Introduction
Methods
Combination Therapy of DPP4 Inhibitors and Insulin: General Overview
Alogliptin
References | Design | Primary outcome | Patients and treatment | Main findings |
---|---|---|---|---|
Rosenstock et al. [16] | Randomized double-blind placebo-controlled | Change of HbA1c at week 26 | Alogliptin 12.5 mg (n = 131) Alogliptin 25 mg (n = 129) Placebo (n = 130) | HbA1c change: − 0.71% for 25 mg dose, − 0.63% for 12.5 mg dose; − 0.13% placebo Decreases of HbA1c ≥ 0.5%, 1% and 1.5% significantly greater in alogliptin vs. placebo |
Kaku et al. [17] | Randomized double-blind placebo-controlled | Change of HbA1c at week 12 | Alogliptin 25 mg (n = 179) | HbA1c change: − 0.96% alogliptin vs. − 0.29% placebo; intergroup difference − 0.66%. Proportions of patients who achieved HbA1c < 8.0%, < 7.0% and < 6.0% were significantly higher in alogliptin group |
Vilsbøll et al. [18] | Randomized placebo-controlled | Change of HbA1c at week 24 | Sitagliptin 100 mg/day (n = 322) Placebo (n = 319) | HbA1c reduction 0.6% sitagliptin vs. 0% placebo HbA1c < 7% in 13% sitagliptin vs. 5% placebo Higher reductions of fasting glucose (15.0 mg/dl) and 2-h postmeal (36.1 mg/dl) relative to placebo |
Hong et al. [19] | Randomized active-competitor parallel-group | Change of HbA1c at week 24 | Sitagliptin 100 mg/day (n = 70) Insulin-increasing arm (n = 70) | HbA1c decreases − 0.6% vs. − 0.2%; hypoglycemic events 7.0 vs. 14.3 per patient-year; weight increase in the insulin-increasing subjects |
Shankar et al. [21] | Randomized double‐blind placebo‐controlled | Change of HbA1c at week 24 | Sitagliptin 100 mg/day (n = 234) Placebo (n = 233) | HbA1c reduction 0.7% vs. 0.3%; HbA1c target of < 7%: 16% vs. 8%; reduction of 2-h postmeal glucose 26.5 mg/dl relative to placebo; no change of body weight |
Mathieu et al. [22] | Randomized double-blind placebo-controlled | Change of HbA1c at week 24 | Sitagliptin 100 mg/day (n = 329) Placebo (n = 329) | HbA1c reduction − 1.3% vs. − 09%; increase in dose of insulin was less in the sitagliptin group (− 4.7 IU); fewer patients in the sitagliptin group experienced hypoglycemia |
Yki-Järvinen et al. [24] | Randomized placebo-controlled | Change of HbA1c at week 24 | Linagliptin 5 mg/day (n = 631) Placebo (n = 630) | HbA1c mean change − 0.58% vs. + 0.07% at 24 weeks, − 0.48% vs. + 0.05% at 52 weeks; HbA1c < 7.0% after 52 weeks: 16% vs. 7%; reduction in HbA1c ≥ 0.5%: 37% vs. 17% |
Sheu et al. [25] | Randomized placebo-controlled (post hoc analysis) | Change of HbA1c at week 24 | Linagliptin 5 mg/day (n = 80) Placebo (n = 74) | HbA1c placebo-corrected mean change was − 0.9% ± 0.1% at weeks 24 and 52; changes in mean body weight − 0.67 vs. − 0.38 kg |
Durán-Garcia et al. [26] | Randomized placebo-controlled (post hoc analysis) | Change of HbA1c at week 24 | Linagliptin 5 mg/day (n = 475) Placebo (n = 475 | HbA1c adjusted mean change − 0.63% vs. 0.04 at week 24; HbA1c ≤ 7%: 16.4% vs. 6.5% at week 52; placebo-corrected adjusted mean reduction of fasting plasma glucose -0.8 mmol/l at week 24; mean change of insulin dose 2.3 U vs. 4.0 U at week 52 versus baseline |
Barnett et al. [27] | Randomized placebo-controlled | Change of HbA1c at week 24 | Saxagliptin 5 mg/day (n = 304) Placebo (n = 151) | HbA1c change − 0.73% vs. − 0.32%; HbA1c < 7%: 17.3% vs. 6.7%; adjusted-mean change fasting plasma glucose − 10 vs. − 6 mg/dl |
Barnett et al. [28] | Randomized placebo-controlled | Change of HbA1c at week 52 | Saxagliptin 5 mg/day (n = 304) Placebo (n = 151) | Adjusted mean change HbA1c − 0.75% vs. − 0.38%; adjusted between-group difference − 0.37%; HbA1c < 7%: 21.3% vs. 8.7%; increase mean total insulin dose 5.67 vs. 6.67 U; similar results in metformin-treated patients |
Li et al. [29] | Randomized-controlled open label | Changes of MAGE by CGM | Saxagliptin 5 mg/day (n = 31) Continuous subcutaneous insulin infusion (n = 38) | After 4 weeks of therapy, glycemic control reached in 3.62 vs. 4.54 days; total daily dose insulin 16.16 vs. 21.12 U; MAGE 2.47 vs. 3.37; hourly mean glucose levels (0:00–6:00 a.m.) lower in the saxagliptin group |
Fonseca et al. [30] | Randomized placebo-controlled | Change of HbA1c at week 24 | Vildagliptin 50 mg bid (n = 144) Placebo (n = 152) | HbA1c mean change − 0.5 vs. − 0.2% (between-group difference − 0.3%); increase in total daily insulin dose + 1.2 vs. + 4.1 U; hypoglycemia events 1.95 vs. 2.96 per patient-year (severe 0 vs. 0.10) |
Kothny et al. [32] | Randomized placebo-controlled | Change of HbA1c at week 24 | Vildagliptin 50 mg bid (n = 228) Placebo (n = 221) | HbA1c mean change − 0.8 vs. − 0.1% (between-group difference − 0.7%; − 0.6% in the presence of metformin, − 0.8% without metformin); similar hypoglycemic events (8.4% vs. 7.2%); no weight gain |
Hirose et al. [33] | Randomized placebo-controlled | Change of HbA1c at week 12 | Vildagliptin 50 mg bid (n = 76) Placebo (n = 75) | HbA1c mean change − 1.01% vs. − 0.11% (between-group difference − 0.91%); HbA1c < 7%: 50% vs. 3.9%; reductions in FPG higher in the vildagliptin group |
Ning et al. [34] | Randomized placebo-controlled | Change of HbA1c at week 24 | Vildagliptin 50 mg bid (n = 146) Placebo (n = 147) | Adjusted mean change HbA1c − 1.08% vs. − 0.38% (between-group difference − 0.7%); HbA1c < 7%: 23.6% vs. 11.2%; hypoglycemia 2.7% vs. 5.4% |
Sitagliptin
Linagliptin
Saxagliptin
Vildagliptin
Real-World Studies on the Combination of DPP4 Inhibitors and Insulin
DPP4 Inhibitors in Chronic Renal Disease
Drug | Comment |
---|---|
Alogliptin | Doses should be halved in moderate-to severe renal failure eGFR 30–50 mL/min/1.73 m2: halve doses eGFR < 30 mL/min/1.73 m2: quarter doses |
Linagliptin | Dose adjustment is not needed |
Sitagliptin | Doses should be halved in moderate-to severe renal failure Should be avoided in end-stage renal disease or hemodialysis |
Sitagliptin | Doses should be halved in moderate-to severe renal failure eGFR 30–50 mL/min/1.73 m2: halve doses eGFR < 30 mL/min/1.73 m2: quarter doses |
Vildagliptin | Doses should be halved in moderate-to severe renal failure Use with caution in end-stage renal disease or hemodialysis |
DPP4 Inhibitor Use in Elderly Patients
DPP4 Inhibitors in Hospitalized Patients
References | Design | Patients and treatment | Main findings |
---|---|---|---|
Umpierrez (2013) [66] | Pilot randomized study | 90 in-patients; sitagliptin alone or combined with glargine or a basal-bolus (glargine and lispro) both with correctional insulin doses | No differences in glycemic control, length of hospital stay and hypoglycemia events Fewer total daily insulin doses and numbers of insulin injections in sitagliptin groups |
Pasquel (2017) [67] | Non-inferiority randomized-controlled trial | 277 in-patients; sitagliptin plus basal glargine once daily or basal-bolus (glargine and lispro) both with correctional insulin doses | Mean daily glucose concentration was non-inferior No differences in hospital complications, length of stay, hypoglycemic events and treatment failures |
Garg (2017) [68] | Randomized-controlled trial | 66 in-patients; saxagliptin or basal-bolus insulin therapy, both with correctional insulin doses | Non-inferior in mean daily blood glucose control Lower glycemic variability Basal-bolus insulin: higher number of injections and daily insulin dose |