Rehan Qayyum, MD; Shari Bolen, MD, MPH; Nisa Maruthur, MD, MHS; Leonard Feldman, MD; Lisa M. Wilson, ScM; Spyridon S. Marinopoulos, MD, MBA; Padmini Ranasinghe, MD, MPH; Muhammed Amer, MD; Eric B. Bass, MD, MPH
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Grant Support: This article is based on research conducted by the Johns Hopkins Evidence-based Practice Center under contract number 290-02-0018 with the Agency for Healthcare Research and Quality, Rockville, Maryland.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Rehan Qayyum, MD, Johns Hopkins Hospital, Hospitalist Program, 600 North Wolfe Street, Park 307-A, Baltimore, MD 21287; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Qayyum: Johns Hopkins Hospital, Hospitalist Program, 600 North Wolfe Street, Park 307-A, Baltimore, MD 21287.
Dr. Bolen: 2024 East Monument Street, Suite 2-600, Baltimore, MD 21205.
Dr. Maruthur: 2024 East Monument Street, Suite 2-500, Baltimore, MD 21205.
Drs. Feldman, Ranasinghe, and Amer: Johns Hopkins Hospital, Hospitalist Program, 600 North Wolfe Street, Park 307, Baltimore, MD 21287.
Ms. Wilson: Johns Hopkins Evidence-based Practice Center, 1830 East Monument Street, Room 8064, Baltimore, MD 21287.
Dr. Marinopoulos: Johns Hopkins Outpatient Center Practice, 601 North Caroline Street, Suite 7143, Baltimore, MD 21287.
Dr. Bass: Johns Hopkins Evidence-based Practice Center, 1830 East Monument Street, Room 8068, Baltimore, MD 21287.
Evidence comparing premixed insulin analogues (a mixture of rapid-acting and intermediate-acting insulin analogues) with other antidiabetic agents is urgently required to guide appropriate therapy.
To summarize the English-language literature on the effectiveness and safety of premixed insulin analogues compared with other antidiabetic agents in adults with type 2 diabetes.
The authors searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to February 2008 and sought unpublished data from the U.S. Food and Drug Administration, European Medicines Agency, and industry.
Studies with control groups that compared premixed insulin analogues with another antidiabetic medication in adults with type 2 diabetes.
2 reviewers using standardized protocols performed serial abstraction.
Evidence from clinical trials was inconclusive for clinical outcomes, such as mortality. Therefore, the review focused on intermediate outcomes. Premixed insulin analogues were similar to premixed human insulin in decreasing fasting glucose levels, hemoglobin A1c levels, and the incidence of hypoglycemia but were more effective in decreasing postprandial glucose levels (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]). Compared with long-acting insulin analogues, premixed insulin analogues were superior in decreasing postprandial glucose levels (mean difference, −1.5 mmol/L; CI, −1.9 to −1.2 mmol/L [−27.9 mg/dL; CI, −34.3 to −21.5 mg/dL]) and hemoglobin A1c levels (mean difference, −0.39% [CI, −0.50% to −0.28%]) but were inferior in decreasing fasting glucose levels (mean difference, 0.7 mmol/L; CI, 0.3 to 1.0 mmol/L [12.0 mg/dL; CI, 6.0 to 18.1 mg/dL]) and were associated with a higher incidence of hypoglycemia. Compared with noninsulin antidiabetic agents, premixed insulin analogues were more effective in decreasing fasting glucose levels (mean difference, −1.1 mmol/L; CI, −1.7 to −0.6 mmol/L [−20.5 mg/dL; CI, −29.9 to −11.2 mg/dL]), postprandial glucose levels (mean difference, −2.1 mmol/L; CI, −3.4 to −0.8 mmol/L [−37.4 mg/dL; CI, −61.0 to −13.7 mg/dL]), and hemoglobin A1c levels (mean difference, −0.49% [CI, −0.86% to −0.12%]) but were associated with a higher incidence of hypoglycemia.
The literature search was restricted to studies published in English. Data on clinical outcomes were limited. The small number of studies for each comparison limited assessment of between-study heterogeneity.
Premixed insulin analogues provide glycemic control similar to that of premixed human insulin and may provide tighter glycemic control than long-acting insulin analogues and noninsulin antidiabetic agents.
The relative effects of premixed insulin analogues, other insulin regimens, and noninsulin antidiabetic agents for adults with type 2 diabetes are unclear.
This systematic review of comparative trials in adults with type 2 diabetes found that premixed insulin analogues and premixed human insulin provided similar glycemic control. Premixed analogues provided tighter glycemic control and caused more hypoglycemia than long-acting insulin analogues and noninsulin antidiabetic agents.
Evidence for effects on clinical outcomes was scant and inconclusive.
We need large, long-term trials that compare premixed insulin analogues with other agents to see whether improvements in glucose control lead to improved clinical outcomes.
Study flow diagram.
FDA = U.S. Food and Drug Administration.
* The total may exceed the number in the corresponding box because articles could be excluded for more than 1 reason at this level.
Table. Strength of the Evidence Comparing Premixed Insulin Analogues with Other Antidiabetic Agents for Intermediate Outcomes and Adverse Events
Weighted mean difference of change in postprandial glucose level with premixed insulin analogues versus other antidiabetic agents.
Error bars represent 95% CIs. To convert glucose values to mmol/L, multiply by 0.0555.
* Pooled results include those of a study (43) that administered insulin lispro 50/50 in the morning and afternoon and insulin lispro 75/25 in the evening.
† Pooled results include those of a study (55) that administered insulin lispro 50/50 in the morning and insulin lispro 75/25 in the evening.
‡ Reference 21 was excluded.
Weighted mean difference of change in fasting glucose level with premixed insulin analogues versus other antidiabetic agents.
† Reference 21 was excluded.
Weighted mean difference of change in hemoglobin A1c level with premixed insulin analogues versus other antidiabetic agents.
Error bars represent 95% CIs.
Incidence of unclassified hypoglycemia, serious hypoglycemia, mild hypoglycemia, and symptom-only hypoglycemia with premixed insulin analogues versus other antidiabetic agents.
Incidence of clinical outcomes with premixed insulin analogues versus other antidiabetic agents.
* Combined outcome includes all-cause mortality and cardiovascular morbidity.
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Rehan Qayyum, Shari Bolen, Nisa Maruthur, Leonard Feldman, Lisa M. Wilson, Spyridon S. Marinopoulos, et al. Systematic Review: Comparative Effectiveness and Safety of Premixed Insulin Analogues in Type 2 Diabetes. Ann Intern Med. 2008;149:549–559. doi: 10.7326/0003-4819-149-8-200810210-00242
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Published: Ann Intern Med. 2008;149(8):549-559.
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism.
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