Therapeutics
Review: In type 2 diabetes, GLP-1 agonists plus basal insulin reduce HbA1c without increasing hypoglycemia Clinical impact ratings:
多多多多多多夞
Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and metaanalysis. Lancet. 2014:Sep 11. [Epub ahead of print].
多多多多多多夞
Question In type 2 diabetes, do glucagon-like peptide–1 (GLP-1) agonists plus basal insulin improve glycemic and weight control and reduce hypoglycemia compared with other antidiabetes treatments?
Review scope Included studies compared GLP-1 agonists plus basal insulin with other antidiabetic treatments in adults with type 2 diabetes, had treatment duration ≥ 8 weeks, and reported glycemic outcomes. Outcomes were changes in hemoglobin (Hb) A1c levels, proportion of patients with HbA1c≤ 7.0%, hypoglycemia, and weight change. International Prospective Register of Systematic Reviews CRD42014010688.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Library, Web of Knowledge, FDA.gov, and ClinicalTrials.gov (all to Jul 2014), and reference lists were searched for randomized controlled trials (RCTs). 15 RCTs (n = 4348; mean age 43 to 61 y and 51% men across 13 RCTs) met the inclusion criteria. 7 RCTs evaluated the GLP-1 agonist liraglutide, 4 lixisenatide, 3 exenatide, and 1 albiglutide. 6 RCTs compared GLP-1 agonists with placebo, 3 with no GLP-1 agonists, 3 with intensive basal-bolus insulin, and 3 with other treatments. 13 RCTs included other antidiabetes treatments in both groups. Trial duration was 12 to 36 weeks (mean 25 wk). All RCTs had adequate allocation concealment; 6 blinded patients, health care providers, data collectors, and outcome assessors; and 10 had ≤ 20% with incomplete outcome data. 12 RCTs had industry funding.
Main results Meta-analysis showed that GLP-1 agonists plus basal insulin improved HbA1c and weight outcomes compared with other antidiabetes treatments; groups did not differ for hypoglycemia (Table). In the subgroup of 3 RCTs (n = 1136) comparing GLP-1 agonists plus basal insulin with intensive basal-bolus insulin, the GLP-1 combination reduced HbA1c levels (weighted mean difference [WMD] ⫺0.10%, 95% CI ⫺0.17 to ⫺0.02), hypoglycemia (relative risk [RR] 0.67, CI 0.56 to 0.80), and weight gain (WMD
⫺5.66 kg, CI ⫺9.80 to ⫺1.51); groups did not differ for patients with HbA1c ≤ 7.0% (2 RCTs, RR 1.07, CI 0.91 to 1.26).
Conclusion In type 2 diabetes, glucagon-like peptide-1 agonists plus basal insulin reduce hemoglobin A1c levels and weight without increasing hypoglycemia compared with other antidiabetes treatments. Source of funding: No external funding. For correspondence: Dr. R. Retnakaran, Mount Sinai Hospital, Toronto, ON, Canada. E-mail [email protected].
Commentary How clinicians and patients should combine antidiabetes agents to improve diabetes control and reduce the risk for complications is unclear. Recent guidelines recommend engaging patients in shared decision-making (1), which requires trustworthy information about the benefits, harms, and inconveniences of the alternatives. Beyond effects on HbA1c levels, no reliable data distinguish available agents by their effects on patient-important benefits or long-term harms. Of note, GLP-1 agonists are costly, and gastrointestinal side effects reduce their tolerability. The review by Eng and colleagues found that the known and usually desirable effects of GLP-1 agonists (2)— glycemic control, weight loss, and reduced hypoglycemia—are maintained when they are used in combination with basal insulin. Between-study differences in patients (e.g., degree of insulin deficiency) and comparisons (use of other antidiabetes agents) contribute to inconsistent results and call into question the applicability of these findings to patients in practice. The included trials had short durations and could not assess the effect of combination therapy on diabetes complications. Also, 12 of the 15 RCTs included in the review were sponsored by industry, which offers an alternative explanation for the favorable findings supporting GLP-1 agonist use (3). At best, the review by Eng and colleagues provides low- to moderate-quality evidence that the known effects of GLP-1 agonists remain when used in combination with basal insulin.
GLP-1 agonists plus basal insulin (GLP-1 combination) vs other antidiabetic treatments (control) in patients with type 2 diabetes* Outcomes
Number of trials (n)
HbA1c level, %
15 (4348)
Weight change, kg
12 (3941)
GLP-1 combination
Control
Hypoglycemia
14 {4267}§
11 (3356)
Naykky Singh Ospina, MD Victor M. Montori, MD, MSc Mayo Clinic Rochester, Minnesota, USA
⫺0.44 (⫺0.60 to ⫺0.29) ⫺3.2 (⫺4.9 to ⫺1.5)
Weighted event rates HbA1c level ≤ 7.0%
At 12 to 36 wk† Weighted mean difference (95% CI)‡
Patients and clinicians will need to make decisions using this evidence, despite its limitations. In this context, informed preferences of patients, after evaluation of risks and benefits of the alternatives, should play a major role in designing evidence-based and patient-centered diabetes regimens.
59%
27.6%
31%
27.9%
RBI (CI)
NNT (CI)
References
92% (43 to 156)
4 (3 to 8)
RRR (CI)
NNT
1. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37 Suppl 1:S14-80.
1% (⫺29 to 24)
Not significant
*GLP-1 = glucagon–like peptide–1; Hb = hemoglobin; other abbreviations defined in Glossary. Weighted event rates, RBI, RRR, NNT, and CI calculated from risk ratios in article and control event rates provided by the author using a random-effects model. 2
†Heterogeneity: I = 77% (hypoglycemia) to 99.6% (weight change), all P < 0.001.
2. Shyangdan DS, Royle P, Clar C, et al. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(10):CD006423. 3. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2012;(12):MR000033.
‡Negative values favor GLP-1 combination. §Provided by the author.
姝 2015 American College of Physicians JC6 ACP Journal Club Downloaded From: http://annals.org/ by a University of Pittsburgh User on 01/20/2015
Annals of Internal Medicine
20 January 2015
Review: In type 2 diabetes, GLP-1 agonists plus basal insulin reduce HbA1c without increasing hypoglycemia Clinical impact ratings:
多多多多多多夞
Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and metaanalysis. Lancet. 2014:Sep 11. [Epub ahead of print].
多多多多多多夞
Question In type 2 diabetes, do glucagon-like peptide–1 (GLP-1) agonists plus basal insulin improve glycemic and weight control and reduce hypoglycemia compared with other antidiabetes treatments?
Review scope Included studies compared GLP-1 agonists plus basal insulin with other antidiabetic treatments in adults with type 2 diabetes, had treatment duration ≥ 8 weeks, and reported glycemic outcomes. Outcomes were changes in hemoglobin (Hb) A1c levels, proportion of patients with HbA1c≤ 7.0%, hypoglycemia, and weight change. International Prospective Register of Systematic Reviews CRD42014010688.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Library, Web of Knowledge, FDA.gov, and ClinicalTrials.gov (all to Jul 2014), and reference lists were searched for randomized controlled trials (RCTs). 15 RCTs (n = 4348; mean age 43 to 61 y and 51% men across 13 RCTs) met the inclusion criteria. 7 RCTs evaluated the GLP-1 agonist liraglutide, 4 lixisenatide, 3 exenatide, and 1 albiglutide. 6 RCTs compared GLP-1 agonists with placebo, 3 with no GLP-1 agonists, 3 with intensive basal-bolus insulin, and 3 with other treatments. 13 RCTs included other antidiabetes treatments in both groups. Trial duration was 12 to 36 weeks (mean 25 wk). All RCTs had adequate allocation concealment; 6 blinded patients, health care providers, data collectors, and outcome assessors; and 10 had ≤ 20% with incomplete outcome data. 12 RCTs had industry funding.
Main results Meta-analysis showed that GLP-1 agonists plus basal insulin improved HbA1c and weight outcomes compared with other antidiabetes treatments; groups did not differ for hypoglycemia (Table). In the subgroup of 3 RCTs (n = 1136) comparing GLP-1 agonists plus basal insulin with intensive basal-bolus insulin, the GLP-1 combination reduced HbA1c levels (weighted mean difference [WMD] ⫺0.10%, 95% CI ⫺0.17 to ⫺0.02), hypoglycemia (relative risk [RR] 0.67, CI 0.56 to 0.80), and weight gain (WMD
⫺5.66 kg, CI ⫺9.80 to ⫺1.51); groups did not differ for patients with HbA1c ≤ 7.0% (2 RCTs, RR 1.07, CI 0.91 to 1.26).
Conclusion In type 2 diabetes, glucagon-like peptide-1 agonists plus basal insulin reduce hemoglobin A1c levels and weight without increasing hypoglycemia compared with other antidiabetes treatments. Source of funding: No external funding. For correspondence: Dr. R. Retnakaran, Mount Sinai Hospital, Toronto, ON, Canada. E-mail [email protected].
Commentary How clinicians and patients should combine antidiabetes agents to improve diabetes control and reduce the risk for complications is unclear. Recent guidelines recommend engaging patients in shared decision-making (1), which requires trustworthy information about the benefits, harms, and inconveniences of the alternatives. Beyond effects on HbA1c levels, no reliable data distinguish available agents by their effects on patient-important benefits or long-term harms. Of note, GLP-1 agonists are costly, and gastrointestinal side effects reduce their tolerability. The review by Eng and colleagues found that the known and usually desirable effects of GLP-1 agonists (2)— glycemic control, weight loss, and reduced hypoglycemia—are maintained when they are used in combination with basal insulin. Between-study differences in patients (e.g., degree of insulin deficiency) and comparisons (use of other antidiabetes agents) contribute to inconsistent results and call into question the applicability of these findings to patients in practice. The included trials had short durations and could not assess the effect of combination therapy on diabetes complications. Also, 12 of the 15 RCTs included in the review were sponsored by industry, which offers an alternative explanation for the favorable findings supporting GLP-1 agonist use (3). At best, the review by Eng and colleagues provides low- to moderate-quality evidence that the known effects of GLP-1 agonists remain when used in combination with basal insulin.
GLP-1 agonists plus basal insulin (GLP-1 combination) vs other antidiabetic treatments (control) in patients with type 2 diabetes* Outcomes
Number of trials (n)
HbA1c level, %
15 (4348)
Weight change, kg
12 (3941)
GLP-1 combination
Control
Hypoglycemia
14 {4267}§
11 (3356)
Naykky Singh Ospina, MD Victor M. Montori, MD, MSc Mayo Clinic Rochester, Minnesota, USA
⫺0.44 (⫺0.60 to ⫺0.29) ⫺3.2 (⫺4.9 to ⫺1.5)
Weighted event rates HbA1c level ≤ 7.0%
At 12 to 36 wk† Weighted mean difference (95% CI)‡
Patients and clinicians will need to make decisions using this evidence, despite its limitations. In this context, informed preferences of patients, after evaluation of risks and benefits of the alternatives, should play a major role in designing evidence-based and patient-centered diabetes regimens.
59%
27.6%
31%
27.9%
RBI (CI)
NNT (CI)
References
92% (43 to 156)
4 (3 to 8)
RRR (CI)
NNT
1. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37 Suppl 1:S14-80.
1% (⫺29 to 24)
Not significant
*GLP-1 = glucagon–like peptide–1; Hb = hemoglobin; other abbreviations defined in Glossary. Weighted event rates, RBI, RRR, NNT, and CI calculated from risk ratios in article and control event rates provided by the author using a random-effects model. 2
†Heterogeneity: I = 77% (hypoglycemia) to 99.6% (weight change), all P < 0.001.
2. Shyangdan DS, Royle P, Clar C, et al. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(10):CD006423. 3. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2012;(12):MR000033.
‡Negative values favor GLP-1 combination. §Provided by the author.
姝 2015 American College of Physicians JC6 ACP Journal Club Downloaded From: http://annals.org/ by a University of Pittsburgh User on 01/20/2015
Annals of Internal Medicine
20 January 2015
