Table 3A.

Studies comparing combination of insulin with incretin-based therapies

Study	Design	Patients (n)	Duration	Results
GLP-1 based
Yoon et al. 200950	Retrospective analysis, heterogeneous group; mean baseline HbA1C 8.05%. Exenatide added to insulin (different regimes).	188	27 months (split in four intervals)	Sustained HbA1C reduction Initial weight loss, maximum mean loss of 6.2 kg (P<0.001) from baseline in 12–18 month interval. Adverse effects — mainly GI (mild). Two serious adverse events: 1) acute renal failure (one patient, not related to exenatide); 2) acute pancreatitis (one patient in one month after starting exenatide).
Buse et al. 201051	Prospective placebo controlled, randomized study; 12 years duration of T2DM. Addition of exenatide or matched placebo or glargine (+/− OAD).	259	30 weeks	HbA1C reduced by 1.7% from baseline (8.3%) while in placebo group, HbA1C reduced by 1% from baseline (8.5%; P<0.001, between treatments). Placebo group showed 1 kg weight gain, while exenatide group showed weight loss of 1.8 kg (P=0.001, between treatments). Significantly more GI side effects in the exenatide group with nausea experienced by 41% versus 8%.
Arnolds et al. 201055 (both GLP-1 and DPP-4 inhibitor based)	Proof of concept study. Prospective, single centre study involving both GLP-1 analog and DPP-4 inhibitor. Assess post-prandial glycemic control while comparing the response of addition of exenatide (5–10 μg b.i.d.) or sitagliptin (100 mg o.d.) or no further treatment to a regime of metformin and insulin glargine (titrated to fasting blood glucose target <5.6 mmol/L)	48	4 weeks	The six-hour postprandial blood glucose excursion was significantly lower with both exenatide (P=0.0036) and sitagliptin (P=0.0008) compared to the non-incretin intervention group. HbA1C changed by −1.9% (exenatide), −1.5% (sitagliptin) and by −1.2% in the non-intervention group. Hypoglycaemia rates were low. Weight loss was seen in the exenatide group (−0.9 kg) and was significantly different to a slight gain in the nonincretin group (+0.4 kg, P=0.0377)
DPP-4 inhibitor based
Fonseca et al. 200752	Prospective placebo controlled, randomized study, mean duration 14.7 years of T2DM, mean HbA1C 8.4% on high dose insulin with average three injections/day. Randomized to receive 50 mg b.i.d. of vildagliptin or matched placebo.	296	24 weeks	Mean HbA1C change: −0.5% in the vildagliptin group and −0.2% in the placebo group (P=0.01 between treatments difference). No difference in adverse events rate between both groups. Both mild (1.95 vs 2.96 events/patient/year, P<0.01) and severe hypoglycemia (0.0 vs 0.1 events/patient/year, P<0.05) were less common in the vildagliptin group.
Rosenstock et al. 200953	Prospective, placebo-controlled, randomized study. Mean duration of T2DM 12–13 years with baseline HbA1C of 9.3%. Once daily alogliptin (12.5 mg or 25 mg) or placebo added to insulin therapy +/- metformin. No change in insulin dose.	390	26 weeks	HbA1C change: −0.63% with 12.5 and −0.71% with 25 mg of alogliptin versus −0.13 % with placebo; P<0.001). No difference in reported hypoglycemia.
Vilsboll et al. 200954	Prospective placebo controlled randomized study. Duration of T2DM >12 years with mean baseline HbA1C of >8.6%. Sitagliptin 100 mg or placebo was added to insulin (basal or premixed regimes) +/- metformin. Insulin and metformin doses were kept constant.	641	24 weeks	HbA1C changed by −0.6% in the sitagliptin group with no change in the placebo group (P<0.001) Hypoglycemia was more common with sitagliptin. No significant change in body weight.
Fonseca et al. 200867	Extension of previous study from 2007. Patients in placebo group were given vildagliptin 50 mg/day.	200	52 weeks	Patients on 50 mg b.i.d. of vildagliptin from the original study showed sustained HbA1C reduction (−0.5%). Those who switched from placebo to vildagliptin 50 mg o.d. showed mean reduction of −0.4%. Weight remained stable.