Supplementary Table 1. Key Randomized, Controlled Clinical Trials of Insulin Glargine

Supplementary Table 1. Key Randomized, Controlled Clinical Trials of Insulin Glargine

Online appendix

Supplementary Table 1. Key randomized, controlled clinical trials of insulin glargine

Study / Patient population / Study design / Key findings
Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analogglargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes2000;49(12):2142–8 / 20 people with T1DM, negative for c-peptide and undergoing long-term intensive treatment / Randomized four-period crossover trial involving 24-hour isoglycemic clamps comparing insulin glargine, NPH insulin, ultralente and CSII /
  • Onset of action (reduction of IV insulin >50%) significantly later with insulin glargine (1.5 ± 0.3 h) vs NPH insulin (0.8 ± 0.2 h), CSII (0.5 ± 0.1 h) and ultralente (1 ± 0.2 h); p<0.05 for all
  • End of action (increase in plasma glucose >150 mg/dL) significantly later with insulin glargine (22 ± 4 h) than with NPH insulin (14 ± 3 h; p<0.05), but similar to ultralente (20 ± 6 h)
  • Insulin glargine had no peak concentration and a flat concentration/action profile
  • Intraindividual variability was significantly lower with insulin glarginevs NPH insulin and ultralente (p<0.05)

Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care2003;26(11):3080–6 [TREAT-TO-TARGET STUDY] / 756 overweight people with T2DM and inadequate glycemic control (HbA1c >7.5%) on one or two OADs / 24-week randomized, open-label, parallel group, multicentre trial comparing insulin glargine and NPH insulin once daily titrated to target FPG ≤100 mg/dL (5.5 mmol/L) /
  • Mean FPG at endpoint similar with NPH insulin and insulin glargine (120 vs 117 mg/dL [6.7 vs 6.5 mmol/L])
  • Mean HbA1c at endpoint similar with NPH insulin and insulin glargine 6.97 vs 6.96%)
  • Significantly more people achieved HbA1c ≤7% without documented nocturnal hypoglycaemia (≤72 mg/dL [4.0 mmol/L]) with insulin glarginevs NPH insulin (33.2 vs 26.7%; p<0.05)
  • Rates of other categories of symptomatic hypoglycemiawere 21–48% lower with insulin glarginevs NPH insulin

Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-Jävinen H. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for Type 2 diabetes. Diabetes Care 2005;28:254–9 [LAPTOP STUDY] / 371 insulin-naïve people with T2DM with poor glycemic control (FBG ≥120 mg/dL, HbA1c 7.5–10.5%) on OADs (metformin plus sulfonylurea) / 24-week, open-label, parallel-group, multinational, multicentre clinical trial comparing once-daily insulin glargine plus glimepiride and metformin with twice-daily 30% regular/70% human NPH insulin without OADs /
  • Mean HbA1c decrease from baseline significantly greater with insulin glargine plus OADsvs NPH 70/30 insulin (–1.64 vs –1.31%; p=0.0003)
  • Significantly more people achieved HbA1c ≤7% without confirmed nocturnal hypoglycaemia (≤60 mg/dL [3.3 mmol/L]) with insulin glargine plus OADsvs NPH 70/30 insulin (45.5 vs 26.8%; p=0.0013)
  • Significantly more people achieved target FBG ≤100 mg/dL (5.6 mmol/L) with insulin glargine plus OADsvs NPH 70/30 insulin (31.6 vs15.0%; p=0.0001)
  • There were significantly fewer confirmed hypoglycemic episodes with insulin glargine plus OADs compared with NPH 70/30 insulin (mean 4.07 vs 9.87/patient-year; p<0.0001)

Yki-Järvinen H, Kauppinen-Mäkelin R, Tiikkainen M, Vähätalo M, Virtamo H, Nikkilä K, Tulokas T, Hulme S, Hardy K, McNulty S, Hänninen H, Levänen H, Lahdenperä S, Lehtonen R, Ryysy L. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia2006;49(3):442–51 [LANMET STUDY] / 110 insulin-naïve people with T2DM with poor glycemic control (HbA1c ≥8.0%) on OADs (90% receiving sulfonylurea plus metformin) / 36 week, open-label, parallel-group, multicenter clinical trial comparing once-daily insulin glargine plus metformin with once-daily NPH insulin plus metformin (both insulins injected at bedtime) self-adjusted to target FPG of 4.0–5.5 mmol/L (72–99 mg/dL) /
  • During the last 12 study weeks average FPG was significantly lower with insulin glarginevs NPH insulin (5.75 ± 0.02 vs 5.96 ± 0.03 mmol/l; p<0.001)
  • At the end of the study HbA1c was similar in both groups (7.14 ± 0.12 and 7.16 ± 0.14% with insulin glargine and NPH insulin, respectively)
  • Symptomatic, but not confirmed symptomatic hypoglycaemia was significantly lower with insulin glarginevs NPH insulin during the first 12 weeks of the trial (4.1 ± 0.8 vs 9.0 ± 2.3 episodes/patient-year; p<0.05), but was not significantly different after this timepoint
  • Pre-dinner glucose levels were significantly higher with NPH insulin vs insulin glargine throughout the trial (10.1 ± 0.3 vs 8.6 ± 0.3 mmol/L; p=0.002)

Porcellati F, Rossetti P, Busciantella NR, et al. Comparison of pharmacokinetics and dynamics of the long-acting insulin analogsglargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study. Diabetes Care2007;30(10):2447–52 / 24 people with T1DM naïve to insulinsglargine and detemir / Randomized, double-blind, two-period crossover studty involving a 24-hour euglycaemic clamps (blood glucose target: 100 mg/dL) /
  • Plasma glucose remained at 103 ± 3.6 mg/dL up to 24 hours with insulin glargine, whilst plasma glucose increased progressively after 16 hours with insulin detemir and only eight (33%) people completed the study with plasma glucose <180 mg/dL
  • Glucose infusion rate was similar for insulinsglargine and detemir during the first 12 hours, after which the infusion rate declined significantly more rapidly with detemir (p<0.001)
  • Median time of end of action (plasma glucose >150 mg/dL) was significantly longer with insulin glargine than insulin detemir (24 vs 17.5 hours; p<0.001)

Rosenstock J, Davies M, Home PD, et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia2008;51(3):408–16 / 582 insulin-naïve people with T2DM poorly controlled (HbA1c=7.5–10.0%) with one or two OADs / 52 week, multinational, multicenter, randomized, open-label, parallel-group, non-inferiority trial comparing insulin glargine and insulin detemir in combination OADs titrated to target FPG ≤6.0 mmol/L /
  • Similar decreases in HbA1c were observed with insulin glargine and insulin determir (8.6% to 7.2 and 7.1%)
  • Similar decreases in FPG were observed for insulin detemir and insulin glargine (10.8 to 7.1 and 7.0 mmol/L)
  • 45% of participants completed the study with once-daily dosing of insulin detemir and 55% completed with twice-daily dosing of insulin detemir; only once-daily dosing of insulin glargine was allowed
  • Mean daily insulin dose was higher with insulin detemir than with insulin glargine (0.52 U/kg and 1.00 U/kg with insulin detemir once- and twice-daily, respectively, and 0.44 IU/kg with insulin glargine)
  • A similar proportion of people treated with insulin glargine and insulin detemir achieved HbA1c <7.0% without hypoglycaemia (33% with insulin detemir and 35% with insulin glargine)
  • Within participant variability for self-monitored FPG and pre-dinner plasma glucose did not differ by insulin treatment
  • There was no difference in the relative risk for nocturnal hypoglycaemia with either insulin

Davies M, Sinnassamy P, Storms F, Gomis R; AT.LANTUS Study Group. Insulin glargine-based therapy improves glycemic control in patients with type 2 diabetes sub-optimally controlled on premixed insulin therapies. Diabetes Res ClinPract2008;79(2):368–75 [AT.LANTUS STUDY] / People with T2DM with suboptimal glycemic control (HbA1c 7–12%) on their previous insulin regimen / 24-week multinational, multicentre, randomized study comparing two titration algorithms in four treatment groups of insulin glargine ± OADS alone or with once-, twice- or more than twice-daily prandial insulin /
  • Overall HbA1c levels significantly improved from 9.0 ± 1.3 to 8.0 ± 1.2% (p<0.001) and improvements were seen in all subgroups
  • Overall FPG levels significantly improved from 167.1 ± 50.0 to 106.9 ± 27.2 mg/dL (9.3 ± 2.8 to 5.9 ± 1.5 mmol/L; p<0.001) and improvements were seen in all subgroups
  • The incidence of severe hypoglycaemia was low in all four subgroups

Linn T, Fischer B, Soydan N, et al. Nocturnal glucose metabolism after bedtime injection of insulin glargine or neutral protaminehagedorn insulin in patients with type 2 diabetes. J ClinEndocrinolMetab2008;93(10):3839–46 / 10 people with T2DM / Randomized, placebo-controlled, three-way, crossover study involving a 22 hour euglycaemic-hyperinsulinemic clamp (blood glucose target: 6 mmol/L) comparing insulin glargine, NPH insulin and placebo given at bedtime /
  • During the night NPH insulin had a greater effect on glucose disappearance and endogenous glucose production compared with insulin glargine
  • In the morning insulin glargine had a greater effect on glucose disappearance and reducing endogenous glucose production compared with NPH insulin
  • Nearly 80% of insulin glargine’s glucose lowering effect in the morning was due to a reduction of endogenous glucose production
  • Significantly lower morning glucagon levels were observed with insulin glargine compared with NPH insulin (p=0.021)

Bretzel RG, Nuber U, Landgraf W, et al. Once-daily basal insulin glargine versus thrice-daily insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet 2008;371:1073–84 [APOLLO STUDY] / 418 people with T2DM inadequately controlled on OADs / 44-week, parallel-group, open-label, multinational, multicentre study comparing once-daily insulin glargine with three-times daily insulin lispro /
  • Insulin glargine was non-inferior to insulin lispro for reduction of mean HbA1c from baseline to endpoint (–1.7 vs –1.9%)
  • There was a greater decrease in mean FPG (p<0.0001) and nocturnal blood glucose (p=0.0041) with insulin glarginevs insulin lispro (–4.3 and –3.3 vs –1.8 and –2.6 mmol/L, respectively)
  • Insulin lispro better controlled PPG (p<0.0001)
  • The incidence of hypoglycemic events was significantly less with insulin glarginevs insulin lispro (5.2 vs 24.0 events per patient-year; p<0.0001)

Blicklé JF, Hancu N, Piletic M, et al. Insulin glargine provides greater improvements in glycaemic control vs. intensifying lifestyle management for people with type 2 diabetes treated with OADs and 7-8% A1c levels. The TULIP study. Diabetes ObesMetab2009;11(4):379–86 [TULIP STUDY] / 215 insulin-naïve people with T2DM with HbA1c 7–8% who had been treated with maximum dose metformin and sulfonylurea for ≥2 years / 9-month, open-label, multinational, multicentre, randomized study comparing initiation of insulin glargine treatment (titrated to FBG 0.7–1.0 g/L) with intensified lifestyle management /
  • Significantly more patients achieved HbA1c <7% (p<0.0001) and <6.5% (p=0.0001) with insulin glarginevs intensified lifestyle management (66 and 34% vs 38 and 11%, respectively)
  • There was a significantly greater change in FPG from baseline to endpoint with insulin glarginevs intensified lifestyle management (–0.50 ± 0.47 vs –0.05 ± 0.39 g/L; p<0.0001)
  • There was a decrease in weight with intensified lifestyle management vs insulin glargine (–2.5 ± 3.2 vs +0.9 ± 2.9 kg; p<0.0001)
  • There was significantly less symptomatic (p<0.0001) and nocturnal hypoglycaemia (p=0.0016) with intensified lifestyle management vs insulin glargine (25.0 and 5.6% vs 55.3 and 20.4%, respectively)

Meneghini LF, Traylor L, Schwartz SL. Improved glycemic control with insulin glargine versus pioglitazone as add-on therapy to sulfonylurea or metformin in patients with uncontrolled type 2 diabetes mellitus.EndocrPract 2010;16(4)588–99 [4020 STUDY] / 389 adults with poorly controlled T2DM (HbA1c 8.0–12.0%) despite ≥3 months of sulfonylurea or metforminmonotherapy / 48-week, multicentre, parallel-group, open label, randomized study comparing insulin glargine and pioglitazone as add-on to sulfonylurea or metforminmonotherapy /
  • A significantly larger reduction in HbA1c was observed with insulin glarginevspioglitazone (–2.48 vs –1.86%; p=0.0001)
  • A significantly greater reduction in FPG at endpoint was observed with insulin glarginevspioglitazone (–99.1 vs –64.2 mg/dL; p<0.0001)
  • There was a higher rate of confirmed clinically relevant hypoglycemic episodes (blood glucose <70 mg/dL and all severe hypoglycaemia; p<0.0001) and severe hypoglycaemia (p=0.0309) with insulin glarginevspioglitazone (4.97 and 0.07 vs 1.04 and 0.01, respectively)

Fritsche A, Larbig M, Owens D, Häring HU. Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes – results of the GINGER study. Diabetes ObesMetab2010;12(2):115–23 [GINGER STUDY] / 310 people with T2DM receiving premixed insulin ± metformin / 52-week, open-label, randomized, multinational, multicentre trial comparing a basal–bolus regimen (insulin glargine + insulin glulisine) and twice-daily premixed insulin /
  • There was a larger decrease in HbA1c from baseline to endpoint with basal–bolus vs premixed insulin (–1.31 vs –0.80%; p=0.0001)
  • More people achieved HbA1c <7% with basal–bolus vs premixed insulin (46.6 vs 27.9%; p=0.0004)
  • Mean ± SD daytime (p=0.0033) and postprandial blood glucose (p<0.0001) was significantly lower with basal–bolus vs premixed insulin(–2.7 ± 2.3 and –3.1 ± 2.6 vs –2.3 ± 2.5 and –2.5 ± 2.8 mmol/L, respectively)

Dailey G, Admane K, Mercier F, Owens D. Relationship of insulin dose, A1c lowering, and weight in type 2 diabetes: comparing insulin glargine and insulin detemir. Diabetes TechnolTher2010;12(12):1019–27 [META-ANALYSIS] / People with T2DM initiating insulin glargine and insulin detemir / Pooled analysis of 22 studies of at least 20 weeks duration /
  • In an unadjusted model similar results for mean HbA1c change (–1.4 vs –1.4%) and weight gain (2.5 vs 1.7 kg)
  • A significantly higher dose of insulin detemir than insulin glargine was required to achieve the same HbA1cchange (51.5 vs 38.8 U/day)

ORIGIN Trial investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl Med 2012;367(4):319–28 [ORIGIN STUDY] / 12,537 people with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance or T2DM / Multinational, multicentre, randomized clinical trial comparing insulin glarginevs standard care over a median of 6.2 years /
  • Rates of incident cardiovascular outcomes were similar in the insulin glargine and standard care arms (2.94 vs 2.85 per 100 person years for a combination of nonfatal MI, nonfatal stroke or death from CV causes, p=0.63; 5.52 and 5.28 per 100 person years for a combination of nonfatal MI, nonfatal stroke, death from CV causes or revascularization or hospitalization for heart failure, p=0.27)
  • New diabetes was diagnosed approximately 3 months after treatment was stopped in 30 and 35% of people without baseline diabetes (p=0.05)
  • Rates of severe hypoglycaemia were 1.00 vs 0.31 per 100 patient-years with insulin glargine and standard care, respectively
  • Median weight increased in the insulin glargine group (+1.6 kg) and decreased in the standard care group (–0.5 kg)
  • There was no significant difference in cancers between groups (p=0.97)

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