Systematic Review: Comparative Effectiveness and Safety of Premixed Insulin Analogues in Type 2 Diabetes

Abstract

Background Evidence comparing premixed insulin analogues with other antidiabetic agents is urgently required to guide appropriate therapy. Purpose To summarize the English-language literature on the effectiveness and safety of premixed insulin analogues as compared with other antidiabetic agents in adults with type 2 diabetes. Data Sources We searched MEDLINE®, EMBASE®, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to February 2008, and unpublished data from U.S. Food and Drug Administration, European Medicines Agency, and industry. Study Selection Studies with control arms that compared premixed insulin analogues to another antidiabetic medication in adults with type 2 diabetes Data Extraction Serial abstraction by 2 reviewers using standardized protocols Data Synthesis Evidence from clinical trials was inconclusive for clinical outcomes, such as mortality. Therefore, the review focused on intermediate outcomes. Premixed analogues were similar to premixed human insulin in lowering fasting glucose, hemoglobin A1c, and the incidence of hypoglycemia but were more effective in lowering postprandial glucose (mean difference = -1.1 mmol/L; 95% CI = -1.4 to -0.7 mmol/L [-19.2 mg/dL; 95% CI=-25.9 to -12.5 mg/dL]). As compared to long-acting insulin analogues, premixed analogues were superior in lowering postprandial glucose (mean difference= -1.5 mmol/L; 95%CI = -1.9 to -1.2 mmol/L [-27.9 mg/dL; 95% CI=-34.3 to -21.5 mg/dL]) and hemoglobin A1c (mean difference=-0.39%; 95% CI=-0.50% to -0.28%) but inferior in lowering fasting glucose (mean difference=0.7 mmol/L; 95%CI = 0.3 to 1.0 mmol/L [12.0 mg/dL; 95% CI=6.0 to 18.1 mg/dL]) and had higher incidence of hypoglycemia. When compared to noninsulin antidiabetic agents, premixed analogues were more effective in lowering fasting glucose (mean difference= -1.1mmol/L; 95%CI = -1.7 to 0.6 mmol/L [-20.5 mg/dL; 95% CI=-29.9 to -11.2 mg/dL]), postprandial glucose (mean difference= -2.1 mmol/L; 95%CI = -3.4 to -0.8 mmol/L [-37.4 mg/dL; 95% CI=-61.0 to -13.7 mg/dL]), and hemoglobin A1c (mean difference=-0.49%; 95% CI=-0.86% to -0.12%) but had higher incidence of hypoglycemia. Limitations Searching was restricted to studies published in English. Data on clinical outcomes was limited. The small number of studies for each comparison limited assessment of between-study heterogeneity. Conclusions Premixed insulin analogues provide glycemic control similar to premixed human insulin and may provide tighter glycemic control than long-acting insulin analogues and noninsulin antidiabetic agents.

AHRQ's Comparative Effectiveness Research on Premixed Insulin Analogues for Adults with Type 2 Diabetes: Understanding and Applying the Systematic Review Findings

“…55 For lowering A1c, the pooled analysis including all premixed analogues indicated their better effectiveness compared with all noninsulin antidiabetic agents (mean difference = −0.50%; 95% CI = −0.9% to −0.10%; P = 0.034). 63 However, exceptions were evident in the individual studies comprising this analysis. For example, no differences were observed for A1c reductions among patients treated with insulin aspart 70/30 versus glibenclamide and pioglitazone 49 or in patients treated with insulin aspart 70/30 plus rosiglitazone versus rosiglitazone plus glibenclamide.…”

“…n Study Limitations and Implications for Clinical Applications As recognized by Qayyum et al in their AHRQ report 10 and in a review published in the Annals of Internal Medicine, 63 methodological issues may have compromised the precision and generalizability of some of their findings. A number of these issues are inherent to the studies on which the systematic review was based.…”

“…As noted by Qayyum et al, in many of the studies that made this comparison, the premixed human insulin was administered late ( < 30 minutes before meals), which could have reduced its effectiveness. 63 The authors also note studies that did not control for between-group differences in total daily insulin dose. As explained earlier, in some studies therapy doses for individual patients were adjusted to optimize glycemic control.…”

“…The pooled analysis of all relevant studies indicated no significant difference between premixed insulin analogues and premixed human insulin in lowering fasting blood glucose (pooled mean difference = 4.3 mg/dL; 95% CI = −1.5 to 10.2 mg/ dL; P > 0.05). 63 The strength of evidence for all analyses involving fasting glucose was rated as moderate.…”

Mixtard 30 withdrawal: farewell to a convenient biphasic insulin

“…They were no better than premixed insulins such as Mixtard 30 when it came to reducing fasting glucose (HbA 1c ) and the incidence of hypoglycaemia. 3 Novo Nordisk has said that Mixtard 30 is no longer commercially viable, and no doubt the profitability of analogues is greater. Mixtard 30 is significantly cheaper than all the alternative twice-daily mixtures listed above.…”