Trial ID	Intervention(s) and comparator(s)	Rescue medication
Bilezikian 2013	I: metformin, orally, initially 1000 mg/day and force‐titrated to 2000 mg/day, Calcium, orally, 500 mg/day to 1000 mg/day (500 mg to 1000 mg, once a day), vitamin D, orally, at least 400 IU/day (at least 400 IU, once a day). Rosiglitazone placebo	From weeks 8 to 16, participants with mean daily glucose 6.1 mmol/L at the maximum tolerated doses of metformin or rosiglitazone received open‐label sulphonylurea. After 4 months of double‐blind study medication, participants with HbA1c 7.5% at the maximum dose of medication could up‐titrate or add open‐label sulphonylurea
	C1: rosiglitazone, orally, initially 4 mg/day and force‐titrated to 8 mg/day, Calcium, orally, 500 mg/day to 1000 mg/day (500 mg to 1000 mg, once a day), Vitamin D, orally, at least 400 IU/day (at least 400 IU, once a day). Metformin placebo
Campbell 1994	I: metformin, orally, initially 1000 mg/day (500 mg, twice a day) and titrated to 3000 mg/day in increments of 500 mg/day if not to target (FPG < 8 mmol/L). Dose was reduced by 500 mg/day if FPG < 4 mmol/L	—
	C1: glipizide, orally, initially 5 mg/day (5 mg, once a day) and titrated to 30 mg/day in increments of 5 mg/day if not to target (FPG < 8 mmol/L). Dose was reduced by 5 mg/day if FPG < 4 mmol/L
Derosa 2003	I: metformin, orally, initially 1000 mg/day (500 mg, twice a day, after lunch and dinner) and titrated to 1500 mg/day to 2500 mg/day (three times a day, after breakfast, lunch and dinner) if not to target (FPG < 6.7 mmol/L and 2h‐PPG < 8.8 mmol/L), diet and exercise	—
	C1: repaglinide, orally, initially 1 mg/day (0.5 mg, twice a day, before lunch and dinner) and titrated to 2 mg/day to 4 mg/day (three times a day, before breakfast, lunch and dinner) if not to target (FPG < 6.7 mmol/L and 2h‐PPG < 8.8 mmol/L), diet and exercise
Derosa 2004	I: metformin, orally, initially 1000 mg/day and titrated to 3000 mg/day (1000 mg, three times a day, after breakfast, lunch and dinner) during the first 8 weeks if not to target (FPG < 120 mg/dL and 2h‐PPG < 160 mg/dL), diet and exercise	—
	C1: glimepiride, orally, initially 1 mg/day and titrated to 4 mg/day (2 mg, two times a day, before breakfast and dinner) if not to target (FPG < 120 mg/dL and 2h‐PPG < 160 mg/dL), diet and exercise
Derosa 2009	I: metformin, orally, initially 1000 mg/day in the first month, force‐titrated to 2000 mg/day in the second month, and force‐titrated to 3000 mg/day in the third month. Continuing this dosage patients entered 12 months of study. Diet and exercise	—
	C1: pioglitazone, orally, initially 15 mg/day in the first month, force‐titrated to 30 mg/day in the second month and force‐titrated to 45 mg/day in the third month. Continuing this dosage patients entered 12 months of study. Diet and exercise
Erem 2014	I: metformin, orally, initially 500 mg/day and titrated to 2000 mg/day (1000 mg, twice a day) according to tolerability. Diet and exercise	—
	C1: gliclazide, orally, modified‐release, initially 30 mg/day (30 mg, once a day) and titrated to 120 mg/day. Diet and exercise
	C2: pioglitazone, orally, initially 15 mg/day and titrated to 45 mg/day. Diet and exercise
Kahn 2006	I: metformin, orally, initially 500 mg/day and titrated to 2000 mg/day (1000 mg, twice a day) if not to target (FPG < 140 mg/dL and no adverse events from medication)	—
	C1: rosiglitazone, orally, initially 4 mg/day titrated to 8 mg/day (4 mg, twice a day) if not to target (FPG < 140 mg/dL and no adverse events from medication)
	C2: glibenclamide, orally, initially 2.5 mg/day titrated to 15 mg/day (7.5 mg, twice a day) if not to target (FPG < 140 mg/dL and no adverse events from medication)
Kiyici 2009	I: metformin, orally, 850/mg day. Diet and exercise	—
	C1: rosiglitazone, orally, 4 mg/day. Diet and exercise
	C2: no intervention. Diet and exercise
Onuchin 2010	I: metformin, orally, 500 mg/day to 2500 mg/day	—
	C1: insulin (variable dose), p.e. long‐acting, 0.2‐0.4 IU/1 kg body weight/day (two thirds before breakfast and one third before bedtime) and short‐acting before main meals taking into account consumable bread units, 1‐1.5 IU/1 unit bread (equal to 10 g carbohydrates)
Pfützner 2011	I: metformin, orally, initially 1000 mg/day in the first week, titrated to 2000 mg/day in increments of 500 mg/day if not to target (FPG < 110 mg/dL) in weeks 2‐5 (taken in two divided doses before breakfast and dinner). Diet and exercise	Patients were eligible for rescue therapy based on progressively strict glycaemic control criteria over 24 weeks if FPG levels were as follows: > 240 mg/dL (week 6); > 220 mg/dL (week 8) and > 200 mg/dL (weeks 12, 16, 20 and 24). Patients who met rescue criteria were entered directly into the long‐term extension period, where they were administered open‐label pioglitazone 15 mg, which could be uptitrated to 45 mg, in addition to blinded study medication. Patients with HbA1c > 8.0% at week 30, 37 or 50, or > 7.5% at week 63 were similarly rescued with pioglitazone 15 mg once daily, titrated to a maximum of 45 mg once daily according to local or regional policy, in addition to their blinded study medication.
	C1: saxagliptin, orally, 10 mg/day (before breakfast). Diet and exercise
Rahman 2011	I: metformin, orally, initially 500 mg/day and titrated to 2000 mg/day if not to target (FPG < 140 mg/dL)	—
	C1: glimepiride, orally, initially 2 mg/day and titrated to 8 mg/day if not to target (FPG < 140 mg/dL)
Schernthaner 2004	I: metformin, orally, initially 850 mg/day (850 mg, once a day) force‐titrated to 2550 mg/day (850 mg, three times a day) in the first 12 weeks, and dose was increased, maintained or decreased at week 4, 8 and 12 according to tolerability. Diet. Pioglitazone placebo	—
	C1: pioglitazone, orally, initially 30 mg/day force‐titrated to 45 mg/day in the first 12 weeks, and dose was increased, maintained or decreased at week 4, 8 and 12 according to tolerability. Diet. Metformin placebo
Schweizer 2007	I: metformin, orally, titrated to 2000 mg/day (1000 mg, twice a day)	Pioglitazone was added to the blinded study drug from the first visit of the extension as rescue medication for patients with confirmed FPG > 10 mmol/L, according to the investigator's clinical judgment and prescribing guidelinesb
	C1: vildagliptin, orally, titrated to 100 mg/day (50 mg, twice a day)
Teupe 1991	I: metformin, orally, maximum of 1700 mg/day. Diet	—
	C1: no intervention. Diet
UKPDS 34 1998	I: metformin, orally, initially 850 mg/day (850 mg, once a day), titrated to 1700 mg/day (850 mg, twice a day) and titrated to 2550 mg/day (1700 mg in the morning and 850 mg with dinner) according to tolerability. Diet	If the participants allocated to metformin monotherapy developed marked hyperglycaemia, glibenclamide was added with the aim of maintaining fasting plasma glucose below 6.0 mmol/L. If marked hyperglycaemia again developed, the patient was changed to insulin. If participants allocated to sulphonylurea developed fasting plasma glucose concentrations of 6.1–15.0 mmol/L but no symptoms on maximum doses, were then assigned either continuing treatment with sulphonylurea alone or addition of metformin to sulphonylurea (according to protocol amendment) Participants allocated to basal insulin regime who could not be adequately controlled were receiving more complex insulin regimens
	C1: glibenclamide, orally, 2.5 mg/day to 20 mg/day. Diet
	C2: insulin, sc., initial once daily ultralente insulin or isophane insulin. If the daily dose was more than 14 units or pre‐meal or bed‐time home blood glucose measurements were more than 7 mmol/L, a short‐acting insulin, usually soluble (regular) insulin was added, i.e., basal/bolus regimen. Diet
Umpierrez 2014	I: metformin, orally, titrated to 1500 mg/day to 2000 mg/day in the first 4 weeks depending upon tolerability. Diet and exercise. Dulaglutide placebo	An add‐on rescue therapy was allowed for patients who met prespecified criteria for severe, persistent hyperglycaemia
	C1: dulaglutide, sc., 1.5 mg/week (1.5 mg, once a week). Diet and exercise. Metformin placebo
	C2: dulaglutide, sc., 0.75 mg/week (0.75 mg, once a week). Diet and exercise. Metformin placebo
Williams‐Herman 2010	I: metformin, orally, initially 500 mg/day (500 mg, once a day) titrated to 1000 mg/day (500 mg, twice a day) in increments of 500 mg/week (taken before breakfast and dinner). Participants continued study medication for a total of 54 weeks and were eligible for the 50‐week extension if: they completed the 54‐week base study, were at least 75% compliant in taking study medication (as assessed by the investigator based on patient interview and tablet count), had not developed a contraindication to study medication or other medical condition that would make participation in the study not in their best interest, and had provided written informed consent. Diet and exercise. Sitagliptin placebo	Participants received rescue glibenclamide if FPG > 270 mg/dL between day 1 and week 6, > 240 mg/dL between weeks 6 and 12, and > 200 mg/dL between weeks 12–24. Between weeks 30 and 50 rescue was initiated if HbA1c > 8.0%. After week 50 rescue was initiated if HbA1c > 7.5 % and continued until end of study
	I2: metformin, orally, initially 500 mg/day (500 mg, once a day) titrated to 2000 mg/day (1000 mg, twice a day) in increments of 500 mg/week (taken before breakfast and dinner). Participants continued study medication for a total of 54 weeks and were eligible for the 50‐week extension if: they completed the 54‐week base study, were at least 75% compliant in taking study medication (as assessed by the investigator based on patient interview and tablet count), had not developed a contraindication to study medication or other medical condition that would make participation in the study not in their best interest, and had provided written informed consent. Diet and exercise. Sitagliptin placebo
	C1: sitagliptin, orally, 100 mg/day (50 mg, twice a day) taken before breakfast. Participants continued study medication for a total of 54 weeks and were eligible for the 50‐week extension if: they completed the 54‐week base study, were at least 75% compliant in taking study medication (as assessed by the investigator based on patient interview and tablet count), had not developed a contraindication to study medication or other medical condition that would make participation in the study not in their best interest, and had provided written informed consent. Diet and exercise. Metformin placebo
Yamanouchi 2005	I: metformin, orally, 750 mg/day. Diet and exercise	—
	C1: pioglitazone, orally, 30‐45 mg/day. Diet and exercise
	C2: glimepiride, orally, 1–2 mg/day. Diet and exercise
—: denotes not reported 2h‐PPG: 2‐hour post‐prandial glucose; C: comparator; FPG: fasting plasma glucose; HbA1c: glycated haemoglobin; I: intervention; IU: international unit; N/CPS: no specification of clinical practice setting possible; pe.: parenteral administration; PPG: post prandial glucose, sc.: subcutaneous administration; UKPDS: United Kingdom Prospective Diabetes Study.