Long-Acting Insulin Analogues Versus Nph Insulin (Human Isophane Insulin) for Type 2 Diabetes Mellitus

A Cochrane review [Abstract] 1 included 24 studies with a total of 4740 subjects. Duration of the included trials ranged from 24 weeks to 5 years. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) did not differ in a clinical relevant way between treatment groups. Compared to NPH insulin, insulin glargine (Glar) had a risk ratio (RR) for nocturnal hypoglycaemia of 0.78 (0.68 to 0.89) and insulin detemir (Det) had a RR of 0.57 (0.47 to 0.68).

A meta-analysis 2 included 28 RCTs involving a total of 12 669 T2DM patients followed for 12-52 weeks. Insulin glargine (Glar) + oral drug use was associated with higher probability of reaching target HbA1c level without hypoglycemia as compared to NPH insulin + orall drugs (RR 1.32, 95% CI 1.09 to 1.59) or premixed insulin without oral drugs (RR 1.61, 95% CI 1.22 to 2.13) and similar effect as insulin detemir (Det) + oral drugs (RR 1.07, 95% CI 0.87 to 1.33) and premixed insulin with oral drugs (RR 1.09, 95% CI 0.86 to 1.38). Glar + oral drugs demonstrated lower risk of symptomatic hypoglycemia as compared to NPH + oral drugs (RR 0.89, 95% CI 0.83 to 0.96), premixed insulin + oral drugs (RR 0.75, 95% CI 0.68 to 0.83) and premixed insulin without oral drugs (RR 0.75, 95% CI 0.68 to 0.83), but not with Det + oral drugs (RR 0.99, 95% CI 0.90 to 1.08). In basal-bolus regimens, Glar demonstrated similar proportion of patients achieving target HbA1c as compared to NPH (RR 1.14, 95% CI 0.91 to 1.44) but higher than premixed insulin (RR 1.26, 95% CI 1.12 to 1.42) or Det (RR 1.38, 95% CI 1.11 to 1.72). The risk of severe hypoglycemia was lower in Glar than in NPH (RR 0.77, 95% CI 0.63 to 0.94), with no differences in comparison with premixed insulin (RR 0.74, 95% CI 0.46 to 1.20) and Det (RR 1.10, 95% CI 0.54 to 2.25).

A Cochrane review [Abstract] 3 included 4 studies with a total of 2 250 subjects comparing the effects of insulin detemir and insulin glargine in the treatment of patients with T2D.The mean difference in HbA1c level between insulin glargine (Glar) and insulin detemir (Det) was not statistically significant: 0.08% (95% CI -0.10 to 0.27, p = 0.38, I2 = 73%). The percentage of patients achieving good glycaemic control (HbA1c < 7%) was similar between the two insulins (RR 0.96; 95% CI 0.81 to 1.14). There was no difference in nocturnal or severe hypoglycaemia (RR 1.00; 95% CI 0.90 to 1.11, 1.00; 95% CI 0.03 to 1.09 and 0.88; 95% CI 0.59 to 1.30 respectively).

A systematic review and meta-analysis 4 comparing glargine-U300 with glargine-U100 included 9 studies with 3977 adult patients with T1D and T2D. Compared with Gla-100, the use of Gla-300 reduced confirmed nocturnal hypoglycemia (RR 0.81, 95% CI 0.69 to 0.95) and clinically significant nocturnal hypoglycemia (RR 0.75, 95% CI 0.63 to 0.91).

Another systematic review and meta-analysis 5 comparing glargine-U100 with glargine-U300 in adult patients with T2D and T1D included 15 RCTs with 7082 patients with T2D and 2222 with T1D. All safety parameters were comparable between Gla-100 and Gla-300. In T2D, statistically significant differences were observed in favour of Gla-300 over Gla-100 for nocturnal and total hypoglycaemia. For efficacy parameters, a statistically and clinically significant difference favouring Gla-100 in basal insulin dose requirement was observed for both T2D and T1D.

A systematic review and indirect treatment comparison 6 comparing degludec U100 and glargine U300 in T1D included 9 trials were included. Efficacy analysis suggested that Deg-100 was non-inferior to Gla-300 in reducing HbA1c (MD 0.03, 95% CI - 0.09 to 0.15; P = 0.60). Safety analysis suggested that Deg-100 appeared to have lower rates of both severe (HR 0.44, 95% CI 0.25 to 0.78; P = 0.005) and nocturnal severe (HR 0.19, 95% CI 0.08-0.44; P < 0.001) hypoglycemia.

An RCT 7 comparing Gla-300 and Deg-100 included 343 adults with T1D. Continuous glucose monitoring (CGM)-based time-in-range (TIR) was used as a primary efficacy endpoint. Non-inferiority of Gla-300 versus Deg-100 was shown (percentage TIR ≥ 70 to ≤ 180 mg/dl: least squares (LS) mean 52.74%, 95% CI 51.06% to 54.42% for Gla-300 and 55.09%, 95% CI 53.34% to 56.84% for Deg-100. Superiority of Gla-300 over Deg-100 was not shown on TIR. Occurrences of self-measured and CGM-derived hypoglycaemia were comparable between treatment groups.

Comment: The quality of evidence is downgraded by study qualities (risk of bias).

Weak recommendation: Use long-acting insulin analogues in patients with type 2 diabetes who have nocturnal hypoglycaemia with NPH insulin. The strength of recommendation is downgraded by questionable cost-effectiveness.

References

• Semlitsch T, Engler J, Siebenhofer A et al. (Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev 2020;(11):CD005613. [PubMed]
• Rys P, Wojciechowski P, Rogoz-Sitek A et al. Systematic review and meta-analysis of randomized clinical trials comparing efficacy and safety outcomes of insulin glargine with NPH insulin, premixed insulin preparations or with insulin detemir in type 2 diabetes mellitus. Acta Diabetol 2015;52(4):649-62. [PubMed]
• Swinnen SG, Simon AC, Holleman F, et al. Insulin detemir versus insulin glargine for type 2 diabetes mellitus. Cochrane Database Syst Rev 2011;2011(7):CD006383 [PubMed]
• Díez-Fernández A, Cavero-Redondo I, Moreno-Fernández J, et al. Effectiveness of insulin glargine U-300 versus insulin glargine U-100 on nocturnal hypoglycemia and glycemic control in type 1 and type 2 diabetes: a systematic review and meta-analysis. Acta Diabetol 2019;56(3):355-364 [PubMed]
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• Martin, Zhou Y, Takagi T, et al. Safety, efficacy, and cost-effectiveness of insulin degludec U100 versus insulin glargine U300 in adults with type 1 diabetes: a systematic review and indirect treatment comparison. Int J Clin Pharm 2022;44(3):587-598 [PubMed]
• Battelino T, Danne T, Edelman SV, et al. Continuous glucose monitoring-based time-in-range using insulin glargine 300 units/ml versus insulin degludec 100 units/ml in type 1 diabetes: The head-to-head randomized controlled InRange trial. Diabetes Obes Metab 2023;25(2):545-555[PubMed]