Study ID	Endpoints	Definition
Bartley 2008	All‐cause mortality	ND (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Hypoglycaemia requiring third party assistance (IO)
	Cardiovascular mortality	One participant died due to cardiovascular disease (IO)
	Non‐fatal myocardial infarction	Acute myocardial infarctionb (IO)
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosisb (IO)
	Non‐serious adverse events	An adverse event is any undesirable medical event occurring to a participant in a clinical study, whether or not related to the study product(s). A non‐serious adverse event is any adverse event which does not fulfil the definition of a serious adverse eventb (SO)
	Noctural hypoglycaemia	Hypoglycaemia between 23:00 to 06:00 h (SO)
	Mild/moderate hypoglycaemia	All SMPG values < 3.1 mmol/L as well as signs and symptoms of hypoglycaemia minor if plasma glucose < 3.1 mmol/L and the individual dealt with the episode him/herself, and as symptoms only if episodes were not confirmed by a plasma glucose measurement and no assistance was required (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	Percentage of participants reaching HbA1c ≤ 7.0% at the end of the study without symptomatic hypoglycaemia with a plasma glucose < 4.0 mmol/L or any single plasma glucose value < 3.1 mmol/L during the last month of treatment" (IO)
BEGIN Basal‐Bolus Type 1	All‐cause mortality	All‐cause mortality (IO, AO)
	Health‐related quality of life	Short Form‐36 v2 (SO)
	Severe hypoglycaemia	Hypoglycaemia requiring third party assistance (IO)
	Cardiovascular mortality	Cause of each death described separately (myocardial infarction event; sudden death; ventricular tachycardia event) (IO, AO)
	Non‐fatal myocardial infarction	Myocardial infarction (IO, AO)
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Ketoacidosis (IO)
	Non‐serious adverse events	A non‐serious adverse event is any adverse event which does not fulfil the definition of a serious adverse eventb (SO)
	Noctural hypoglycaemia	Hypoglycaemic episodes occurring from 00:01 to 05:59 h (SO)
	Mild/moderate hypoglycaemia	Confirmed hypoglycaemic episodes included those with a plasma glucose value of < 3.1 mmol/L (SO)
	Socioeconomic effects	—
	HbA1c	ND
	Combined HbA1c and severe hypoglycaemia	HbA1c < 7% without severe hypoglycaemiab (IO)
BEGIN Flex T1	All‐cause mortality	Fatal serious adverse events (one committed suicide) (IO, AO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Hypoglycaemia requiring third party assistance (IO, AO)
	Cardiovascular mortality	ND
	Non‐fatal myocardial infarction	Acute coronary syndrome (IO, AO)
	Non‐fatal stroke	Stroke (IO, AO)
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect; • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	A non‐serious adverse event is any adverse event that does not fulfil the definition of a serious adverse eventb (SO)
	Nocturnal hypoglycaemia	Episodes occurring between 00:01 and 05:59 hours (inclusive) (SO)
	Mild/moderate hypoglycaemia	Minor hypoglycaemic episodes are defined as participants able to treat her/himself and plasma glucose below 3.1 mmol/L (OBS page 68 + 69 in CSR ‐ different definitions) (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	Treatment targets at the end of study achieved without hypoglycaemic episodes in the last 12 weeks of treatment considering severe episodes only, and severe and minor episodes togetherb (IO)
BEGIN Young	All‐cause mortality	ND (IO, AO)
	Health‐related quality of life	—
	Severe hypoglycaemia	The child has altered mental status and cannot assist in their own care, is semiconscious or unconscious, or in a coma ± convulsions and may require parenteral therapy (glucagon or iv glucose) (IO)
	Cardiovascular mortality	ND (IO, AO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect; • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	A non‐serious AE is any AE which does not fulfil the definition of an SAEb (IO)
	Nocturnal hypoglycaemia	Hypoglycaemic episodes occurring between 11 p.m. and 7 a.m. inclusive were classified as nocturnal (SO)
	Mild/moderate hypoglycaemia	Confirmed hypoglycaemia was defined as SMPG < 3.1 mmol/Lc (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Bolli 2009	All‐cause mortality	—
	Health‐related quality of life	Well‐Being Enquiry for Diabetics questionnaire (SO)
	Severe hypoglycaemia	Serious hypoglycaemia was defined as an event with blood glucose < 2.3 mmol/L, severe hypoglycaemia an event with symptoms consistent with hypoglycaemia, during which the participant required the assistance of another person, or with prompt recovery after oral carbohydrate, iv glucose or glucagon administration (IO)
	Cardiovascular mortality	—
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	Serious adverse events (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	Adverse events (SO)
	Nocturnal hypoglycaemia	Serious nocturnal hypoglycaemia (blood glucose < 2.3 mmol/Lc); hypoglycaemia which occurred between bedtime and before getting up in the morning (IO)
	Mild/moderate hypoglycaemia	Blood glucose ≤ 4.0 mmol/Lc (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Chase 2008	All‐cause mortality	—
	Health‐related quality of life	The Diabetes Quality of Life for Youth questionnaire and Parents' Diabetes Quality of Lifeb (SO)
	Severe hypoglycaemia	Severe hypoglycaemia was defined as an event requiring assistance from another person and associated with either BG < 2.0 mmol/L or prompt recovery after oral carbohydrate, iv glucose, or intramuscular or subcutaneous glucagon administration (IO)
	Cardiovascular mortality	—
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect; • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	The term adverse event covered any unfavourable and unintended sign, symptom, syndrome, or illness that developed or worsened during the period of observation in the clinical studyb (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia from midnight and 6 a.m. (SO)
	Mild/moderate hypoglycaemia	The rates of biochemical hypoglycaemia were ascertained by analysis of SMBG data and divided into 3 categories: < 3.9 mmol/L, < 2.8 mmol/L and < 2.0 mmol/Lc (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Davies 2014	All‐cause mortality	All‐cause mortality (IO, AO)
	Health‐related quality of life	Short Form‐36 v2b (SO)
	Severe hypoglycaemia	Hypoglycaemia requiring third party assistance (IO)
	Cardiovascular mortality	Cardiovascular mortality (IO, AO)
	Non‐fatal myocardial infarction	Non‐fatal myocardial infarction (IO, AO)
	Non‐fatal stroke	Non‐fatal stroke (IO, AO)
	End‐stage renal disease	End‐stage renal disease (IO)
	Blindness	Blindness (IO)
	Serious adverse events	Serious adverse events: adverse event that at any dose results in any of the following death, a life‐threatening experience, in‐participant hospitalisations/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect or important medical issues (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	Mild: no/transient symptoms, no interference with participant's daily activities. Moderate: marked symptoms, moderate interference with participant's daily activities (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia between 00:01 and 05:59 hours (SO)
	Mild/moderate hypoglycaemia	Confirmed hypoglycaemia was defined as plasma glucose < 3.1 mmol/L regardless of symptoms (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	HbA1c < 7% without confirmed severe hypoglycaemia during the last 12 weeks of treatmentb (IO)
Fulcher 2005	All‐cause mortality	ND (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Symptoms consistent with hypoglycaemia required the assistance of another person and was associated with a blood glucose level < 2.8 mmol/L or prompt recovery after oral carbohydrate, iv glucose or sc glucagon administration (IO)
	Cardiovascular mortality	ND (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect; • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	Adverse event covers any sign, symptom, syndrome, or illness that appears or worsens in a patient during the period of observation in the clinical study and that may impair the well‐being of the patient. The term also covers laboratory findings or results of other diagnostic procedures that are considered to be clinically relevantb. A non‐serious adverse event is any adverse event not meeting the serious adverse event criteriab (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia occurring after the evening insulin injection and before the morning insulin dose
	Mild/moderate hypoglycaemia	Symptomatic hypoglycaemia was defined as an event with symptoms consistent with hypoglycaemia that was mild (2.8–3.6 mmol/L) or moderate (< 2.8 mmol/L)
	Socioeconomic effects	Information in relation to whether participants had suffered any income loss because of diabetes during the study (SO, IO)
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Heller 2009	All‐cause mortality	ND (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	The patient could not treat the episode by himself/herself (IO)
	Cardiovascular mortality	One patient died from acute myocardial infarction (IO)
	Non‐fatal myocardial infarction	Myocardial ischaemia (IO)
	Non‐fatal stroke	Cerebrovascular accident (IO)
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect; • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	A non‐serious adverse event is any adverse event which does not fulfil the definition of a serious adverse eventb (SO)
	Nocturnal hypoglycaemia	Episodes of hypoglycaemia occurring from 11 p.m. up to but not including 6 a.m. (SO)
	Mild/moderate hypoglycaemia	Minor: the patient could treat himself/herself and the measured plasma glucose value was < 3.1 mmol/L; symptoms only: the patient could treat himself/herself and no plasma glucose measurement was taken or the measured plasma glucose value was ≥ 3.1 mmol/L (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	HbA1c ≤ 7% without major hypoglycaemia during the last month of treatment (IO)
Home 2005	All‐cause mortality	ND (IO)
	Health‐related quality of life	Well‐being Questionnaire (W‐BQ) (SO)
	Severe hypoglycaemia	Severe symptomatic hypoglycaemia was defined as an event consistent with symptomatic hypoglycaemia requiring the assistance of another person, with either a blood glucose level < 2.8 mmol/L or prompt recovery after administration of oral carbohydrate, iv glucose or glucagon (IO)
	Cardiovascular mortality	ND (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect; • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis
	Non‐serious adverse events	A non‐serious adverse event is any adverse event not meeting the serious adverse event criteria (SO)
	Nocturnal hypoglycaemia	Symptomatic hypoglycaemia occurring during sleep between bedtime and rising in the morning, or before the morning pre‐breakfast self‐blood glucose measurement and the morning insulin injection. Only participants with confirmed blood glucose < 2.0 mmol/L were considered clinically relevant (SO)
	Mild/moderate hypoglycaemia	Hypoglycaemia was categorised as symptomatic (clinical symptoms confirmed by blood glucose < 2.8 mmol/L) or asymptomatic (confirmed by blood glucose < 2.8 mmol/L without symptoms) (SO)
	Socioeconomic effects	Information about loss of income during the study (SO, IO)
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Kobayashi 2007	All‐cause mortality	"No participants died" (IO)
	Health‐related quality of life	Insulin Therapy Related Quality of Life at Night
	Severe hypoglycaemia	Any event requiring assistance of another person to recover from hypoglycaemic symptoms with or without measurement of blood glucose levels (IO)
	Cardiovascular mortality	"No participants died" (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	Serious adverse events (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	Adverse events (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia occurring between 23:00 to 06:00 (SO)
	Mild/moderate hypoglycaemia	Any symptoms consistent with hypoglycaemia (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Liu 2016	All‐cause mortality	ND (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Hypoglycaemia requiring the assistance of a third party or involving a seizure, coma, unconsciousness or the use of glucagon (IO)
	Cardiovascular mortality	ND (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	An adverse event is any untoward medical occurrence in a patient or clinical investigation where a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatmentb (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia occurring between 23:00–07:00 (SO)
	Mild/moderate hypoglycaemia	Hypoglycaemia was defined as asymptomatic (blood glucose values < 3.9 mmol/L without clinical symptoms), symptomatic (blood glucose < 3.9 mmol/L with associated clinical symptoms) (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
NCT00595374	All‐cause mortality	Reported no one died (IO)
	Health‐related quality of life	Quality of life (SO)
	Severe hypoglycaemia	—
	Cardiovascular mortality	Reported no one died (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	Serious adverse event (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	Any adverse event that started one day or more after the start of active medication (SO)
	Nocturnal hypoglycaemia	—
	Mild/moderate hypoglycaemia	—
	Socioeconomic effects	—
	HbA1c	—
	Combined HbA1c and severe hypoglycaemia	—
NCT00605137	All‐cause mortality	No patients died (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Hypoglycaemia requiring third party assistance (IO)
	Cardiovascular mortality	No patients died (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition(IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	An adverse event is any untoward medical occurrence in a patient or clinical investigation where a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. A non‐serious adverse event is any adverse event which does not fulfil the definition of a serious adverse event (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia from 23:00 ‐ 06:00, inclusive (SO)
	Mild/moderate hypoglycaemia	Minor hypoglycaemic episodes blood glucose < 3.1 mmol/L and able treat the period themselves), symptoms only (no blood glucose measurement or blood glucose > 3.1 mmol/L) and biochemical hypoglycaemia (defined as asymptomatic hypoglycaemic with blood glucose value < 3.1 mmol/L) (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Pieber 2007	All‐cause mortality	No patients died (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Hypoglycaemia requiring third party assistance (IO)
	Cardiovascular mortality	No patients died (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	From CSR: An adverse event (AE) is any undesirable medical event occurring to a participant in a clinical study, whether or not related to the study product(s). A non‐serious adverse event is any AE that does not fulfil the definition of an SAE (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia between 23:00 and 06:00 (SO)
	Mild/moderate hypoglycaemia	Confirmed hypoglycaemia if plasma glucose was < 3.1 mmol/L and the individuals dealt with the episode themselves (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	Risk of severe hypoglycaemia adjusted for HbA1c (IO)
Porcellati 2004	All‐cause mortality	ND (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Hypoglycaemia requiring external help (IO)
	Cardiovascular mortality	ND (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	—
	Diabetic ketoacidosis	—
	Non‐serious adverse events	—
	Nocturnal hypoglycaemia	Nocturnal episodes of hypoglycaemia were calculated from values measured at 03.00 h or any time between 01.00 and 07.30 h when participants awoke with symptoms suggestive of hypoglycaemia (SO)
	Mild/moderate hypoglycaemia	Hypoglycaemia was defined as any episode associated with measurement of blood glucose ≤ 4.0 mmol/L irrespective of symptoms. Hypoglycaemia was considered mild when the episodes were self‐treated by the patients (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
PRESCHOOL	All‐cause mortality	All‐cause mortality (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Severe hypoglycaemia was defined as an event requiring assistance from another person, as a result of altered consciousness, to administer carbohydrate, glucagon or to take other actions (IO)
	Cardiovascular mortality	ND (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect; • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	An adverse event is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatmentb (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia between 23:00 hours and 07:00 hours (SO)
	Mild/moderate hypoglycaemia	Composite hypoglycaemia rate consisting of (i) symptomatic hypoglycaemia episodes, which were recorded in patient diaries, then validated by study investigators; (ii) low CGM glucose excursions (< 3.9 mmol/L), which were confirmed by finger stick blood glucose < 3.9mmol/L 10 min before to 10 min after the low CGM excursion (i.e. confirmed low CGM); (iii) FSBG < 3.9 mmol/L, which was recorded ≥ 1 h from the end of a confirmed low CGM excursion (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Ratner 2000	All‐cause mortality	ND (IO)
	Health‐related quality of life	Well‐being Questionnaireb (SO)
	Severe hypoglycaemia	Symptomatic hypoglycaemia requiring third party assistance (IO)
	Cardiovascular mortality	One died secondary to cardiopulmonary arrest (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	Events causing death, life‐threatening, hospitalisations, medical intervention to prevent impairment (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	The term adverse event covers any sign, symptom, syndrome, or illness that appears or worsens in a participant during the period of observation in the clinical study and that may impair the well‐being of the participant, but do not meet the criteria of severeness (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia occurring while asleep after the bedtime insulin dose and before the morning insulin dose and before the morning blood glucose measurement (SO)
	Mild/moderate hypoglycaemia	Hypoglycaemia was divided into 3 subsets; all events, severe hypoglycaemia and nocturnal hypoglycaemia (SO)
	Socioeconomic effects	Pharmacoeconomics was assessed throughout the treatment phase in terms of direct costs (volumes of health care resource utilisation) and indirect costs (time lost from work and other usual activities, and time lost by informal caregivers)b (SO, IO)
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Robertson 2007	All‐cause mortality	No patients died (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Episodes requiring assistance from another person due to severe central nervous system dysfunction (IO)
	Cardiovascular mortality	No patients died (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	An adverse event is any undesirable medical event occurring to a participant in a clinical study, whether or not related to the study product(s). A non‐serious adverse event is any adverse event which does not fulfil the definition of a serious adverse eventb (SO)
	Nocturnal hypoglycaemia	Hypoglycaemic between 22.00 (included) − 07.00 h (excluded) (SO)
	Mild/moderate hypoglycaemia	Self‐treated episodes of hypoglycaemia with plasma glucose measurements < 3.1 mmol/L whether symptomatic or notb (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	Quote: "HbA 1c as a covariate, since there is an association between HbA1c and hypoglycaemia" (IO)
Russell‐Jones 2004	All‐cause mortality	No participants died (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Requiring third party assistance (from CSR: an episode with severe central nervous system symptoms consistent with hypoglycaemia in which the participant is unable to treat himself/herself and which has one of the following characteristics: Blood glucose < 2.8 mmol/L or reversal of symptoms after either food intake or glucagon/iv glucose administration) (IO)
	Cardiovascular mortality	No participants died (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	Serious adverse events A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect; • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	An adverse event is any undesirable medical event occurring to a participant in a clinical study, whether or not considered related to the study product(s). A non‐serious adverse event is any adverse event that does not fulfil the definition of a serious adverse eventb (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia between 11 p.m. to 6 a.m. (SO)
	Mild/moderate hypoglycaemia	Minor if the blood glucose value was < 2.8 mmol/L and the patient dealt with the episode alone; and as symptoms only if no assistance was required and the event was not confirmed by a blood glucose measurement (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Schober 2002	All‐cause mortality	No patients died (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	An event with symptoms consistent with hypoglycaemia in which the participant required assistance from another person, and which was associated with a blood glucose level below 2.8 mmol/L or prompt recovery after oral carbohydrate or iv glucose or glucagon administrationb(IO)
	Cardiovascular mortality	No patients died (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	Adverse events were considered 'serious' because they either required hospitalisations, were life‐threatening or medically important (quote: "If a symptomatic hypoglycaemic event led to hospitalisation or was considered life‐threatening or medically important, it had to be reported as a serious adverse event") (IO)
	Diabetic ketoacidosis	Ketoacidosis (IO)
	Non‐serious adverse events	Quote from CSR: "The term adverse event covers any sign, symptom, syndrome, or illness that appears or worsens in a participant during the period of observation in the clinical study and that may impair the well‐being of the participant." (SO)
	Nocturnal hypoglycaemia	Nocturnal hypoglycaemia was defined as hypoglycaemia while the participant was sleeping between bedtime and after the evening injection and before getting up in the morning (SO)
	Mild/moderate hypoglycaemia	Hypoglycaemia was categorised as either symptomatic, i.e. with clinical symptoms that could be confirmed by blood glucose levels below 2.8 mmol/L, or asymptomatic, i.e. any event with a confirmed blood glucose level below 2.8 mmol/L but without any symptoms (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Standl 2004	All‐cause mortality	One participant died (IO)
	Health‐related quality of life	Diabetes Health Profileb(SO)
	Severe hypoglycaemia	Requiring third party assistance (IO)
	Cardiovascular mortality	—
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	ND
	Non‐serious adverse events	Adverse events were considered treatment‐emergent if reported during treatment and not present beforehand, or if they increased in severity during treatment (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia between 23:00 to 06:00 h (SO)
	Mild/moderate hypoglycaemia	If blood glucose was below 2.8 mmol/L and the patient handled the episode him‐ or herself (footnote: the study had an additional definition 'symptoms only' if not confirmed by BG measurement) (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	ND
SWITCH 1	All‐cause mortality	All‐cause death (IO, AO)
	Health‐related quality of life	SF‐36 v2 (SO)
	Severe hypoglycaemia	Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions, neurological recovery following the return of plasma glucose to normal, or both (IO, AO)
	Cardiovascular mortality	ND
	Non‐fatal myocardial infarction	All types of myocardial infarction: Spontaneous myocardial infarction (including re‐infarction) Myocardial infarction secondary to ischaemia due to imbalance between oxygen demand and supplies Percutaneous coronary intervention‐related myocardial infarction (including myocardial infarction associated with stent thrombosis) Coronary artery bypass graft surgery‐related myocardial infarction Silent myocardial infarction Hospitalisation for unstable angina pectoris All events with symptoms of myocardial ischaemia requiring hospitalisation (IO, AO)
	Non‐fatal stroke	Cerebrovascular event is defined: Any acute episode of focal or global neurological dysfunction caused by brain, spinal cord or retinal vascular injury as a result of haemorrhage or infarction (IO, AO)
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	A serious adverse event is an experience that at any dose results in any of the following: • death • a life‐threatening experience • in‐participant hospitalisation or prolongation of existing hospitalisation • a persistent or significant disability/incapacity • a congenital anomaly/birth defect • important medical events that may not result in death, be life‐threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgement, they may jeopardise the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definitionb (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	Any untoward medical occurrence in a participant administered a product, and which does not necessarily have a causal relationship with this treatment. A non‐serious adverse event is any adverse event which does not fulfil the definition of a serious adverse event (SO)
	Nocturnal hypoglycaemia	Episodes between 12:01 a.m. and 5:59 a.m. (SO)
	Mild/moderate hypoglycaemia	Blood glucose ≤ 3.9 mmol/L or > 3.9 mmol/L when they occur in conjunction with hypoglycaemic symptoms, able to treat themselves (SO)
	Socioeconomic effects	Cost‐effectiveness analysis/quality‐adjusted life years (IO)
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	Association between the individual patient‐level risk of hypoglycaemia and HbA1c was investigated (IO)
Thalange 2013	All‐cause mortality	All‐cause mortality (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Severe hypoglycaemia was defined as episodes where the persons were semi‐conscious, unconscious or in a coma, with or without convulsions (IO)
	Cardiovascular mortality	ND (IO)
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	Serious adverse events were defined as, amongst others, a life‐threatening experience, inpatient hospitalisations or prolongation of existing hospitalisations, a persistent or significant disability/incapacity or death (IO)
	Diabetic ketoacidosis	Diabetic ketoacidosis (IO)
	Non‐serious adverse events	Any undesirable medical event occurring to a participant in a clinical study, whether or not related to the study product(s) (SO)
	Nocturnal hypoglycaemia	Nocturnal if they occurred between 22:00 and 07:00 h (SO)
	Mild/moderate hypoglycaemia	Mild hypoglycaemia was defined as episodes where the participants were able to treat themselves. Moderate hypoglycaemia was categorised as episodes where participants required assistance, but responded to oral treatment (SO)
	Socioeconomic effects	—
	HbA1c	ND
	Combined HbA1c and severe hypoglycaemia	—
Urakami 2017	All‐cause mortality	—
	Health‐related quality of life	—
	Severe hypoglycaemia	Severe hypoglycaemia is defined as an event associated with impaired consciousness or seizure (IO)
	Cardiovascular mortality	Cardiovascular mortality (IO)
	Non‐fatal myocardial infarction	Non‐fatal myocardial infarction (IO)
	Non‐fatal stroke	Non‐fatal stroke (IO)
	End‐stage renal disease	End‐stage renal disease (IO)
	Blindness	Blindness (IO)
	Serious adverse events	Serious adverse events (IO)
	Non‐serious adverse events	Non‐serious adverse events (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia occurring between 22:00 h – 06:59 h. Nocturnal hypoglycaemia was defined as when the person noted symptoms of hypoglycaemia with self‐monitored plasma glucose levels < 70 mg/dL (SO)
	Mild/moderate hypoglycaemia	Hypoglycaemia was defined as a self‐monitored plasma glucose level < 3.9 mmol/L (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	—
Vague 2003	All‐cause mortality	No patients died (IO)
	Health‐related quality of life	—
	Severe hypoglycaemia	Hypoglycaemic episode with severe central nervous system symptoms consistent with hypoglycaemia, in which the participant was unable to treat himself/herself and which had one of the following characteristics: blood glucose recorded as < 2.8 mmol/L or symptom reversal achieved with food, glucose or glucagon (IO)
	Cardiovascular mortality	—
	Non‐fatal myocardial infarction	—
	Non‐fatal stroke	—
	End‐stage renal disease	—
	Blindness	—
	Serious adverse events	Serious adverse events if resulting in a fatal or life‐threatening illness, prolonged significant disability, hospitalisations or prolongation of hospitalisations (IO)
	Diabetic ketoacidosis	—
	Non‐serious adverse events	An adverse event was defined as an undesirable medical incident occurring during the study, irrespective of its relation to study products (SO)
	Nocturnal hypoglycaemia	Hypoglycaemia between 23:00 to 06:00 (SO)
	Mild/moderate hypoglycaemia	Minor if blood glucose was < 2.8 mmol/L and the patients dealt with the episode themselves (in addition according to CSR: any asymptomatic blood glucose measurement) (SO)
	Socioeconomic effects	—
	HbA1c	ND (IO)
	Combined HbA1c and severe hypoglycaemia	HbA1c adjustment and risk of severe hypoglycaemia (IO)
—: denotes not reported aIn addition to definition of endpoint measurement, description of who measured the outcome (AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; SO: self‐reported outcome measurement). bDefinition of outcome from clinical study report. cConverted from mg/dL to mmol/L from https://www.diabetes.co.uk/blood-sugar-converter.html). AE: adverse events; a.m.: ante meridiem; BG: blood glucose;CGM: continuous glucose monitoring;CSR: clinical study report; FSBG: finger stick blood glucose; HbA1c: glycosylated haemoglobin A1c; iv: intravenous; ND: not defined; p.m.: post meridiem; SAE: serious adverse events; sc: subcutaneous; SF‐36: short‐form 36; SMPG: self‐monitored plasma glucose; W‐BQ: well‐being questionnaire.