Comparison of gliclazide vs linagliptin on hypoglycemia and cardiovascular events in type 2 diabetes mellitus: A systematic review

Table 1 Inclusion and exclusion criteria of the records included in the systematic review

Inclusion criteria	Exclusion criteria
Age 19 yr and < 70 yr; Male and Female; type 2 diabetes	Age below 19 yr or ≥ 70 yr; type 1 diabetes; no diabetes
Human studies: Any race, ethnicity	Clinical trials evaluating gliclazide or linagliptin in patients with specific comorbidites including CVD1
Randomized clinical trials on safety of:	Review articles, systematic reviews and meta-analysis, network meta-analysis, pooled analysis of trials, case studies, non-randomized trials
-Gliclazide monotherapy versus linagliptin monotherapy
-Gliclazide + metformin versus linagliptin + metformin
Randomized clinical trials on safety of:	Pharmacokinetic, pharmacodynamic and bioequivalence study; retrospective chart review; observational real-world study; case study; trials studying mechanism of action of gliclazide or linagliptin; literature reporting only study design; trial summaries and implications; animal studies; preclinical studies
-Gliclazide versus DPP4 inhibitors
-Linagliptin versus sulfonylureas
Randomized clinical trials on gliclazide or linagliptin monotherapy evaluating the following outcomes:	Clinical trials evaluating gliclazide or linagliptin versus PBO
-Hypoglycemia or low blood sugar	Clinical trials evaluating gliclazide or linagliptin in combination with other GLDs except metformin
-Occurrence of 3 point major adverse cardiovascular events (3P-MACE): Cardiovascular death, nonfatal myocardial infarction/ischemia/acute coronary syndrome, or nonfatal stroke (transient ischemic attack included)	Clinical trials evaluating gliclazide or linagliptin versus other GLDs except: (1) DPP4 inhibitors for gliclazide; and (2)sulfonylureas for linagliptin
	Clinical trials evaluating other glycemic, cardiac, cardiovascular outcomes than those of interest; other outcomes (e.g., microvascular complications)

¹History of myocardial infarction, stroke, unstable angina, transient ischemic attack, percutaneous coronary intervention for coronary occlusion or coronary artery bypass graft.

Note: Efficacy was synthesized from the gliclazide and linagliptin studies that met the inclusion criteria. CVD: Cardiovascular disease; DPP4: Dipeptidyl peptidase-4; GLD: Glucose-lowering drugs; PBO: Placebo.

Table 2 Gliclazide vs dipeptidyl peptidase-4 inhibitor /linagliptin vs sulfonylurea

Ref.	Primary study objective	Study design	Study population	CVD excluded	Number of participants	Study duration	Endpoint (hypoglycemia)	Hypoglycemia definition	Hypoglycemia results	Endpoint (MACE)	MACE definition	MACE results
Gliclazide vs DPP4 inhibitor (vildagliptin)
Foley et al[34], 2009	Compare the efficacy and safety of vildagliptin vs gliclazide	Randomized, multicenter, double-blind, active-controlled study	Drug-naïve patients with T2D, HbA1c of 7.5%-11.0%	CHF NYHA class III or IV, ECG abnormalities	1092	104 wk	AEs were safety endpoints	Grade 1 hypoglycemic events per week: symptoms suggestive of low blood glucose confirmed by SMBG measurement of < 3.1 mmol/L plasma glucose equivalent not requiring the assistance of another party; Grade 2 hypoglycemic event (requiring the assistance of another party) or if there were 3 or more asymptomatic glucose values < 3.1 mmol/L per week	Grade 1 hypoglycemia: 4 patients (0.7%) in the vildagliptin group and 14 (1.7%) in the gliclazide group. ≥ 2 HEs: 2 patients in the gliclazide group and none in vildagliptin group No grade 2 HEs in either group	-	-	-
Gliclazide + metformin vs DPP4 inhibitor (vildagliptin) + metformin
Vianna et al[35], 2018 (Part of BoneGlic Trial)	Compare the effects on glycemic variability and bone metabolism	Single center, randomized, controlled, open-label (blinded to the observer)	Postmenopausal Brazilian women with T2D and treated with a stable metformin dose for ≤ 3 mo	CV complications	56 (42 randomized)	2-wk pre-randomization period followed by 24 wk	As AE	Major hypoglycemia: glucagon, carbohydrates administration by another person or other resuscitative measures; minor hypoglycemia: BG ≤ 3.9 mmol/L with or without typical symptoms or hypoglycemia symptoms without BG test	No differences from baseline in time to hypoglycemia (% of time ≤ 3.9 mmol/L)	As SAE		Vildagliptin: 1 hemorrhagic stroke gliclazide MR group: 1 death due to AMI, the investigator did not consider the SAEs to be related to the study medications
									No major hypoglycemia
									Minor hypoglycemia events: 7 in the gliclazide; 2 in the vildagliptin group (P = 0.062)
Hassanein et al[36], 2014 (STEADFAST study)	HE during Ramadan	Multiregional, randomized double-blind	Patients fasting during Ramadan	CHF (NYHA class III or IV); other significant CV history within 6 mo	557	4-wk Ramadan period	Primary	Hypoglycemia: Low BG symptoms with or without confirmatory, SMBG measurement < 3.9 mmol/L; PGE or asymptomatic SMBG < 3.9 mmol/L PGE; confirmed hypoglycemia: symptomatic/asymptomatic SMBG measurement < 3.9 mmol/L; PGE and severe HE requiring assistance from another party irrespective of whether SMBG value was available or not	Confirmed and/or severe HE during Ramadan: vildagliptin vs glicalzide was 3.0% vs 7.0% (P = 0.039; one-sided test); HEs: vildagliptin vs gliclazide was 6.0% and 8.7% (P = 0.173)	-	-	-
Filozof and Gautier[37], 2010	Demonstrate non-inferiority of vildagliptin compared with gliclazide, as an add-on therapy	Randomized, double-blind, active-controlled	T2D uncontrolled with metformin	Serious cardiac conditions (torsades de pointes, sustained and clinically relevant VT or VF, PCI ≤ 3 mo, MI, CABG, unstable angina, or stroke ≤ 6 mo and CHF requiring pharmacological treatment, 2nd- or 3rd-degree AV block or prolonged QTc)	1007	52 wk	AE	Symptoms suggestive of hypoglycemia and confirmed by SMBG < 3.1 mmol/L	HE vildagliptin vs gliclazide (6 vs 11 events)	-	-	-

AE: Adverse event; AMI: Acute myocardial infarction; AV: Atrioventricular; BG: Blood glucose; CABG: Coronary artery bypass surgery; CHF: Congestive heart failure; CV: Cardiovascular; CVD: Cardiovascular disease; DPP4: Dipeptidyl peptidase-4; ECG: Electrocardiogram; HbA1c: Glycated hemoglobin: HE: Hypoglycemia event/episode; MACE: Major adverse cardiovascular event; MI: Myocardial infarction; MR: Modified release; NYHA: New York Heart Association; PCI: Percutaneous coronary intervention; PGE: Plasma glucose equivalent; SAE: Serious adverse event; SMBG: Self-monitored blood glucose; T2D: Type 2 diabetes; VF: Ventricular fibrillation; VT: Ventricular tachycardia.

Table 3 Gliclazide ± metformin and linagliptin ± metformin (no comparator)

Ref./treatment	Primary study objective	Study design	Study population	CVD excluded	Number of participants	Study duration	Endpoint (hypoglycemia)	Hypoglycemia definition	Hypoglycemia results	Endpoint (MACE)	MACE definition	MACE results
Barnett et al[33], 2008/DINAMIC 1/Gliclazide	Compare the efficacy, tolerability and acceptability of gliclazide in SMBG vs non-SMBG group	Multicenter randomized parallel-group	T2D patients managed on diet alone	Not mentioned	610	6 mo	Safety endpoint (AE)	Grade 1: Suspected mild hypoglycemia	SMBG group: 8.7% patients had 51 HE: symptomatic (27), asymptomatic (11), SMBG-confirmed (11) and non-graded (2)	-	-	-
								Grade 2: Suspected moderate hypoglycemia	Non-SMBG group: 7.0% patients had 66 HE: Symptomatic (66) and non-graded (2). Two HE-related withdrawals
								Grade 3: Suspected severe hypoglycemia with need of third party assistance	No grade 3 or 4 symptoms
								Grade 4: Suspected severe hypoglycemia with need of medical assistance	Symptoms suggestive of nocturnal hypoglycemia: SMBG group: 3 and non-SMBG group: 7
Ross et al[42], 2015/Linagliptin/metformin vs linagliptin monotherapy	Change from baseline in HbA1c	Randomized, double-blind, active-controlled, parallel group, multinational	Newly diagnosed (≤ 12 mo) T2D and marked hyperglycemia (≥ 8.5 and ≤ 12.0%)	ACS, stroke or TIA < 3 mo	316	24 wk	Safety endpoint (AE)	Severe hypoglycemia: Requiring assistance from another person to administer carbohydrate or other resuscitative action	Linagliptin/metformin: 1.9% of patients and linagliptin: 3.2% of patients no severe hypoglycemia	-	-	No deaths

ACS: Acute coronary syndrome; AE: Adverse event; CVD: Cardiovascular disease; DINAMIC: Diamicron MR in NIDDM: Assessing Management and Improving Control; HbA1c: Glycosylated hemoglobin; HE: Hypoglycemic event; MACE: Major adverse cardiovascular event; SMBG: Self-monitoring of blood glucose; T2D: Type 2 diabetes; TIA: Transient ischemic attack.