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Clinical Review | Clinician's Corner

Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes FREE

Olivia J. Phung, PharmD; Jennifer M. Scholle, PharmD; Mehak Talwar, BS; Craig I. Coleman, PharmD
[+] Author Affiliations

Author Affiliations: University of Connecticut School of Pharmacy, Storrs, and Drug Information Center, Hartford Hospital, Hartford, Connecticut.


JAMA. 2010;303(14):1410-1418. doi:10.1001/jama.2010.405.
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Context Metformin is the recommended initial drug therapy for patients with type 2 diabetes mellitus (DM). However, the optimal second-line drug when metformin monotherapy fails is unclear.

Objective To determine the comparative efficacy, risk of weight gain, and hypoyglycemia associated with noninsulin antidiabetic drugs in patients with type 2 DM not controlled by metformin alone.

Data Sources A literature search via MEDLINE (beginning in January 1950) and Cochrane CENTRAL through January 2010 and a manual search of references for additional relevant studies.

Study Selection Randomized controlled trials (RCTs) with at least 3 months’ duration, evaluating noninsulin antidiabetic drugs added to metformin in patients experiencing an inadequate response to maximized and stable (≥4 weeks at ≥1500 mg or maximally tolerated dose) metformin therapy.

Data Extraction Inclusion/exclusion criteria; duration of patient follow-up; drug, dose, and schedule used; use of concurrent lifestyle modification; and baseline characteristics (age, sex, anthropometrics, glycated hemoglobin A1c [HbA1c], duration of DM, and metformin dose). End points collected included mean change in HbA1c, proportion of patients achieving HbA1c goal of less than 7%, change in weight, and incidence of hypoglycemia. Mixed-treatment comparison meta-analysis was used to calculate the weighted mean difference for changes from baseline in HbA1c and body weight and relative risk (RR) of HbA1c goal attainment and hypoglycemia, with associated 95% credible intervals.

Data Synthesis Overall, 27 RCTs (n = 11 198) were included. Mean (range) trial duration was 32 (12-52) weeks. The different classes of drugs were associated with similar HbA1c reductions (range, 0.64%-0.97%) compared with placebo. Although use of thiazolidinediones, sulfonylureas, and glinides were associated with weight gain (range, 1.77-2.08 kg), glucagon-like peptide-1 analogs, α-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo (RR range, 4.57-7.50).

Conclusion When added to maximal metformin therapy, all noninsulin antidiabetic drugs were associated with similar HbA1c reductions but differed in their associations with weight gain and risk of hypoglycemia.

Figures in this Article

Quiz Ref IDThe American Diabetes Association (ADA) recommends metformin and lifestyle modifications for initial pharmacological therapy of type 2 diabetes mellitus (DM).1 However, due to the progressive nature of the disease, most patients will require the use of combination pharmacological therapy to reach therapeutic goals. The ADA recommends adding a sulfonylurea or insulin when metformin monotherapy is insufficient to reach or maintain target goals.1 The thiazolidinedione pioglitazone may be recommended when the risk of hypoglycemia is especially undesirable, and the glucagon-like peptide-1 (GLP-1) analog exenatide may be recommended if weight loss is a major goal of therapy.1 Remaining drugs (glinides, α-glucosidase inhibitors [AGIs], and dipeptidyl peptidase-4 [DPP-4] inhibitors) get only cursory mention in the ADA guidelines due to limited data supporting their relative efficacy.1

Much of the available literature in type 2 DM evaluates antidiabetic drugs as monotherapy or in combination with drugs other than metformin.2,3 However, the efficacy of an agent may be smaller when combined with another drug compared with the agent as monotherapy.2 Furthermore, patients with uncontrolled disease while receiving metformin monotherapy may differ from those with uncontrolled DM while receiving other types of monotherapies either in individual patient characteristics or their disease progression, thereby affecting their response to different classes of drugs. Because the current recommendations from the ADA do not address these concerns, our goal was to evaluate the efficacy of antidiabetic drugs for second-line therapy in addition to stable doses of metformin in a mixed-treatment comparison meta-analysis. A mixed-treatment comparison method was selected specifically to allow the use of direct comparisons and the indirect estimates via a network of trials.

Study Selection

A systematic literature search for all relevant articles through January 2010 was conducted in MEDLINE (beginning January 1950) and Cochrane CENTRAL. The search strategy combined the Medical Subject Headings and keywords metformin with terms for type 2 DM (type 2 diabetes mellitus, T2DM, noninsulin dependent diabetes, NIDDM) and for glycated hemoglobin A1c (glycosylated hemoglobin, hemoglobin A1c, HbA1c, A1c). No language restrictions were imposed. For our MEDLINE search, we used the Cochrane Collaboration's Highly Sensitive Search Strategy sensitivity maximizing version for randomized controlled trials (RCTs).4 A manual search of references from reports of clinical trials or review articles was performed to identify additional relevant studies. When applicable, efforts were made to contact investigators for clarification or additional data. Two investigators (O.J.P. and C.I.C.) reviewed all potentially relevant articles independently.

Trials were included in the analysis if they (1) were parallel-design RCTs; (2) compared noninsulin antidiabetic drugs with either placebo or another noninsulin antidiabetic drug in addition to metformin in all treatment groups; (3) treated patients for at least 12 weeks but no more than 52 weeks after randomization; (4) included only patients who showed inadequate response to stable metformin monotherapy at randomization; and (5) reported outcomes of glycated hemoglobin A1c (HbA1c).3 For the purposes of our meta-analysis, the criterion of stable metformin monotherapy was considered met if a study included patients who received a total metformin dose of at least 1500 mg/d maintained for at least the preceding 4 weeks before randomization or if the total dose was at least 1000 mg/d for at least the preceding 4 weeks before randomization (allowing a patient to have a lower dose only if specified as the maximally tolerated dose), as long as the mean metformin dose of enrolled patients was at least 1500 mg/d during the study.

Trials that included patients not previously taking metformin monotherapy (including those receiving sulfonylureas, thiazolidinediones, or other nonmetformin therapies) were eligible if they assigned patients to a metformin monotherapy titration and dose-stable period of at least 4 weeks before randomization. Trials were excluded if they evaluated the addition of more than 1 drug to metformin, participants were not considered to have inadequate response to a stable metformin monotherapy, participants were taking background therapies other than metformin, or they evaluated insulin. Although insulin is generally considered the most effective antidiabetic treatment in patients with type 2 DM, it was not evaluated in this mixed-treatment comparison because unlike other medications, it is conceivable that any degree of hyperglycemia can be corrected by insulin treatment, provided adequate doses are administered (because the therapeutic effect of insulin maintains a dose-response relationship in virtually any dose range).1,3

Validity Assessment

Validity assessment was performed by using the Jadad scale.5 The Jadad scale assesses inherent controllers of bias by assessing randomization, double-blinding, and patient withdrawals. These individual components were assessed and an aggregate score was calculated for each included trial (0 = weakest, 5 = strongest). Trials scoring less than 3 were deemed to have lower methodological quality. All trials were reviewed and graded by 2 investigators (O.J.P. and J.M.S.) independently. Disagreement was resolved through discussion.

Data Abstraction

Two investigators (O.J.P. and J.M.S.), through use of a standardized tool, independently abstracted all data with disagreements resolved by discussion.4 The following information was sought from each trial (1) author identification; (2) year of publication; (3) study design and method quality; (4) sample size; (5) inclusion/exclusion criteria; (6) duration of follow-up; (7) drug, dose, and schedule used; (8) use of concurrent lifestyle modification (diet, exercise, or both); and (9) baseline characteristics (age, sex, anthropometrics, HbA1c, duration of DM, and metformin dose). End points collected included mean change in HbA1c, number of patients achieving HbA1c goal of less than 7%, change in weight, and incidence of hypoglycemia.1 In cases in which there was more than 1 published article on the same population, the longest duration of follow-up (between 12 and 52 weeks) was incorporated into the meta-analysis, although all records were maintained for determining study design characteristics.

Statistical Analysis

Traditional meta-analyses analyzing changes in HbA1c and body weight as continuous variables were undertaken. Separate analyses were conducted for each class of oral antidiabetic drug. In all cases, weighted mean differences (WMDs) and associated 95% confidence intervals (CIs) were calculated using a DerSimonian and Laird random-effects model.6 Net changes in each study variable were calculated as the difference between treatment groups in the changes (baseline − follow-up) in these mean values (also referred to as the change score). In instances where variances for net changes were not reported directly, they were calculated from CIs, P values, or individual variances. When the variance for paired differences was not reported, we calculated it from variances at baseline and at the end of follow-up.

As suggested by Follmann et al,7 we assumed a correlation coefficient of 0.5 between initial and final values. Achievement of HbA1c goal of less than 7% and overall hypoglycemic events were meta-analyzed as dichotomous end points, with weighted averages reported as relative risks (RRs) and associated 95% CIs. Again, a DerSimonian and Laird random-effects model was used.6 The likelihood of statistical heterogeneity was assessed by using the I2 statistic (I2>50% was considered representative of important statistical heterogeneity). Traditional meta-analysis was performed by using StatsDirect statistical software version 2.4.6 (StatsDirect Ltd, Cheshire, England). P<.05 was considered statistically significant.

In addition to traditional meta-analysis, a mixed-treatment comparison meta-analysis was conducted to compare the different oral antidiabetic drug treatment classes (sulfonylureas, glinides, thiazolidinediones, AGIs, DPP-4 inhibitors, and GLP-1 analogs). Along with analyzing the direct within-trial comparisons between 2 treatments (such as thiazolidinediones vs placebo), the mixed-treatment comparison framework enables incorporation of indirect comparisons constructed from 2 trials that have 1 treatment in common, such as thiazolidinediones vs placebo and placebo vs sulfonylureas, allowing the indirect comparison of thiazolidinediones with sulfonylureas. This type of analysis safeguards the within-trial randomized treatment comparison of each trial while combining all available comparisons between treatments. Mixed-treatment comparison analyses were conducted by using a Bayesian Markov chain Monte Carlo method and fitted in the freely available Bayesian software, WinBUGS (available at http://www.mrc-bsu.cam.ac.uk/bugs).8,9

Mixed-treatment comparison methods were used to calculate the WMDs of HbA1c and body weight, and RRs for achievement of HbA1c goal of less than 7% and occurrence of hypoglycemia for all treatments relative to placebo (referent), with accompanying 95% credible intervals (CrIs). In all cases, a random-effects model was fitted. Residual deviance was calculated for each outcome. Within a Bayesian framework, a residual deviance that approximates the number of unconstrained data points within the model suggests a good fit.8

The degree of incoherence between mixed-treatment comparison and traditional meta-analysis results was assessed through qualitatitive comparison of results for each matched drug-drug comparison derived from both meta-analytic methods. In the absence of marked differences in effect size, the traditional and mixed-treatment comparison meta-analyses were considered to provide coherent results.

To assess the potential confounding effect of heterogeneity on our results, subgroup and sensitivity analyses were performed on the change in HbA1c end point, by which trials were stratified by patient or trial characteristics and data from specific trials reanalyzed. Baseline disease severity was considered by performing subgroup analysis according to baseline HbA1c, evaluating trials with baseline HbA1c of less than 8% and those with baseline HbA1c of 8% or more. Trials of shorter duration (12-24 weeks inclusive) and those of longer duration (>24 weeks) were analyzed separately in subgroup analyses. In addition, a sensitivity analysis was performed whereby the meta-analysis was reanalyzed, excluding studies with a Jadad score of less than 3.

Study Characteristics

Of the 410 nonduplicate citations identified from the literature search, 45 full-text articles were screened for eligibility (Figure). Assessment of the full-text articles revealed that 2 were not parallel-design RCTs and 12 did not evaluate patients receiving a stable dose of metformin. Thirty-one articles were eligible for inclusion, representing 27 unique RCTs.1040 Twenty-six articles reported a change in HbA1c, 13 reported HbA1c goal achieved, 15 reported a change in body weight, and 24 reported hypoglycemia. Nine studies were not included in the body weight analysis because measures of variance (SD, SE, or 95% CI) for changes in body weight were not reported in these studies.10,12,19,25,27,28,30,31,36,40 Attempts to obtain this information from authors were unsuccessful.

Place holder to copy figure label and caption
Figure. Flow Diagram of RCTs Evaluating the Use of Noninsulin Antidiabetic Drugs Added to Metformin in Patients With Type 2 Diabetes
Graphic Jump Location

RCTs indicate randomized controlled trials.

aProvided information about study design or patient demographics.

A total of 27 RCTs (n = 11 198 participants; age range, 53-62 years; 23%-75% were men; mean [range] trial duration, 32 [12-52] weeks; and baseline HbA1c range, 6.4%-9.3%) met all of the inclusion criteria (eTable) and reported outcomes (Table 1). eFigure 1, eFigure 2, eFigure 3, eFigure 4, and eFigure 5 illustrate the network of clinical trials according to the comparison of specific classes of noninsulin antidiabetic drugs for the overall body of literature and for each outcome evaluated.

Table Graphic Jump LocationTable 1. Outcomes Reported by RCTs Evaluating Noninsulin Antidiabetic Drugs Added to Metformin in Patients With Type 2 Diabetes
Change in HbA1c and HbA1c Goal

Quiz Ref IDAll classes of antidiabetic drugs were associated with statistically significant reductions in HbA1c compared with placebo in both traditional and mixed-treatment comparison meta-analyses (Table 2, eFigure 2, and eFigure 6). In the mixed-treatment comparison meta-analysis, sulfonylureas (0.79% reduction; 95% CrI, 0.62%-0.97%), glinides (0.65% reduction; 95% CrI, 0.36%-0.97%), thiazolidinediones (0.85% reduction; 95% CrI, 0.66%-1.08%), AGIs (0.64% reduction; 95% CrI, 0.26%-1.03%), DPP-4 inhibitors (0.78% reduction; 95% CrI, 0.64%-0.93%), and GLP-1 analogs (0.97% reduction; 95% CrI, 0.65%-1.30%) were associated with significant reductions in HbA1c compared with placebo. Good model fit was suggested by a calculated residual deviance similar to the number of unconstrained data points (45 and 48, respectively). Review of funnel plots and Egger weighted regression statistic P values suggested a low likelihood of publication bias in all traditional analyses (all P > .25). Results of mixed-treatment comparison meta-analysis were coherent with results of traditional meta-analysis (eFigure 2).

Table Graphic Jump LocationTable 2. Results of Traditional Meta-analysis Comparing Noninsulin Antidiabetic Drugs With Placebo on Change in HbA1c, HbA1c Goal Achieved, Change in Body Weight, and Overall Hypoglycemia

All classes of antidiabetic drugs were significantly more likely to achieve the HbA1c goal compared with placebo in both traditional and mixed-treatment comparison meta-analyses (Table 2, eFigure 3, and eFigure 6). In mixed-treatment comparison meta-analysis, sulfonylureas (RR, 2.49; 95% CrI, 1.95-3.32), glinides (RR, 2.25; 95% CrI, 1.48-3.90), thiazolidinediones (RR, 2.71; 95% CrI, 1.74-3.80), DPP-4 inhibitors (RR, 2.51; 95% CrI, 2.04-3.22), and GLP-1 analogs (RR, 3.20; 95% CrI, 2.01-6.24) were associated with increased rates of achieving the HbA1c goal. However, there were insufficient data to evaluate AGIs for this outcome. Good model fit was suggested by a calculated residual deviance similar to the number of unconstrained data points (33 and 28, respectively). Results of mixed-treatment comparison meta-analysis were coherent with results of traditional meta-analysis (eFigure 3).

When evaluating the subgroup of studies in mixed-treatment comparison with baseline HbA1c of less than 8%, we found an association with greater decreases in HbA1c with sulfonylurea, glinide, thiazolidinedione, and DPP-4 inhibitor treatment compared with placebo (Table 3). In patients with baseline HbA1c of 8% or more, there was also an association with greater decreases in HbA1c with sulfonylurea, glinide, thiazolidinedione, AGI, DPP-4 inhibitor, and GLP-1 analog treatment compared with placebo. When evaluating the subgroup of studies in mixed-treatment comparison lasting 12 to 24 weeks, an association was found with greater decreases in HbA1c with sulfonylurea, glinide, thiazolidinedione, and DPP-4 inhibitor treatment compared with placebo. In studies lasting more than 24 weeks in duration, there was also an association with greater HbA1c reductions with sulfonylurea, glinide, thiazolidinedione, AGI, DPP-4 inhibitor, and GLP-1 analog treatment compared with placebo. All of the above-mentioned subgroup analyses provided results consistent with our base case analysis. With sensitivity analysis, there was no significant change from results reported above when studies with a Jadad score of less than 3 were excluded from the analysis.

Table Graphic Jump LocationTable 3. Results of Sensitivity and Subgroup Mixed-Treatment Comparison Meta-analysis of Change in HbA1c Presented as WMD
Body Weight

Quiz Ref IDSulfonylurea, glinide, and thiazolidinedione treatments were associated with increases in body weight compared with placebo in mixed-treatment comparison, with gains in body weight of 2.06 kg (95% CrI, 1.15-2.96 kg), 1.77 kg (95% CrI, 0.46-3.28 kg), and 2.08 kg (95% CrI, 0.98-3.17 kg), respectively (eFigure 4 and eFigure 6). There was no weight change with AGIs (WMD, −1.80 kg; 95% CrI, −3.79 to 0.21 kg) or DPP-4 inhibitors (WMD, −0.14 kg; 95% CrI, −0.94 to 0.63 kg). The GLP-1 analogs were associated with significant weight loss (WMD, −1.74 kg; 95% CrI, −3.11 to −0.48 kg). Good model fit was suggested by a calculated residual deviance similar to the number of unconstrained data points (27 and 29, respectively). Results of mixed-treatment comparison meta-analysis were coherent with results of traditional meta-analysis (eFigure 4).

Hypoglycemia

Quiz Ref IDIn mixed-treatment comparison meta-analysis, sulfonylurea (RR, 4.57; 95% CrI, 2.11-11.45) and glinide (RR, 7.50; 95% CrI, 2.12-41.52) treatments were associated with increased risk of hypoglycemia compared with placebo (eFigure 5 and eFigure 6). Thiazolidinediones (RR, 0.56; 95% CrI, 0.19-1.69), AGIs (RR, 0.42; 95% CrI, 0.01-9.00), DPP-4 inhibitors (RR, 0.63; 95% CrI, 0.26-1.71), and GLP-1 analogs (RR, 0.89; 95% CrI, 0.22-3.96) were not associated with increased risk of hypoglycemia compared with placebo. Good model fit was suggested by a calculated residual deviance similar to the number of unconstrained data points (50 and 50, respectively). Results of mixed-treatment comparison meta-analysis were coherent with results of traditional meta-analysis (eFigure 5).

The ADA recommends drug therapy for treatment of type 2 DM based on the drug's ability to reduce hyperglycemia.1 The ADA recommends that patients inadequately treated with metformin monotherapy (and lifestyle modification) should be initiated on either sulfonylureas or insulin.1 Pioglitazone and the GLP-1 analog exenatide may also be selected and are listed as tier 2 drugs. However, the remaining drug classes (glinides, AGIs, and DPP-4 inhibitors) get only cursory mention due to the limited data supporting their efficacy.1 Through conducting this mixed-treatment comparison and traditional meta-analysis, we determined the comparative efficacy (comparisons resulting from direct and indirect evidence) of different classes of noninsulin antidiabetic drugs. Traditional meta-analysis revealed HbA1c reductions ranging between 0.62% and 1.00% in patients treated with various adjunctive drugs (added to inadequate, stable metformin) vs placebo. Patients treated with each adjunctive drug also had an increased RR of achieving an HbA1c goal of less than 7% (RR range, 1.69-3.96) compared with placebo.

Our change in HbA1c results were similar to a previous meta-analysis evaluating antidiabetic drug additions to metformin, in which HbA1c reductions ranged between 0.42% and 0.85% vs placebo.3 The previous meta-analysis evaluated trials of sulfonylureas, glinides, thiazolidindiones, AGIs, and GLP-1 analogs, but not DPP-4 inhibitors.3 Furthermore, the meta-analysis by Monami et al3 did not use methods for incorporating indirect comparisons, and therefore was unable to assess the comparative efficacy of drugs. Our mixed-treatment comparison meta-analysis demonstrated that the different classes of drugs provided similar reductions in HbA1c (range, 0.64%-0.97%) compared with placebo. The US Food and Drug Administration considers a margin of 0.4% to be the upper margin of noninferiority between drugs.41 Despite this, the ADA guidelines do not suggest that these drugs have similar glucose-lowering ability. The rate of HbA1c goal attainment was also similar among classes of drugs (RR range, 2.25-3.20) using mixed-treatment comparison meta-analysis, with no statistically significant differences between noninsulin antidiabetic drugs.

In addition to demonstrating comparative efficacy of antidiabetic drugs, our meta-analysis also evaluated their associations with hypoglycemia and weight gain. In patients with type 2 DM, many are obese or overweight and have other comorbidities that can be affected by body weight.42 Potential increases in body weight due to antidiabetic drugs may negatively influence patient health by increasing the risk of cardiovascular disease43 and should be a consideration when selecting drug therapy. Our mixed-treatment comparison meta-analysis demonstrated that glinides, sulfonylureas, and thiazolidinediones were associated with weight gain ranging between 1.77 kg and 2.08 kg compared with placebo. Glinides and sulfonylureas likely promote weight gain by increasing insulin secretion. Thiazolidinediones likely promote weight gain by increasing fluid retention.44,45 Glucagon-like peptide-1 analogs, AGIs, and DPP-4 inhibitors resulted in weight loss or no change in weight. Compared with sulfonylureas and thiazolidinediones, GLP-1 analogs were associated with an approximately 4-kg difference in weight, which in some patients may be close to the clinically relevant weight reduction value of 5% typically associated with decreased insulin resistance and improvements in serum lipids and blood pressure.42 Glucagon-like peptide-1 analogs may promote weight loss by increasing satiety and prolonging gastric emptying time.46 α-Glucosidase inhibitors likely promote weight loss by decreased caloric absorption and as a result of gastrointestinal adverse effects.1

The ADA guidelines emphasize the prevention of hypoglycemia as critical to the treatment strategy in type 2 DM.42 Therefore, considering a drug's hypoglycemic rate is warranted when selecting a drug. Although mild hypoglycemia produces bothersome symptoms, excessive decrease in blood glucose is associated with complications, including coma, cardiac arrhythmias, or myocardial ischemia.47 Of the studies that reported hypoglycemia, patients receiving sulfonylureas or glinides experienced higher rates of hypoglycemia than placebo (RR range, 4.57-7.50). This increased risk is likely related to the increase in insulin release, which may occur independent of the presence of a glucose load.48 The remaining drugs did not exhibit statistically significant differences in hypoglycemia risk compared with placebo.

Quiz Ref IDIn addition to the efficacy and safety aspects evaluated by this meta-analysis, considerations of contraindications (eg, heart failure, renal dysfunction), other adverse effects (eg, bone fracture, pancreatitis, or cardiovascular, gastrointestinal, and renal dysfunction), other therapeutic benefits (eg, pleiotrophic effects), or cost may guide selection of therapy. Due to the limited reporting of these outcomes in RCTs, these were not included in our traditional or mixed-treatment comparison meta-analyses. Although DPP-4 inhibitors and GLP-1 analogs are associated with no change in weight or weight loss, they are not available as generic products. Monthly costs for sitagliptin or exenatide range between US $200 and $250, but sulfonylureas may have monthly costs as low as $5.49

Our meta-analysis had limitations. Limitations typically observed in traditional meta-analysis, such as variations in treatment regimens or populations (heterogeneity), also apply to mixed-treatment comparison meta-analysis. Although estimates from the mixed-treatment comparison meta-analysis cannot simply be assumed accurate, we believe the reliability and robustness of our results are supported by (1) well-defined and strict inclusion and exclusion criteria, (2) observed goodness of model fit, (3) qualitative assessment demonstrating strong coherence, and (4) similarity of conclusions in subgroup and sensitivity analysis. Although many trials reported changes in body weight, data from some trials could not be meta-analyzed because measures of variance (SD, SE, or 95% CI) were not reported.10,12,19,25,27,28,30,31,36,40 The underreporting of weight outcomes in these trials may reflect an underappreciation of the effect of treatment on body weight by investigators. Associations of weight gain or loss on serum lipids or blood pressure could not be assessed in our meta-analysis because these end points were not reported. Future studies should report these end points. We could not assess the effect of AGIs on attainment of an HbA1c goal because trials evaluating AGIs did not report this end point. Therefore, we are unable to provide conclusions about the ability of AGIs to reach HbA1c goal. Another limitation of our meta-analysis is that the duration of type 2 DM in patients in the studies ranged between 4.6 and 10.7 years, which may influence the efficacy of certain classes of drugs. In particular, sulfonylureas may have decreased efficacy in patients who have had DM for at least 6 years, because of pancreatic β-cell decline that goes along with the disease progression.50 Additionally, the duration of prior metformin use may influence responsiveness to additional antidiabetic drugs, but this was not assessed due to the underreporting of this patient characteristic. Although the duration of prior metformin treatment may differ between trials, the use of randomization would likely have attenuated intrastudy variation.

In conclusion, noninsulin antidiabetic drugs when combined with metformin lowered HbA1c to a similar degree; however, these drugs did not perform similarly in terms of body weight change and rates of hypoglycemia. These factors and other considerations should be taken into account when selecting a second-line treatment to add to stable, maximum metformin therapy.

Corresponding Author: Craig I. Coleman, PharmD, University of Connecticut School of Pharmacy, 80 Seymour St, Hart- ford, CT 06102-5037 (ccolema@harthosp.org).

Author Contributions: Drs Phung and Coleman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Phung, Coleman.

Acquisition of data: Phung, Scholle, Talwar, Coleman.

Analysis and interpretation of data: Phung, Scholle, Coleman.

Drafting of the manuscript: Phung, Scholle, Talwar.

Critical revision of the manuscript for important intellectual content: Phung, Scholle, Coleman.

Statistical analysis: Phung, Scholle.

Obtained funding: Phung, Coleman.

Administrative, technical, or material support: Phung, Scholle, Talwar, Coleman.

Study supervision: Coleman.

Financial Disclosures: Drs Phung and Coleman reported previously receiving research support from Takeda Pharmaceuticals North America, a manufacturer of antidiabetic drugs. Dr Scholle and Ms Talwar reported no disclosures.

Funding/Support: This work was supported financially by the Hartford Hospital Research Foundation, Hartford, Connecticut.

Role of the Sponsor: The Hartford Hospital Research Foundation had no role in the design and conduct of the study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank the Hartford Hospital Research Foundation, Hartford, Connecticut, for the financial support of this study. Nancy White (Department of Research Administration, Hartford Hospital, Hartford, Connecticut) provided editing assistance without compensation.

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Hamann A, Garcia-Puig J, Paul G, Donaldson J, Stewart M. Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with type 2 diabetes inadequately controlled on metformin alone.  Exp Clin Endocrinol Diabetes. 2008;116(1):6-13
PubMed   |  Link to Article
Khanolkar MP, Morris RHK, Thomas AW,  et al.  Rosiglitazone produces a greater reduction in circulating platelet activity compared with gliclazide in patients with type 2 diabetes mellitus: an effect probably mediated by direct plately PPARγ activation.  Atherosclerosis. 2008;197(2):718-724
PubMed   |  Link to Article
Raz I, Chen Y, Wu M,  et al.  Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes.  Curr Med Res Opin. 2008;24(2):537-550
PubMed   |  Link to Article
Scott R, Loeys T, Davies MJ, Engel SS.Sitagliptin Study 801 Group.  Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes.  Diabetes Obes Metab. 2008;10(10):959-969
PubMed   |  Link to Article
Ahrén B, Pacini G, Tura A, Foley JE, Schweizer A. Improved meal-related insulin processing contributes to the enhancement of B-cell function by the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes.  Horm Metab Res. 2007;39(11):826-829
PubMed   |  Link to Article
Ahrén B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes.  Diabetes Care. 2004;27(12):2874-2880
PubMed   |  Link to Article
Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin.  Diabetes Care. 2007;30(4):890-895
PubMed   |  Link to Article
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP.Sitagliptin Study 024 Group.  Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial.  Diabetes Obes Metab. 2007;9(2):194-205
PubMed   |  Link to Article
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G.Sitagliptin Study 020 Group.  Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.  Diabetes Care. 2006;29(12):2638-2643
PubMed   |  Link to Article
Garber A, Klein E, Bruce S, Sankoh S, Mohideen P. Metformin-glibenclamise versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.  Diabetes Obes Metab. 2006;8(2):156-163
PubMed   |  Link to Article
Ristic S, Collober-Maugeais C, Pecher E, Cressier F. Comparison of nateglinide and gliclazide in combination with metformin, for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone.  Diabet Med. 2006;23(7):757-762
PubMed   |  Link to Article
Ristic S, Collober-Maugeais C, Cressier F, Tang P, Pecher E. Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum dose of metformin alone: 1-year trial results.  Diabetes Obes Metab. 2007;9(4):506-511
PubMed   |  Link to Article
DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.  Diabetes Care. 2005;28(5):1092-1100
PubMed   |  Link to Article
Feinglos M, Dailey G, Cefalu W,  et al.  Effect on glycemin control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM.  Diabetes Res Clin Pract. 2005;68(2):167-175
PubMed   |  Link to Article
Matthews DR, Charbonnel BH, Hanefeld M, Brunetti P, Schernthaner G. Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study.  Diabetes Metab Res Rev. 2005;21(2):167-174
PubMed   |  Link to Article
Gómez-Perez FJ, Fanghänel-Salmón G, Antonio Barbosa J,  et al.  Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes.  Diabetes Metab Res Rev. 2002;18(2):127-134
PubMed   |  Link to Article
Marre M, Van Gaal L, Usadel K-H, Ball M, Whatmough I, Guitard C. Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients.  Diabetes Obes Metab. 2002;4(3):177-186
PubMed   |  Link to Article
Charpentier G, Fleury F, Kabir M, Vaur L, Halimi S. Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients.  Diabet Med. 2001;18(10):828-834
PubMed   |  Link to Article
Van Gaal L, Maislos M, Schernthaner G, Rybka J, Segal P. Miglitol combined with metformin improves glycaemic control in type 2 diabetes.  Diabetes Obes Metab. 2001;3(5):326-331
Link to Article
Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus.  JAMA. 2000;283(13):1695-1702
PubMed   |  Link to Article
Halimi S, Le Berre MA, Grangé V. Efficacy and safety of acarbose add-on therapy in the treatment of overweight patients with type 2 diabetes inadequately controlled with metformin: a double-blind, placebo-controlled study.  Diabetes Res Clin Pract. 2000;50(1):49-56
PubMed   |  Link to Article
Moses R, Slobodniuk R, Boyages S,  et al.  Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes.  Diabetes Care. 1999;22(1):119-124
PubMed   |  Link to Article
Moses R. Repaglinide in combination therapy with metformin in type 2 diabetes.  Exp Clin Endocrinol Diabetes. 1999;107:(suppl 4)  S136-S139
PubMed   |  Link to Article
Rosenstock J, Brown A, Fischer J,  et al.  Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes.  Diabetes Care. 1998;21(12):2050-2055
PubMed   |  Link to Article
US Food and Drug Administration.  Guidance for industry: diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf. Accessed May 20, 2009
American Diabetes Association.  Standard of medical care in diabetes—2010.  Diabetes Care. 2010;33:(suppl 1)  S11-S61
PubMed   |  Link to Article
Guh DP, Zhang W, Bansback N, Amarsi C, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis.  BMC Public Health. 2009;9:88
PubMed   |  Link to Article
 Actos (pioglitazone) [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2008
 Avandia (rosiglitazone) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009
 Byetta (exenatide) [package insert]. San Diego, CA: Amylin Pharmaceuticals Inc; 2009
Frier BM. How hypoglycaemia can affect the life of a person with diabetes.  Diabetes Metab Res Rev. 2008;24(2):87-92
PubMed   |  Link to Article
Nathan DM. Initial management of glycemia in type 2 diabetes mellitus.  N Engl J Med. 2002;347(17):1342-1349
PubMed   |  Link to Article
 Drug Topics Red Book. 112th ed. Montvale, NJ: Thomson; 2008
Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective.  Metabolism. 2006;55(5):(suppl 1)  S2-S5
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure. Flow Diagram of RCTs Evaluating the Use of Noninsulin Antidiabetic Drugs Added to Metformin in Patients With Type 2 Diabetes
Graphic Jump Location

RCTs indicate randomized controlled trials.

aProvided information about study design or patient demographics.

Tables

Table Graphic Jump LocationTable 1. Outcomes Reported by RCTs Evaluating Noninsulin Antidiabetic Drugs Added to Metformin in Patients With Type 2 Diabetes
Table Graphic Jump LocationTable 2. Results of Traditional Meta-analysis Comparing Noninsulin Antidiabetic Drugs With Placebo on Change in HbA1c, HbA1c Goal Achieved, Change in Body Weight, and Overall Hypoglycemia
Table Graphic Jump LocationTable 3. Results of Sensitivity and Subgroup Mixed-Treatment Comparison Meta-analysis of Change in HbA1c Presented as WMD

References

Nathan DM, Buse JB, Davidson MB,  et al; American Diabetes Association; European Association for Study of Diabetes.  Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care. 2009;32(1):193-203
PubMed   |  Link to Article
DeFronzo RA, Goodman AM.The Multicenter Metformin Study Group.  Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus.  N Engl J Med. 1995;333(9):541-549
PubMed   |  Link to Article
Monami M, Lamanna C, Marchionni N, Mannucci E. Comparison of different drugs as add-on treatments to metformin in type 2 diabetes: a meta-analysis.  Diabetes Res Clin Pract. 2008;79(2):196-203
PubMed   |  Link to Article
Higgins JPT, ed, Green S, ed. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0. The Cochrane Collaboration; 2008. http://www.cochrane-handbook.org. Updated February 2008. Accessed May 20, 2009
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response.  J Clin Epidemiol. 1992;45(7):769-773
PubMed   |  Link to Article
Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons.  Stat Med. 2004;23(20):3105-3124
PubMed   |  Link to Article
Salanti G, Higgins JPT, Ades AE, Ioannidis JPA. Evaluation of networks of randomized trials.  Stat Methods Med Res. 2008;17(3):279-301
PubMed   |  Link to Article
DeFronzo RA, Hissa MN, Garber AJ,  et al; Saxagliptin 014 Study Group.  The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone.  Diabetes Care. 2009;32(9):1649-1655
PubMed   |  Link to Article
Ferrannini E, Fonseca V, Zinman B,  et al.  Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy.  Diabetes Obes Metab. 2009;11(2):157-166
PubMed   |  Link to Article
Goodman M, Thurston H, Penman J. Efficacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy.  Horm Metab Res. 2009;41(5):368-373
PubMed   |  Link to Article
Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q.Alogliptin Study 008 Group.  Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study.  Int J Clin Pract. 2009;63(1):46-55
PubMed   |  Link to Article
Nauck M, Frid A, Hermansen K,  et al; LEAD-2 Study Group.  Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes.  Diabetes Care. 2009;32(1):84-90
PubMed   |  Link to Article
Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study.  Diabetes Obes Metab. 2008;10(1):82-90
PubMed
Bolli G, Dotta F, Colin L, Minic B, Goodman M. Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin.  Diabetes Obes Metab. 2009;11(6):589-595
PubMed   |  Link to Article
Hamann A, Garcia-Puig J, Paul G, Donaldson J, Stewart M. Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with type 2 diabetes inadequately controlled on metformin alone.  Exp Clin Endocrinol Diabetes. 2008;116(1):6-13
PubMed   |  Link to Article
Khanolkar MP, Morris RHK, Thomas AW,  et al.  Rosiglitazone produces a greater reduction in circulating platelet activity compared with gliclazide in patients with type 2 diabetes mellitus: an effect probably mediated by direct plately PPARγ activation.  Atherosclerosis. 2008;197(2):718-724
PubMed   |  Link to Article
Raz I, Chen Y, Wu M,  et al.  Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes.  Curr Med Res Opin. 2008;24(2):537-550
PubMed   |  Link to Article
Scott R, Loeys T, Davies MJ, Engel SS.Sitagliptin Study 801 Group.  Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes.  Diabetes Obes Metab. 2008;10(10):959-969
PubMed   |  Link to Article
Ahrén B, Pacini G, Tura A, Foley JE, Schweizer A. Improved meal-related insulin processing contributes to the enhancement of B-cell function by the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes.  Horm Metab Res. 2007;39(11):826-829
PubMed   |  Link to Article
Ahrén B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes.  Diabetes Care. 2004;27(12):2874-2880
PubMed   |  Link to Article
Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin.  Diabetes Care. 2007;30(4):890-895
PubMed   |  Link to Article
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP.Sitagliptin Study 024 Group.  Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial.  Diabetes Obes Metab. 2007;9(2):194-205
PubMed   |  Link to Article
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G.Sitagliptin Study 020 Group.  Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.  Diabetes Care. 2006;29(12):2638-2643
PubMed   |  Link to Article
Garber A, Klein E, Bruce S, Sankoh S, Mohideen P. Metformin-glibenclamise versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.  Diabetes Obes Metab. 2006;8(2):156-163
PubMed   |  Link to Article
Ristic S, Collober-Maugeais C, Pecher E, Cressier F. Comparison of nateglinide and gliclazide in combination with metformin, for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone.  Diabet Med. 2006;23(7):757-762
PubMed   |  Link to Article
Ristic S, Collober-Maugeais C, Cressier F, Tang P, Pecher E. Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum dose of metformin alone: 1-year trial results.  Diabetes Obes Metab. 2007;9(4):506-511
PubMed   |  Link to Article
DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.  Diabetes Care. 2005;28(5):1092-1100
PubMed   |  Link to Article
Feinglos M, Dailey G, Cefalu W,  et al.  Effect on glycemin control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM.  Diabetes Res Clin Pract. 2005;68(2):167-175
PubMed   |  Link to Article
Matthews DR, Charbonnel BH, Hanefeld M, Brunetti P, Schernthaner G. Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study.  Diabetes Metab Res Rev. 2005;21(2):167-174
PubMed   |  Link to Article
Gómez-Perez FJ, Fanghänel-Salmón G, Antonio Barbosa J,  et al.  Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes.  Diabetes Metab Res Rev. 2002;18(2):127-134
PubMed   |  Link to Article
Marre M, Van Gaal L, Usadel K-H, Ball M, Whatmough I, Guitard C. Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients.  Diabetes Obes Metab. 2002;4(3):177-186
PubMed   |  Link to Article
Charpentier G, Fleury F, Kabir M, Vaur L, Halimi S. Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients.  Diabet Med. 2001;18(10):828-834
PubMed   |  Link to Article
Van Gaal L, Maislos M, Schernthaner G, Rybka J, Segal P. Miglitol combined with metformin improves glycaemic control in type 2 diabetes.  Diabetes Obes Metab. 2001;3(5):326-331
Link to Article
Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus.  JAMA. 2000;283(13):1695-1702
PubMed   |  Link to Article
Halimi S, Le Berre MA, Grangé V. Efficacy and safety of acarbose add-on therapy in the treatment of overweight patients with type 2 diabetes inadequately controlled with metformin: a double-blind, placebo-controlled study.  Diabetes Res Clin Pract. 2000;50(1):49-56
PubMed   |  Link to Article
Moses R, Slobodniuk R, Boyages S,  et al.  Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes.  Diabetes Care. 1999;22(1):119-124
PubMed   |  Link to Article
Moses R. Repaglinide in combination therapy with metformin in type 2 diabetes.  Exp Clin Endocrinol Diabetes. 1999;107:(suppl 4)  S136-S139
PubMed   |  Link to Article
Rosenstock J, Brown A, Fischer J,  et al.  Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes.  Diabetes Care. 1998;21(12):2050-2055
PubMed   |  Link to Article
US Food and Drug Administration.  Guidance for industry: diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf. Accessed May 20, 2009
American Diabetes Association.  Standard of medical care in diabetes—2010.  Diabetes Care. 2010;33:(suppl 1)  S11-S61
PubMed   |  Link to Article
Guh DP, Zhang W, Bansback N, Amarsi C, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis.  BMC Public Health. 2009;9:88
PubMed   |  Link to Article
 Actos (pioglitazone) [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2008
 Avandia (rosiglitazone) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009
 Byetta (exenatide) [package insert]. San Diego, CA: Amylin Pharmaceuticals Inc; 2009
Frier BM. How hypoglycaemia can affect the life of a person with diabetes.  Diabetes Metab Res Rev. 2008;24(2):87-92
PubMed   |  Link to Article
Nathan DM. Initial management of glycemia in type 2 diabetes mellitus.  N Engl J Med. 2002;347(17):1342-1349
PubMed   |  Link to Article
 Drug Topics Red Book. 112th ed. Montvale, NJ: Thomson; 2008
Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective.  Metabolism. 2006;55(5):(suppl 1)  S2-S5
PubMed   |  Link to Article
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