin glargine alone or in combination with metformin and/or pioglitazone [29] | – | −1.78* | – | NR | – | −2.7†
|
*P < 0.001 for comparison with placebo (+0.96); P = 0.01 for comparison with placebo (+1.7) |
Drug comparison/study design and duration | ∆ BW (kg) | ∆ β-cell function (HOMA-B) (%) | ∆ SBP (mmHg) | |||
---|---|---|---|---|---|---|
Treatment | DPP-4 inhibitor | DPP-4 inhibitor + Insulin | DPP-4 inhibitor | DPP-4 inhibitor + Insulin | DPP-4 inhibitor | DPP-4 inhibitor + Insulin |
Linagliptin vs placebo; 1-year, randomized, double-blind, placebo-controlled study in patients with T2D and severe renal impairment [30] | – | −1.83 | – | NR | – | NR |
Sitagliptin vs placebo; 24-week, parallel group [31] | – | −0.7* | – | NR | – | NR |
*P < 0.05 vs stable dose of insulin alone (+1.1 kg) | ||||||
Sitagliptin vs placebo; 24-week, double-blind, placebo-controlled, parallel group [32] | – | +0.1 NS | – | NR | – | NR |
NS—not significantly different from placebo (+0.1) | ||||||
Saxagliptin vs placebo 24-week, double-blind, placebo-controlled, parallel group [33] | – | −0.39 | – | −1086.8* (304.25) | NR | NR |
*Adjusted mean change from baseline (SE) in postprandial glucagon AUC (pg min/mL) |