Title: Efficacy and Safety of Incretin Therapy in Type 2 Diabetes: systematic review
and meta-analysis
Authors: RE. Amori, JL. Lau, AG Pittas
Source: JAMA. July 11, 2007, Vol. 298, No. 2: 194-206
Objective: To assess the efficacy and safety of incretin-based therapy in adults with
type 2 diabetes.
Data sources and selection:

Articles were searched from MEDLINE and the Cochrane Central Register of
Controlled Trials for English-language randomized controlled trials involving
GLP-1 or DDP4 inhibitor. The search was also including abstracts presented at
recent conference, relevant Websites, reference lists and citations. Out of 355

potential articles, 29 articles were met selected criteria.
Inclusion criteria: 1) Randomized controlled trials 2) At least 12 weeks in
duration 3) Compared incretin therapy with placebo or other diabetes medication
4) With HbA1c outcomes

Exclusion criteria: Trial duration less than 12 weeks (inadequate assessment of
change in glycemic efficacy)
Data extraction:
Efficacy
Primary outcome is the difference in HbA1c change from baseline.
Secondary outcomes are difference in fasting plasma glucose and the proportion of
participants reaching HbA1c < 7%.
Safety
Numbers of participants reporting hypoglycemia; all adverse events
Other data were also extracted when available: change in body weight, postprandial
glycemia, lipid profile, level of circulating antibodies to incretin analogue.
Data analysis:
Continuous variables (Hba1c, fasting plasma glucose, weight)
calculate
weighted mean differences and 95% CIs for change from baseline in incretin vs
placebo or hypoglycemic agent
Dichotomous variables (percentages achieving HbA1c < 7% and percentages with
hypoglycemia and adverse events)
calculate the risk ratios and 95% CIs for
change from baseline in incretin vs placebo or hypoglycemic agent
For meta-analysis
use random-effects model weights studies; use the I2 statistic
to quantify the degree of heterogeneity among trials
Results:
Primary outcomes (see figure2. and 3.):

GLP-1 Analogues: Compared to placebo showed statistically significant
difference in HbA1c decline, weighted mean defference –0.97% (95CIs, -1.13%
to -0.81%). There was no difference in HbA1c between exenatide vs insulin.

DDP4 inhibitors: Compared to placebo showed difference in HbA1c decline,
weighted mean difference –0.74% (95% CIs, -0.85% to -0.62%). There were
slightly less effective when DDP4 inhibitors were compared with other
hypoglycemic agents (weighted mean difference, 0.21%, 95CIs, 0.02% - 0.39%)
Secondary outcomes summary (details see table 2. and 3. in the article):

GLP-1 resulted in weight loss, -1.4 kg and -4.8 kg vs placebo and insulin. DDP4
inhibitors were weight neutral.

More GI side effects were reported in GLP-1, risk ratio 2.9 (95CIs, 2.0 - 4.2) for
nausea; 3.2 (95CIs, 2.5 - 4.4) for vomiting. DDP4 inhibitors had an increased
risk of infection and headache, risk ratio 1.2 (95CIs, 1.0 – 1.4) for
nasopharyngitis, 1.5 (95CIs, 1.0 - 2.2) for UTI and 1.4 (95CIs, 1.1 - 1.7) for
headache.
Conclusions:

Incretin-based therapy with GLP-1 analogues or DDP4 inhibitors is moderately




effective in improving glycemia in adults with type II diabetes.
Incretin therapy decreased both fasting and postprandial glycemia but more
declined on postprandial and the effect is dose-dependent.
GLP-1 has favorable effect on weight; DDP4 has neutral effect on weight.
The low risk of hypoglycemia in incretin therapy offers an advantage over other
therapies.
The most common adverse effects with GLP-1 were nausea and vomiting
(possibly due to the inhibition of gastric emptying). This study also found DDP4
inhibitors may increase risk of infection, such as urinary tract infection and
nasopharygitis. (questionable long-term effects on immune function)
Limitations:

The longest study duration is 30 weeks in only 3 studies. Therefore, long-term
efficacy and safety of incretin therapy were not able to assess.

All selected trials were included predominantly white participants. Therefore,
differential effects of incretin-based therapy by race or ethnicity could not be
assessed.
The glycemic efficacy maybe overestimated due to high dropout rate (~20% )
and use of all treated patients analysis instead of intention-to-treat analysis.
Clinical impact:

Incretin therapy offers a new alternative option for treating adults with type 2
diabetes; especially for those are at risk of hypoglycemic events and in need of
weight loss.

Insufficient data of effects on pancreas. Questions on GLP-1 expanding
pancreatic B-cell mass and proliferating B-cells. The are case reports of

pancreatitis caused by exenatide.
Will need post-surveillance study to assess the effects of long-term use DDP4
inhibitors on immune system.
Reference:

RE. Amori, JL. Lau, AG Pittas. Efficacy and safety of incretin therapy in type 2
diabetes: systematic review and meta-analysis. JAMA. 2007; 298(2): 194-206.

Sten Madsbad. Treatment of type 2 diabetes with incretin-based therapies. The
Lancet online published. 2008, 6736(08): 61246-5

Figure 2. Weighted Mean Difference in Change in Hemoglobin A1c Percentage Value for GLP-1 Analogues vs
Control in Adults With Type 2 Diabetes
Figure 3. Weighted Mean Difference in Change in Hemoglobin A1c Percentage Value for DPP4 Inhibitors vs
Control in Adults With Type 2 Diabetes. The I 2 statistic describes the percentage of total variation across studies
that is due to heterogeneity rather than chance. CI indicates confidence interval; DPP4, dipeptidyl peptidase 4.