Skip to main content

Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus

Abstract

Background

The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine.

Methods

Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373.

Results

Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = − 0.12%, 95% CI, − 0.16 to − 0.07%) and weight reduction (ES = − 0.40 kg, 95% CI, − 0.50 to − 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = − 0.22%, 95% CI, − 0.32 to − 0.11%) versus oral types (ES = − 0.09%, 95% CI, − 0.14 to − 0.04%) in T2DM (P = 0.03). Older age (β = − 0.01, 95% CI, − 0.02 to − 0.01, P < 0.01) and longer diabetes duration (β = − 0.02, 95% CI, − 0.03 to − 0.21 × 10−2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10−2, 0.01, P < 0.01), higher baseline BMI (β = − 0.02, 95% CI, − 0.04 to − 0.26 × 10−2, P = 0.02), and higher baseline HbA1c (β = − 0.09, 95% CI, − 0.16 to − 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses.

Conclusion

The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.

Peer Review reports

Background

A placebo is defined as any therapy that is used for its non-specific psychological and physiologic effect, but has no demonstrated pharmacological effect on the condition being treated [1]. Pharmaceutical and clinical studies have used placebos as a methodological tool to avoid bias, and also to evaluate the pure therapeutic effect of interventional therapies, aiming to avoid introducing ineffective or even harmful treatments into clinical practice [1,2,3,4]. Placebo effect is even promoted as a potential treatment modality in medicine [1,2,3].

According to the expert consensus statement in placebo research field, placebo response, defined as any health change after the administration of placebo, including natural history of a disease or fluctuation of symptoms, response biases, effects of co-interventions, or statistical regression to the mean, has been widely observed in many clinical trials [5]. In fact, an increase in the magnitude of placebo response without significant change in the efficacy outcomes with respect to effect size and success rate is an emerging pattern over time in trials of many conditions, such as depression [6], epilepsy [7], and also diabetes mellitus (DM) [8]. A placebo has been widely used in clinical research in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). For example, the results of the new treatment were compared with placebo to prove the effect on glucose and body weight control. The placebo response was also used to estimate sample size in placebo-controlled trials and to evaluate the true effect size in active-controlled studies or real-world observational studies without a placebo group.

As for T2DM, the placebo response was previously reported by Khan et al. by analyzing the data from the U.S. Food and Drug Administration approved between 1999 and 2015 [8]. However, considering the increasing magnitude of placebo response and expanding clinical trial data, placebo response in T2DM, in terms of both glycemic and weight control, needs to be further evaluated and updated. Placebo response in T1DM has still not been systematically evaluated. Moreover, the potential factors associated with placebo response that might include patient age, gender, disease duration, follow-up duration, and ways of medication delivery have not been fully investigated and delineated. Knowledge from such investigations might suggest potential predictors for placebo responders and inform more precise clinical study design that allow more efficient efficacy evaluation of medical intervention in subpopulation of diabetes.

Since nonpharmacological interventions including behavior modification and nutritional therapies also play a role in glucose control in diabetes management, placebo response and its features mediated by psychosocial context may be more likely to be revealed in DM, which makes it an ideal model to explore placebo response. Therefore, we utilized the data of randomized controlled trials (RCTs) in both T1DM and T2DM and performed a meta-analysis to comprehensively outline the placebo response in DM. We also conducted the analysis for associated factors to propose a featured placebo response pattern associated with patient-level and study-level characteristics.

Methods

Data sources and searches

A systemic literature search was conducted for the published studies in the following databases: Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov website, from the inception of each databases until June 2019. A search strategy was performed by using the following terms: metformin (MET); sulfonylurea (SU); alpha glucosidase inhibitor (AGI); thiazolidinedione (TZD); pramlintide; dipeptidyl peptidase-4 (DPP-4) inhibitor; sodium-glucose cotransporter 2 (SGLT2) inhibitor; glucagon-like peptide-1 receptor agonist (GLP-1RA); T1DM; T2DM; placebo-controlled; RCTs; cardiovascular outcome and renal outcome. Searches were firstly performed in January 2014 and subsequently updated in December 2017 and June 2019. This meta-analysis was registered in PROSPERO as CRD42014009373.

Study selection

Studies were included in this meta-analysis if following criteria were met: (1) placebo-controlled, randomized trials; (2) trials in patients with T1DM and T2DM; and (3) trials with HbA1c level and body weight measured in both placebo and active treatment groups. The exclusion criteria were as follows: (1) trials in patients with gestational diabetes or pre-diabetes; (2) trials in which the anti-diabetic treatment in the placebo group could be changed during the period of study; (3) trials with active agent control; and (4) trials with cross-over study design.

Data extraction and quality assessment

Two investigators independently extracted data by using a standardized form. Information including author, publication year, patient age, and male percentage was obtained from each trial for both placebo and active treatment groups. Trials with placebo agents administered by oral route were grouped for oral placebo response, and trials with placebo agents administered by injection route were grouped for injectable placebo response. Any disagreement would be resolved by the discussion between two investigators under the supervision of a third independent investigator. By using the Cochrane instrument [9], we evaluated the quality of each RCT.

Data synthesis and analysis

Placebo response were evaluated as pooled effect size (ES) with 95% confidence intervals (CIs) of HbA1c and weight changes from baseline in placebo treatment group by synthesizing mean value with standard error. Higgins I2 statistics were used to evaluate the between-study heterogeneity. Random-effects model was used in the meta-analysis. Subgroup comparisons for pooled ES were performed within the framework of a meta-analysis. The associations of continuous variables with placebo response on HbA1c and weight changes, including age, male percentage, baseline BMI, baseline HbA1c, diabetes duration, and study duration, were calculated by meta-regression analysis. Since publication year is a discontinuous variable, the associations between it and placebo response on HbA1c as well as weight change were analyzed by ANOVA tendency test. Indirect comparisons between HbA1c reduction and elevation groups as well as between weight reduction and elevation groups were conducted by Mann-Whitney test. The results of indirect comparisons were expressed as median value with accompanying interquartile range (Q1, Q3).

Publication bias was evaluated by Egger’s test, with a P value > 0.05 indicating low risk of publication bias. Pool ES analyses and subgroup comparisons were conducted by Review Manager statistical software package (version 5.3, Nordic Cochrane Centre, Copenhagen, Denmark). Meta-regression analysis was performed by the STATA statistical software package (Version 11.0). Mann-Whitney test and ANOVA tendency analysis were conducted by SPSS software (SPSS 24.0. Armonk, NY: IBM Corp). We conducted this study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for conducting and reporting meta-analyses of RCTs.

Results

Overall characteristics

In all, 432 placebo-controlled clinical trials conducted in patients with DM were included, among which 41 trials were in T1DM with 4328 participants and 391 trials were in T2DM with 33,987 participants (Additional file 1: Figure S1). The baseline characteristics of enrolled RCTs were summarized in detail for T1DM (Additional file 1: Table S1) [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59] and T2DM (Additional file 1: Table S2) [60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432,433,434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450] respectively. The risk of bias was evaluated by the Cochrane instrument. In T1DM, there were 5 RCTs with high risk and 18 RCTs with uncertain risk of selection bias for random sequence generation, 4 RCTs with high risk and 15 RCTs with uncertain risk of selection bias for allocation concealment, and 5 RCTs with high risk of attrition bias (Additional file 1: Table S3). In T2DM, there were 8 RCTs with high risk and 15 RCTs with uncertain risk of selection bias for random sequence generation, 5 RCTs with high risk and 21 RCTs with uncertain risk of selection bias for allocation concealment, 22 RCTs with uncertain risk of performance bias, 13 RCTs with uncertain risk of detection bias, 37 RCTs with high risk and 30 RCTs with uncertain risk of attrition bias, and 12 RCTs with uncertain risk of reporting bias (Additional file 1: Table S4). The publication bias was accessed by Egger’s test in T1DM (t = − 0.29, P = 0.771) (Additional file 1: Figure S2) and T2DM (t = − 1.34, P = 0.179) (Additional file 1: Figure S3) respectively, which both turned out to be insignificant.

Overall placebo response

According to the meta-analysis, placebo treatment was generally associated with significantly HbA1c reduction (ES = − 0.11%, 95% CI, − 0.15 to − 0.07%) and weight reduction (ES = − 0.30 kg, 95% CI, − 0.40 to − 0.20 kg) in patients with DM (Table 1). As for specific DM types, significantly weight elevation (ES = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = − 0.12%, 95% CI, − 0.16 to − 0.07%) and weight reduction (ES = − 0.40 kg, 95% CI, − 0.50 to − 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup (Fig. 1). As for treatment design, significantly HbA1c elevation (ES = 0.08%, 95% CI, 0.01 to 0.16%) was shown in monotherapy subgroup while add-on therapy was significantly associated with HbA1c reduction (ES = − 0.20%, 95% CI, − 0.25 to − 0.15%). Furthermore, significantly weight reduction was observed in both monotherapy (ES = − 0.56 kg, 95% CI, − 0.73 to − 0.39 kg) and add-on therapy (ES = − 0.19 kg, 95% CI, − 0.32 to − 0.07 kg) subgroups (Table 1). However, no significant difference was revealed in placebo response from different treatment designs by subgroup comparisons in terms of HbA1c and weight change. In T1DM, significantly HbA1c reduction was observed in patients with injectable placebo treatment (Fig. 2). In T2DM, significantly HbA1c reduction and weight reduction were observed in both oral and injectable placebo treatment subgroups (Fig. 2). Moreover, the magnitude of HbA1c reduction was greater in patients with injectable placebo (ES = − 0.22%, 95% CI, − 0.32 to − 0.11%) treatment than oral ones (ES = − 0.09%, 95% CI, − 0.14 to − 0.04%, P for subgroup comparison = 0.03) (Table 1).

Table 1 Pooled estimated effect of placebo response in patients with diabetes mellitus
Fig. 1
figure1

Placebo response stratified by types of diabetes mellitus. a HbA1c change. b Weight change

Fig. 2
figure2

Placebo response stratified by administration routes. a HbA1c change. b Weight change

Placebo response stratified by hypoglycemic comparators

Placebo responses stratified by hypoglycemic comparators were also systematically summarized in Table 1. In T1DM, generally distinct degree of HbA1c reductions was observed in different active comparator subgroups except metformin and AGI subgroups (Fig. 3). Comparable weight elevations were observed in most subgroups except a mild weight reduction seen in AGI subgroup (Fig. 3). In T2DM, placebo in metformin, TZD, and SU subgroups conferred HbA1c elevation effect while HbA1c reductions were observed in AGI, SGLT2i, DPP-4i, and GLP-1RA subgroups (Fig. 3). Weight reductions were shown in all hypoglycemic agent subgroups in T2DM (Fig. 3). By subgroup comparisons, greater HbA1c reduction was observed in GLP-1RA subgroup versus metformin subgroup in T1DM (P = 0.01). In terms of T2DM, greater HbA1c reduction was observed in GLP-1RA subgroup versus metformin subgroup (P < 0.01) and TZD subgroup (P < 0.01) respectively (Table 1). Similarly, greater HbA1c reduction was observed in SGLT2i subgroup versus metformin subgroup (P < 0.01), TZD subgroup (P < 0.01), SU (P = 0.02) subgroup, and DPP-4i subgroup (P = 0.02) respectively (Table 1).

Fig. 3
figure3

Placebo response stratified by types of hypoglycemic agents. a HbA1c change. b Weight change

Associated factors with placebo response

Age

The HbA1c level with placebo treatments modestly increased in patients with T1DM below 18 years old (Additional file 1: Figure S4). However, this effect shifted into HbA1c reduction when the patients’ ages became older. Moreover, meta-regression analysis suggested older age was significantly associated with greater HbA1c reduction (β = − 0.01, 95% CI, − 0.02 to − 0.01, P < 0.01) (Fig. 4a). As for body weight, a profound increase with placebo treatments was found in T1DM patients under 18 (Additional file 1: Figure S4), but no specific changing tendency was observed later (Table 2).

Fig. 4
figure4

Meta-regression analysis for factors associated with placebo response in diabetes mellitus. a Association between age and placebo response on HbA1c change in type 1 diabetes (β = − 0.01, 95% CI, − 0.02 to − 0.01, P < 0.01). b Association between age and placebo response on HbA1c change in type 2 diabetes (β = 0.02, 95% CI, 0.01 to 0.03, P < 0.01). c Association between male percentage and placebo response on HbA1c change in type 2 diabetes (β = 0.01, 95% CI, 0.22 × 10−2 to 0.01, P < 0.01). d Association between baseline BMI and placebo response on HbA1c change in type 2 diabetes (β = − 0.02, 95% CI, − 0.04 to − 0.26 × 10−2, P = 0.02). e Association between baseline HbA1c and placebo response on HbA1c change in type 2 diabetes (β = − 0.09, 95% CI, − 0.16 to − 0.01, P = 0.02). f Association between diabetes duration and placebo response on HbA1c change in type 1 diabetes (β = − 0.02, 95% CI, − 0.03 to − 0.21 × 10−2, P = 0.03). g Association between diabetes duration and placebo response on weight change in type 2 diabetes (β = 0.06, 95% CI, 0.02 to 0.10, P < 0.01)

Table 2 Meta-regression analysis and tendency test of placebo response with associated factors in patients with diabetes mellitus

Unlike T1DM, a profound HbA1c reduction with placebo treatments was observed in T2DM below 50 years old. Such effect grew milder along with growing ages and almost diminished in elderly over 60 (Additional file 1: Figure S5). With significantly younger patient ages in HbA1c reduction subgroup versus HbA1c elevation subgroup (Additional file 1: Table S5), meta-regression analysis suggested younger age was associated with more HbA1c reduction (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01) (Fig. 4b). Different degree reductions of body weight were shown in different age subgroups (Additional file 1: Figure S5) but no significant association was discovered.

Sex

In T2DM, HbA1c reduction with placebo treatment was more frequently observed in groups with lower male percentages (Additional file 1: Figure S6) and the male percentages in HbA1c reduction subgroup were significantly lower than those in HbA1c elevation subgroup (Additional file 1: Table S5). Meta-regression analysis consistently showed that a lower male percentage was significantly associated with more HbA1c reduction by placebo in T2DM (β = 0.01, 95% CI, 0.22 × 10−2 to 0.01, P < 0.01) (Fig. 4c). Although weight reduction was displayed in subgroups stratified by male percentage in T2DM (Additional file 1: Figure S6), no significant association was shown by meta-regression. Moreover, no significant association was found between male percentage and placebo response on HbA1c or weight change in T1DM (Additional file 1: Figure S7).

Baseline BMI

In T2DM, the HbA1c level with placebo treatment was decreased in patients with baseline BMI over 25 kg/m2 (Additional file 1: Figure S8). Accordingly, baseline BMI was significantly higher in patients with HbA1c reduction versus HbA1c elevation (Additional file 1: Table S5). Meta-regression further confirmed that higher baseline BMI was significantly associated with more HbA1c reduction (β = − 0.02, 95% CI, − 0.04 to − 0.26 × 10−2, P = 0.02) (Fig. 4d). However, the association turned to be negative after adjusted by age, male percentage, duration of diabetes, study duration, and baseline HbA1c (β = − 0.01, 95% CI, − 0.03 to 0.01, P = 0.41). Weight reductions were observed in different BMI strata with placebo treatments except for the subgroup over 35 kg/m2 (Additional file 1: Figure S8). Although baseline BMI was significantly lower in patients with weight reduction versus weight elevation (Additional file 1: Table S5), no specific response pattern was found for baseline BMI and weight change by meta-regression in T2DM. In T1DM, no significant association was found for BMI and placebo response on HbA1c or weight change (Additional file 1: Figure S9).

Baseline HbA1c

In T2DM, the HbA1c alteration mediated by placebo treatments was mild in patients with baseline HbA1c below 8.5%, but it reduced more when baseline HbA1c got higher (Additional file 1: Figure S10). The comparison for baseline HbA1c level between HbA1c reduction and elevation subgroups also confirmed a significantly higher baseline HbA1c level in patients with HbA1c reduction (Additional file 1: Table S5). Consistently, meta-regression analysis indicated that higher baseline HbA1c was significantly associated with greater HbA1c reduction by placebo in T2DM (β = − 0.09, 95% CI, − 0.16 to − 0.01, P = 0.02) (Fig. 4e). However, this association was insignificant after adjusted by age, male percentage, duration of diabetes, study duration, and baseline BMI (β = − 0.04, 95% CI, − 0.16 to 0.08, P = 0.52). As for weight change, no specific response pattern was observed in T2DM (Additional file 1: Figure S10), although a significant higher baseline HbA1c level was observed in patients with weight elevation versus weight reduction (Additional file 1: Table S5). No significant association was found between baseline HbA1c and HbA1c or weight change in T1DM (Additional file 1: Figure S11).

Diabetes duration

Placebo response on HbA1c reduction in T1DM was more profound in patients with diabetes duration between 10 and 30 years (Additional file 1: Figure S12) and a longer diabetes duration was significantly associated with greater HbA1c reduction by placebo (β = − 0.02, 95% CI, − 0.03 to − 0.21 × 10−2, P = 0.03) (Fig. 4f). With different extents of weight reduction observed in diabetes duration subgroups (Additional file 1: Figure S12), no significant association was observed in T1DM.

In T2DM, although moderate HbA1c reduction in placebo treatment was observed in strata of different diabetes duration (Additional file 1: Figure S13), no significant association was found. However, an attenuated magnitude of placebo response on weight reduction was exhibited with increasing diabetes duration (Additional file 1: Figure S13). With significantly shorter diabetes duration observed in patients with weight reduction versus weight elevation (Additional file 1: Table S5), meta-regression analysis suggested a shorter diabetes duration was significantly associated with more weight reduction by placebo (β = 0.06, 95% CI, 0.02 to 0.10, P < 0.01) (Fig. 4 g).

Study duration

In T1DM, modest HbA1c reduction and weight elevation were observed among most study duration strata (Additional file 1: Figure S14). As for T2DM, with the study duration increasing, tendencies of placebo response shifting from HbA1c elevation to HbA1c reduction and from weight reduction to weight gain were displayed (Additional file 1: Figure S15). However, no specific distribution pattern was supported by meta-regression analyses in both T1DM and T2DM.

Publication year

In T1DM, HbA1c level in placebo treatment groups was increased in 1990s but decreased afterwards while weight level was reduced first but increased after 2000 (Additional file 1: Figure S16). The absolute alteration values for HbA1c and weight both peaked in 2006–2010 (Additional file 1: Figure S16). In T2DM, HbA1c level in placebo treatment arms tended to elevate modestly from the baseline between 1990 and 2005 but to decrease after 2006 (Additional file 1: Figure S17). As for weight change, except for a relatively modest increase before 1990, the placebo treatments mostly resulted in weight reduction in T2DM (Additional file 1: Figure S17). However, although comparisons showed that publication years of studies with HbA1c elevation and weight elevation in placebo treatment arms were significantly earlier than those with HbA1c and weight reduction (Additional file 1: Table S5), no significant associations were shown by ANOVA tendency tests in both T1DM and T2DM.

Discussion

This meta-analysis delineated the placebo response in both T1DM and T2DM with data from over 400 RCTs with almost 40,000 participants. More importantly, we characterized the placebo response pattern associated with patient age, sex, disease duration, and possibly disease severity (indirectly reflected by baseline BMI and baseline HbA1c) in diabetes, which tries to raise researchers’ attention again to weighting important moderators and predictors in placebo response.

As is mentioned, placebo response includes all health changes that result after the administration of an inactive treatment, thus including natural history, spontaneous recovery, and regression to the mean [451, 452]. So far, underlying mechanisms of placebo response are not fully understood. Individual patient and clinician factors, mutual interactions, and treatment environment may also somehow influence the placebo response to different extent. As for DM, placebo response can be related to optimal dietary treatment [453,454,455,456], or increased physical activity [457, 458], or improved education and management [459, 460], or patients’ expectations [461], in addition to fluctuation of symptoms and regression to the mean.

In this meta-analysis, data of T1DM have been included for analysis for the first time. Interestingly, significantly weight elevation was observed in T1DM patients with placebo treatments while significantly HbA1c reduction and weight reduction were observed in T2DM patients with placebo treatments. Considering all included studies in T1DM were with insulin add-on treatments, such difference in placebo response may be due to the background administration of insulin in T1DM population. Furthermore, we differentiated the oral and injection route for drug administration and found injectable placebo led to more HbA1c reduction compared with oral types in T2DM. It was hypothesized that a stronger signal delivered by subcutaneous puncture stimuli might trigger a positive psychological feedback that enhanced the placebo response, for example, raising patients’ expectations towards treatment benefits. But further evidence was still needed.

Patient age has been shown to consistently affect placebo response with different clinical conditions. Evaluations across medicine found that younger age was associated with higher placebo response, predominantly in psychiatric conditions and internal medicine [462]. In our study, older age was associated with more HbA1c reduction with placebo treatments in T1DM while younger age was associated with more HbA1c reduction with placebo treatments in T2DM. Such difference may be explained by distinct patient age distribution in T1DM and T2DM. In T1DM, adolescences and youth may not be mature enough to understand the disease severity and properly stick to the management routine. With their ages growing, their increased knowledge of DM may help them understand and believe in positive effects from well-organized DM management. In T2DM, patients are generally at a relatively mature age with disease onset. When they get older, less confidence and enthusiasm towards treatments and higher chance of experiencing treatment failure are likely to minimize the placebo response in these patients.

Sex is a controversial moderator for placebo response. Systematic reviews from major medical areas (neurology, psychiatry and internal medicine) but not from diabetes showed that only in 3 analyses female sex was associated with a higher placebo response, indicating poor evidence for contribution of sex to placebo response [463, 464]. But still, Enck et al. proposed that placebo response was predominantly the result of a conditioning learning response in females while a verbal manipulating of expectancies in males [463]. As a supplement, we did discover the sex difference of placebo response in T2DM in terms of HbA1c reduction.

Disease severity is another important associated factor with placebo response. In fact, a positive relationship between disease severity and magnitude of placebo response was previously observed in osteoarthritis [464]. As indirect indicators of disease severity, we found higher baseline BMI and higher baseline HbA1c were significantly associated with more HbA1c reduction achieved by placebo in T2DM, which was different from Khan’s finding [8]. The inconsistence between our results and Khan’s results might be due to different databases for placebo-controlled trials and more complicated groups of add-on treatment in our study. However, such associations turned to be negative after adjusted by other baseline parameters, including age, sex, duration of diabetes, and baseline BMI or HbA1c, which might influence the outcomes. Therefore, the correlations between increased disease severity (baseline BMI and higher baseline HbA1c) and greater HbA1c reduction may be the result of regression to the mean, which is also commonly observed in placebo response. Further investigations are needed to assess the potential link between placebo response and disease severity.

Disease duration is accompanied with alterations of patients’ understanding of disease itself and treatments. The association between the shorter disease duration and the larger placebo response effect size has been reported in fibromyalgia [465]. Similarly, we observed a shorter diabetes duration associated with more weight reduction by placebo in T2DM. It is possibly related to increasing treatment inertia and worsening adherence to nonpharmacological interventions in patients with longer durations. Moreover, worsening interrupted internal environment and neuro-endocrine-immune regulatory network with longer disease duration may also make it harder for placebo response to manifest.

This meta-analysis also has several limitations. First, included studies have different inclusion criteria, various baseline characteristics, non-uniform outcome definitions, and variable sample sizes. These factors will lead to heterogeneity among studies in this meta-analysis. Second, we did not include unpublished trials in our meta-analysis. Published studies may have an inherent bias, as unpublished trials tend to have null effects. However, the reported data from such unpublished trials were likely to be incomplete, espacially for placebo treatment group, which makes it hard for the quality evaluation and subsequent analysis. Therefore, we decide to exclude such studies. Moreover, we cannot fully assess the manipulation of each trials. Uncertainty of possibly inadequate blinding, additional bias from clinicians, known as “placebo by proxy” [466], and influence from underestimated interactions between patients and clinicians may affect the interpretation of our results. In addition, as a meta-analysis, data of HbA1c and body weight change in placebo treatment group were used as the surrogate parameters, but not the data at patient-level, which would be more helpful to draw a conclusion. It is noted that the associations between baseline BMI, HbA1c, and placebo response are still not definite, since the adjusted meta-regression tuned out to be negative. The correlations between the baseline severity and placebo response observed in our meta-analysis may be the result of regression to the mean. Therefore, statistical outcomes for this part should be interpreted with caution. Also, since we did not include studies with untreated control, we could only evaluate the placebo response rather than placebo effect in DM. More investigations, especially studies with untreated control, are needed to accurately record and analyze the placebo response and even placebo effect in DM, and possibly better differentiate the effect of regression to the mean.

Conclusions

Placebo response in diabetes was systematically outlined in this meta-analysis. Age, sex, and disease duration were associated factors with placebo response in diabetes, which may require more considerations when designing and conducting placebo-controlled clinical trials in diabetes. Baseline disease severity was also associated with placebo response in diabetes, which is likely to be the result of the regression to the mean. More investigations are encouraged to further explore unique or even potentially generalized placebo response patterns in DM and a wider field of medicine concerning more diseases.

Availability of data and materials

All data generated or analyzed during this study are included in this article and its supplementary information files.

Abbreviations

AGI:

Alpha glucosidase inhibitor

ANOVA:

Analysis of variance

BMI:

Body mass index

CI:

Confidence interval

DM:

Diabetes mellitus

DPP-4:

Dipeptidyl peptidase-4

ES:

Effect size

GLP-1RA:

Glucagon-like peptide-1 receptor agonist

INR:

Interquartile range

MET:

Metformin

RCT:

Randomized controlled trial

SGLT2:

Sodium-glucose cotransporter 2

SU:

Sulfonylurea

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

References

  1. 1.

    Shapiro AK. Semantics of the placebo. Psvchiatr Q. 1968;42:653–95.

    CAS  Article  Google Scholar 

  2. 2.

    Shapiro AP, Schwartz GE, Ferguson DCE, Redmond DP, Weiss SM. Behavioral methods in the treatment of hypertension. Ann Intern Med. 1977;86:626–36.

    Article  Google Scholar 

  3. 3.

    Kaptchuk TJ, Miller FG. Placebo effects in medicine. N Engl J Med. 2015;373(1):8–9.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;20(1):CD003974.

    Google Scholar 

  5. 5.

    Evers AM, Luana C, Charlotte B, et al. Implications of placebo and nocebo effects for clinical practice: expert consensus. Psychother Psychosom. 2018;87(4):204–10.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Khan A, FahlMar K, Faucett J, et al. Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US Food and Drug Administration 1987-2013. World Psychiatry. 2017;16:181–92.

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Rheims S, Perucca E, Cucherat M, et al. Factors determining response to antiepileptic drugs in randomized controlled trials. A systematic review and meta-analysis. Epilepsia. 2011;52:219–33.

    CAS  PubMed  Google Scholar 

  8. 8.

    Khan A, Fahl Mar K, Schilling J, et al. Magnitude and pattern of placebo response in clinical trials of oral antihyperglycemic agents: data from the Food and Drug Administration 1999-2015. Diabetes Care. 2018;41(5):994–1000.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Higgins JPT, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

    PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Anderson JJA, Couper JJ, Giles LC, Leggett CE, Gent R, Coppin B, et al. Effect of metformin on vascular function in children with type 1 diabetes: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 2017;102(12):4448–56.

    PubMed  Article  Google Scholar 

  11. 11.

    Codner E, Iniguez G, Lopez P, Mujica V, Eyzaguirre FC, Asenjo S, et al. Metformin for the treatment of hyperandrogenism in adolescents with type 1 diabetes mellitus. Horm Res Paediatr. 2013;80(5):343–9.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Hamilton J, Cummings E, Zdravkovic V, Finegood D, Daneman D. Metformin as an adjunct therapy in adolescents with type 1 diabetes and insulin resistance: a randomized controlled trial. Diabetes Care. 2003;26(1):138–43.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Jacobsen IB, Henriksen JE, Beck-Nielsen H. The effect of metformin in overweight patients with type 1 diabetes and poor metabolic control. Basic Clin Pharmacol Toxicol. 2009;105(3):145–9.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Lund SS, Tarnow L, Astrup AS, Hovind P, Jacobsen PK, Alibegovic AC, et al. Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. PLoS One. 2008;3(10):e3363.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Lund SS, Tarnow L, Astrup AS, Hovind P, Jacobsen PK, Alibegovic AC, et al. Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes. Diabetes Obes Metab. 2009;11(10):966–77.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Libman IM, Miller KM, DiMeglio LA, Bethin KE, Katz ML, Shah A, et al. Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes: a randomized clinical trial. JAMA. 2015;314(21):2241–50.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Meyer L, Bohme P, Delbachian I, Lehert P, Cugnardey N, Drouin P, et al. The benefits of metformin therapy during continuous subcutaneous insulin infusion treatment of type 1 diabetic patients. Diabetes Care. 2002;25(12):2153–8.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Nadeau KJ, Chow K, Alam S, Lindquist K, Campbell S, McFann K, et al. Effects of low dose metformin in adolescents with type I diabetes mellitus: a randomized, double-blinded placebo-controlled study. Pediatr Diabetes. 2015;16(3):196–203.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Nwosu BU, Maranda L, Cullen K, Greenman L, Fleshman J, McShea N, et al. A randomized, double-blind, placebo-controlled trial of adjunctive metformin therapy in overweight/obese youth with type 1 diabetes. PLoS One. 2015;10(9):e0137525.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Petrie JR, Chaturvedi N, Ford I, Hramiak I, Hughes AD, Jenkins AJ, et al. Metformin in adults with type 1 diabetes: design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): an international multicentre trial. Diabetes Obes Metab. 2017;19(4):509–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Petrie JR, Chaturvedi N, Ford I, Brouwers M, Greenlaw N, Tillin T, et al. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diab Endocrinol. 2017;5(8):597–609.

    CAS  Article  Google Scholar 

  22. 22.

    Pitocco D, Zaccardi F, Tarzia P, Milo M, Scavone G, Rizzo P, et al. Metformin improves endothelial function in type 1 diabetic subjects: a pilot, placebo-controlled randomized study. Diabetes Obes Metab. 2013;15(5):427–31.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Sarnblad S, Kroon M, Aman J. Metformin as additional therapy in adolescents with poorly controlled type 1 diabetes: randomised placebo-controlled trial with aspects on insulin sensitivity. Eur J Endocrinol. 2003;149(4):323–9.

    PubMed  Article  Google Scholar 

  24. 24.

    Ziaee A, Esmailzadehha N, Honardoost M. Comparison of adjunctive therapy with metformin and acarbose in patients with Type-1 diabetes mellitus. Pak J Med Sci. 2017;33(3):686–90.

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Hollander P, Pi-Sunyer X, Coniff RF. Acarbose in the treatment of type I diabetes. Diabetes Care. 1997;20(3):248–53.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Riccardi G, Giacco R, Parillo M, Turco S, Rivellese AA, Ventura MR, et al. Efficacy and safety of acarbose in the treatment of type 1 diabetes mellitus: a placebo-controlled, double-blind, multicentre study. Diab Med. 1999;16(3):228–32.

    CAS  Article  Google Scholar 

  27. 27.

    Bhat R, Bhansali A, Bhadada S, Sialy R. Effect of pioglitazone therapy in lean type 1 diabetes mellitus. Diab Res Clin Pract. 2007;78(3):349–54.

    CAS  Article  Google Scholar 

  28. 28.

    Strowig SM, Raskin P. The effect of rosiglitazone on overweight subjects with type 1 diabetes. Diabetes Care. 2005;28(7):1562–7.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Tafuri KS, Godil MA, Lane AH, Wilson TA. Effect of pioglitazone on the course of new-onset type 1 diabetes mellitus. J Clin Res Pediatr Endocrinol. 2013;5(4):236–9.

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Zdravkovic V, Hamilton JK, Daneman D, Cummings EA. Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes. J Pediatr. 2006;149(6):845–9.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Ahren B, Hirsch IB, Pieber TR, Mathieu C, Gomez-Peralta F, Hansen TK, et al. Efficacy and safety of liraglutide added to capped insulin treatment in subjects with type 1 diabetes: the ADJUNCT TWO randomized trial. Diabetes Care. 2016;39(10):1693–701.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Dejgaard TF, Frandsen CS, Hansen TS, Almdal T, Urhammer S, Pedersen-Bjergaard U, et al. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial. Lancet Diab Endocrinol. 2016;4(3):221–32.

    CAS  Article  Google Scholar 

  33. 33.

    Dejgaard TF, Johansen NB, Frandsen CS, Asmar A, Tarnow L, Knop FK, et al. Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes. Diabetes Obes Metab. 2017;19(5):734–8.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Frandsen CS, Dejgaard TF, Holst JJ, Andersen HU, Thorsteinsson B, Madsbad S. Twelve-week treatment with liraglutide as add-on to insulin in normal-weight patients with poorly controlled type 1 diabetes: a randomized, placebo-controlled, double-blind parallel study. Diabetes Care. 2015;38(12):2250–7.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Frandsen CS, Dejgaard TF, Andersen HU, Holst JJ, Hartmann B, Thorsteinsson B, et al. Liraglutide as adjunct to insulin treatment in type 1 diabetes does not interfere with glycaemic recovery or gastric emptying rate during hypoglycaemia: a randomized, placebo-controlled, double-blind, parallel-group study. Diabetes Obes Metab. 2017;19(6):773–82.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Kuhadiya ND, Dhindsa S, Ghanim H, Mehta A, Makdissi A, Batra M, et al. Addition of liraglutide to insulin in patients with type 1 diabetes: a randomized placebo-controlled clinical trial of 12 weeks. Diabetes Care. 2016;39(6):1027–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Mathieu C, Zinman B, Hemmingsson JU, Woo V, Colman P, Christiansen E, et al. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: the ADJUNCT ONE treat-to-target randomized trial. Diabetes Care. 2016;39(10):1702–10.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Garg SK, Moser EG, Bode BW, Klaff LJ, Hiatt WR, Beatson C, et al. Effect of sitagliptin on post-prandial glucagon and GLP-1 levels in patients with type 1 diabetes: investigator-initiated, double-blind, randomized, placebo-controlled trial. Endocrine Pract. 2013;19(1):19–28.

    Article  Google Scholar 

  39. 39.

    Buse JB, Garg SK, Rosenstock J, Bailey TS, Banks P, Bode BW, et al. Sotagliflozin in in combination with optimized insulin therapy in adults with type 1 diabetes: the north American inTandem1 study. Diabetes Care. 2018;41(9):1970–80.

  40. 40.

    Dandona P, Mathieu C, Phillip M, Hansen L, Griffen SC, Tschope D, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diab Endocrinol. 2017;5(11):864–76.

    CAS  Article  Google Scholar 

  41. 41.

    Danne T, Cariou B, Banks P, Brandle M, Brath H, Franek E, et al. HbA1c and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: the European inTandem2 study. Diabetes Care. 2018;41(9):1981–90.

  42. 42.

    Famulla S, Pieber TR, Eilbracht J, Neubacher D, Soleymanlou N, Woerle HJ, et al. Glucose exposure and variability with empagliflozin as adjunct to insulin in patients with type 1 diabetes: continuous glucose monitoring data from a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Technol Ther. 2017;19(1):49–60.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Pieber TR, Famulla S, Eilbracht J, Cescutti J, Soleymanlou N, Johansen OE, et al. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab. 2015;17(10):928–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Garg SK, Henry RR, Banks P, Buse JB, Davies MJ, Fulcher GR, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017;377(24):2337–48.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care. 2015;38(12):2258–65.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Rodbard HW, Peters AL, Slee A, Cao A, Traina SB, Alba M. The effect of canagliflozin, a sodium glucose cotransporter 2 inhibitor, on glycemic end points assessed by continuous glucose monitoring and patient-reported outcomes among people with type 1 diabetes. Diabetes Care. 2017;40(2):171–80.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Peters AL, Henry RR, Thakkar P, Tong C, Alba M. Diabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes. Diabetes Care. 2016;39(4):532–8.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Kuhadiya ND, Ghanim H, Mehta A, Garg M, Khan S, Hejna J, et al. Dapagliflozin as additional treatment to liraglutide and insulin in patients with type 1 diabetes. J Clin Endocrinol Metab. 2016;101(9):3506–15.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Sands AT, Zambrowicz BP, Rosenstock J, Lapuerta P, Bode BW, Garg SK, et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care. 2015;38(7):1181–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Shimada A, Hanafusa T, Yasui A, Lee G, Taneda Y, Sarashina A, et al. Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial. Diabetes Obes Metab. 2018;20(9):2190–9.

  51. 51.

    Mathieu C, Dandona P, Gillard P, Senior P, Hasslacher C, Araki E, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 24-week results from a randomized controlled trial. Diabetes Care. 2018;41(9):1938–46.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Rosenstock J, Marquard J, Laffel LM, Neubacher D, Kaspers S, Cherney DZ, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41(12):2560–9.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, et al. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care. 2006;29(10):2189–95.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Marrero DG, Crean J, Zhang B, Kellmeyer T, Gloster M, Herrmann K, et al. Effect of adjunctive pramlintide treatment on treatment satisfaction in patients with type 1 diabetes. Diabetes Care. 2007;30(2):210–6.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Kovatchev BP, Crean J, McCall A. Pramlintide reduces the risks associated with glucose variability in type 1 diabetes. Diabetes Technol Ther. 2008;10(5):391–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Herrmann K, Frias JP, Edelman SV, Lutz K, Shan K, Chen S, et al. Pramlintide improved measures of glycemic control and body weight in patients with type 1 diabetes mellitus undergoing continuous subcutaneous insulin infusion therapy. Postgrad Med. 2013;125(3):136–44.

    PubMed  Article  Google Scholar 

  57. 57.

    Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diab Med. 2004;21(11):1204–12.

    CAS  Article  Google Scholar 

  58. 58.

    Ratner R, Whitehouse F, Fineman MS, Strobel S, Shen L, Maggs DG, et al. Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets. Exp Clin Endocrinol Diab. 2005;113(4):199–204.

    CAS  Article  Google Scholar 

  59. 59.

    Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, et al. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care. 2002;25(4):724–30.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004;27(6):1335–42.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract. 2007;61(1):171–80.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Goldberg RB, Holvey SM, Schneider J. A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. The Glimepiride Protocol #201 Study Group. Diabetes Care. 1996;19(8):849–56.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Rosenstock J, Samols E, Muchmore DB, Schneider J. Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Glimepiride Study Group. Diabetes Care. 1996;19(11):1194–9.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Simonson DC, Kourides IA, Feinglos M, Shamoon H, Fischette CT. Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Results of two multicenter, randomized, placebo-controlled clinical trials. The Glipizide Gastrointestinal Therapeutic System Study Group. Diabetes Care. 1997;20(4):597–606.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Fischer S, Patzak A, Rietzsch H, Schwanebeck U, Kohler C, Wildbrett J, et al. Influence of treatment with acarbose or glibenclamide on insulin sensitivity in type 2 diabetic patients. Diabetes Obes Metab. 2003;5(1):38–44.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Hanefeld M, Haffner SM, Menschikowski M, Koehler C, Temelkova-Kurktschiev T, Wildbrett J, et al. Different effects of acarbose and glibenclamide on proinsulin and insulin profiles in people with type 2 diabetes. Diabetes Res Clin Pract. 2002;55(3):221–7.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose, glibenclamide, or placebo in NIDDM patients. The Essen Study. Diabetes Care. 1994;17(6):561–6.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Segal P, Feig PU, Schernthaner G, Ratzmann KP, Rybka J, Petzinna D, et al. The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone. Diabetes Care. 1997;20(5):687–91.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Ebeling P, Teppo AM, Koistinen HA, Koivisto VA. Concentration of the complement activation product, acylation-stimulating protein, is related to C-reactive protein in patients with type 2 diabetes. Metab Clin Exp. 2001;50(3):283–7.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Coniff RF, Shapiro JA, Seaton TB, Bray GA. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med. 1995;98(5):443–51.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Johnson AB, Webster JM, Sum CF, Heseltine L, Argyraki M, Cooper BG, et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metab Clin Exp. 1993;42(9):1217–22.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Tessari P, Biolo G, Bruttomesso D, Inchiostro S, Panebianco G, Vedovato M, et al. Effects of metformin treatment on whole-body and splanchnic amino acid turnover in mild type 2 diabetes. J Clin Endocrinol Metab. 1994;79(6):1553–60.

    CAS  PubMed  Google Scholar 

  73. 73.

    List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32(4):650–7.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Fonseca VA, Ferrannini E, Wilding JP, Wilpshaar W, Dhanjal P, Ball G, et al. Active- and placebo-controlled dose-finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. J Diabetes Complicat. 2013;27(3):268–73.

    PubMed  Article  Google Scholar 

  75. 75.

    Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med. 1997;103(6):491–7.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Natali A, Baldeweg S, Toschi E, Capaldo B, Barbaro D, Gastaldelli A, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care. 2004;27(6):1349–57.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Fujioka K, Brazg RL, Raz I, Bruce S, Joyal S, Swanink R, et al. Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Diabetes Obes Metab. 2005;7(1):28–39.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients: the Essen-II study. Am J Med. 1997;103(6):483–90.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Horton ES, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000;23(11):1660–5.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30(8):1979–87.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle HJ. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2012;14(6):565–74.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Hallsten K, Virtanen KA, Lonnqvist F, Sipila H, Oksanen A, Viljanen T, et al. Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Diabetes. 2002;51(12):3479–85.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Viljanen AP, Virtanen KA, Jarvisalo MJ, Hallsten K, Parkkola R, Ronnemaa T, et al. Rosiglitazone treatment increases subcutaneous adipose tissue glucose uptake in parallel with perfusion in patients with type 2 diabetes: a double-blind, randomized study with metformin. J Clin Endocrinol Metab. 2005;90(12):6523–8.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541–9.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Dornan TL, Heller SR, Peck GM, Tattersall RB. Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care. 1991;14(4):342–4.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Chiasson JL, Naditch L. The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes. Diabetes Care. 2001;24(6):989–94.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Wagner H, Degerblad M, Thorell A, Nygren J, Stahle A, Kuhl J, et al. Combined treatment with exercise training and acarbose improves metabolic control and cardiovascular risk factor profile in subjects with mild type 2 diabetes. Diabetes Care. 2006;29(7):1471–7.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Coniff RF, Shapiro JA, Robbins D, Kleinfield R, Seaton TB, Beisswenger P, et al. Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. A placebo-controlled dose-comparison study. Diabetes Care. 1995;18(6):817–24.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Calle-Pascual A, Garcia-Honduvilla J, Martin-Alvarez PJ, Calle JR, Maranes JP. Influence of 16-week monotherapy with acarbose on cardiovascular risk factors in obese subjects with non-insulin-dependent diabetes mellitus: a controlled, double-blind comparison study with placebo. Diabetes Metab. 1996;22(3):201–2.

    CAS  PubMed  Google Scholar 

  90. 90.

    Scott R, Lintott CJ, Zimmet P, Campbell L, Bowen K, Welborn T. Will acarbose improve the metabolic abnormalities of insulin-resistant type 2 diabetes mellitus? Diabetes Res Clin Pract. 1999;43(3):179–85.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Delgado H, Lehmann T, Bobbioni-Harsch E, Ybarra J, Golay A. Acarbose improves indirectly both insulin resistance and secretion in obese type 2 diabetic patients. Diabetes Metab. 2002;28(3):195–200.

    CAS  PubMed  Google Scholar 

  92. 92.

    Hanefeld M, Schaper F, Koehler C, Bergmann S, Ugocsai P, Stelzer J, et al. Effect of acarbose on postmeal mononuclear blood cell response in patients with early type 2 diabetes: the AI(I) DA study. Horm Metab Res. 2009;41(2):132–6.

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Rosenbaum P, Peres RB, Zanella MT, Ferreira SR. Improved glycemic control by acarbose therapy in hypertensive diabetic patients: effects on blood pressure and hormonal parameters. Braz J Med Biolo Res. 2002;35(8):877–84.

    CAS  Article  Google Scholar 

  94. 94.

    Hotta N, Kakuta H, Sano T, Matsumae H, Yamada H, Kitazawa S, et al. Long-term effect of acarbose on glycaemic control in non-insulin-dependent diabetes mellitus: a placebo-controlled double-blind study. Diab Med. 1993;10(2):134–8.

    CAS  Article  Google Scholar 

  95. 95.

    Chan JC, Chan KW, Ho LL, Fuh MM, Horn LC, Sheaves R, et al. An Asian multicenter clinical trial to assess the efficacy and tolerability of acarbose compared with placebo in type 2 diabetic patients previously treated with diet. Asian Acarbose Study Group. Diabetes Care. 1998;21(7):1058–61.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Gentile S, Turco S, Guarino G, Oliviero B, Annunziata S, Cozzolino D, et al. Effect of treatment with acarbose and insulin in patients with non-insulin-dependent diabetes mellitus associated with non-alcoholic liver cirrhosis. Diabetes Obes Metab. 2001;3(1):33–40.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Coniff RF, Shapiro JA, Seaton TB. Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus. Arch Intern Med. 1994;154(21):2442–8.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Chiasson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. A multicenter controlled clinical trial. Ann Intern Med. 1994;121(12):928–35.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Meneilly GS, Ryan EA, Radziuk J, Lau DC, Yale JF, Morais J, et al. Effect of acarbose on insulin sensitivity in elderly patients with diabetes. Diabetes Care. 2000;23(8):1162–7.

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Josse RG, Chiasson JL, Ryan EA, Lau DC, Ross SA, Yale JF, et al. Acarbose in the treatment of elderly patients with type 2 diabetes. Diabetes Res Clin Pract. 2003;59(1):37–42.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Hasche H, Mertes G, Bruns C, Englert R, Genthner P, Heim D, et al. Effects of acarbose treatment in type 2 diabetic patients under dietary training: a multicentre, double-blind, placebo-controlled, 2-year study. Diab Nutr Metab. 1999;12(4):277–85.

    CAS  Google Scholar 

  102. 102.

    Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care. 1996;19(2):151–6.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Kumar S, Boulton AJ, Beck-Nielsen H, Berthezene F, Muggeo M, Persson B, et al. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group. Diabetologia. 1996;39(6):701–9.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Patel J, Anderson RJ, Rappaport EB. Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diabetes Obes Metab. 1999;1(3):165–72.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Raskin P, Rappaport EB, Cole ST, Yan Y, Patwardhan R, Freed MI. Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes. Diabetologia. 2000;43(3):278–84.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Miyazaki Y, Glass L, Triplitt C, Matsuda M, Cusi K, Mahankali A, et al. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in type II diabetic patients. Diabetologia. 2001;44(12):2210–9.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Juhl CB, Hollingdal M, Porksen N, Prange A, Lonnqvist F, Schmitz O. Influence of rosiglitazone treatment on beta-cell function in type 2 diabetes: evidence of an increased ability of glucose to entrain high-frequency insulin pulsatility. J Clin Endocrinol Metab. 2003;88(8):3794–800.

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Wallace TM, Levy JC, Matthews DR. An increase in insulin sensitivity and basal beta-cell function in diabetic subjects treated with pioglitazone in a placebo-controlled randomized study. Diab Med. 2004;21(6):568–76.

    CAS  Article  Google Scholar 

  109. 109.

    Gastaldelli A, Miyazaki Y, Pettiti M, Santini E, Ciociaro D, Defronzo RA, et al. The effect of rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91(3):806–12.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Sourij H, Zweiker R, Wascher TC. Effects of pioglitazone on endothelial function, insulin sensitivity, and glucose control in subjects with coronary artery disease and new-onset type 2 diabetes. Diabetes Care. 2006;29(5):1039–45.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Oz O, Tuncel E, Eryilmaz S, Fazlioglu M, Gul CB, Ersoy C, et al. Arterial elasticity and plasma levels of adiponectin and leptin in type 2 diabetic patients treated with thiazolidinediones. Endocrine. 2008;33(1):101–5.

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Oz Gul O, Tuncel E, Yilmaz Y, Ulukaya E, Gul CB, Kiyici S, et al. Comparative effects of pioglitazone and rosiglitazone on plasma levels of soluble receptor for advanced glycation end products in type 2 diabetes mellitus patients. Metab Clin Exp. 2010;59(1):64–9.

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Kong AP, Yamasaki A, Ozaki R, Saito H, Asami T, Ohwada S, et al. A randomized-controlled trial to investigate the effects of rivoglitazone, a novel PPAR gamma agonist on glucose-lipid control in type 2 diabetes. Diabetes Obes Metab. 2011;13(9):806–13.

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Colca JR, VanderLugt JT, Adams WJ, Shashlo A, McDonald WG, Liang J, et al. Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer. Clin Pharmacol Ther. 2013;93(4):352–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Ebeling P, Teppo AM, Koistinen HA, Viikari J, Ronnemaa T, Nissen M, et al. Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with type II diabetes. Diabetologia. 1999;42(12):1433–8.

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Miyazaki Y, Mahankali A, Matsuda M, Glass L, Mahankali S, Ferrannini E, et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care. 2001;24(4):710–9.

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, Salzman A. Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care. 2001;24(2):308–15.

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Rosenblatt S, Miskin B, Glazer NB, Prince MJ, Robertson KE. The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus. Coron Artery Dis. 2001;12(5):413–23.

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Carey DG, Cowin GJ, Galloway GJ, Jones NP, Richards JC, Biswas N, et al. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients [corrected]. Obes Res. 2002;10(10):1008–15.

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Rosenstock J, Shen SG, Gatlin MR, Foley JE. Combination therapy with nateglinide and a thiazolidinedione improves glycemic control in type 2 diabetes. Diabetes Care. 2002;25(9):1529–33.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Lautamaki R, Airaksinen KE, Seppanen M, Toikka J, Luotolahti M, Ball E, et al. Rosiglitazone improves myocardial glucose uptake in patients with type 2 diabetes and coronary artery disease: a 16-week randomized, double-blind, placebo-controlled study. Diabetes. 2005;54(9):2787–94.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Thiazolidinediones improve beta-cell function in type 2 diabetic patients. Am J Physiol Endocrinol Metab. 2007;292(3):E871–83.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Tan GD, Fielding BA, Currie JM, Humphreys SM, Desage M, Frayn KN, et al. The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes. Diabetologia. 2005;48(1):83–95.

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Miyazaki Y, Matsuda M, DeFronzo RA. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care. 2002;25(3):517–23.

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Fonseca VA, Valiquett TR, Huang SM, Ghazzi MN, Whitcomb RW. Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. The Troglitazone Study Group. J Clin Endocrinol Metab. 1998;83(9):3169–76.

    CAS  PubMed  Google Scholar 

  126. 126.

    Fonseca VA, Reynolds T, Hemphill D, Randolph C, Wall J, Valiquet TR, et al. Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complicat. 1998;12(4):181–6.

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care. 2000;23(11):1605–11.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation. 2002;106(6):679–84.

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Scherbaum WA, Goke B. Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study. Horm Metab Res. 2002;34(10):589–95.

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Khan M, Murray FT, Karunaratne M, Perez A. Pioglitazone and reductions in post-challenge glucose levels in patients with type 2 diabetes. Diabetes Obes Metab. 2006;8(1):31–8.

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Truitt KE, Goldberg RB, Rosenstock J, Chou HS, Merante D, Triscari J, et al. A 26-week, placebo- and pioglitazone-controlled, dose-ranging study of rivoglitazone, a novel thiazolidinedione for the treatment of type 2 diabetes. Curr Med Res Opin. 2010;26(6):1321–31.

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Chou HS, Truitt KE, Moberly JB, Merante D, Choi Y, Mun Y, et al. A 26-week, placebo- and pioglitazone-controlled monotherapy study of rivoglitazone in subjects with type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14(11):1000–9.

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab. 2005;7(6):692–8.

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP. Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes. Curr Med Res Opin. 2007;23(6):1329–39.

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Nonaka K, Kakikawa T, Sato A, Okuyama K, Fujimoto G, Kato N, et al. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract. 2008;79(2):291–8.

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab. 2008;10(5):376–86.

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Kikuchi M, Abe N, Kato M, Terao S, Mimori N, Tachibana H. Vildagliptin dose-dependently improves glycemic control in Japanese patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2009;83(2):233–40.

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Iwamoto Y, Taniguchi T, Nonaka K, Okamoto T, Okuyama K, Arjona Ferreira JC, et al. Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Endocr J. 2010;57(5):383–94.

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Pattzi HM, Pitale S, Alpizar M, Bennett C, O'Farrell AM, Li J, et al. Dutogliptin, a selective DPP4 inhibitor, improves glycaemic control in patients with type 2 diabetes: a 12-week, double-blind, randomized, placebo-controlled, multicentre trial. Diabetes Obes Metab. 2010;12(4):348–55.

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Rhee EJ, Lee WY, Yoon KH, Yoo SJ, Lee IK, Baik SH, et al. A multicenter, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15-0444 in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12(12):1113–9.

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Seino Y, Fujita T, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study. Curr Med Res Opin. 2011;27(9):1781–92.

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, et al. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab. 2012;14(4):348–57.

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Kadowaki T, Kondo K. Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15(9):810–8.

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Inagaki N, Onouchi H, Sano H, Funao N, Kuroda S, Kaku K. SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Diab Endocrinol. 2014;2(2):125–32.

    CAS  Article  Google Scholar 

  145. 145.

    Sheu WH, Gantz I, Chen M, Suryawanshi S, Mirza A, Goldstein BJ, et al. Safety and efficacy of omarigliptin (MK-3102), a novel once-weekly DPP-4 inhibitor for the treatment of patients with type 2 diabetes. Diabetes Care. 2015;38(11):2106–14.

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Yoon SA, Han BG, Kim SG, Han SY, Jo YI, Jeong KH, et al. Efficacy, safety and albuminuria-reducing effect of gemigliptin in Korean type 2 diabetes patients with moderate to severe renal impairment: a 12-week, double-blind randomized study (the GUARD study). Diabetes Obes Metab. 2017;19(4):590–8.

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Pan C, Han P, Ji Q, Li C, Lu J, Yang J, et al. Efficacy and safety of alogliptin in patients with type 2 diabetes mellitus: a multicentre randomized double-blind placebo-controlled phase 3 study in mainland China, Taiwan, and Hong Kong. J Diab. 2017;9(4):386–95.

    CAS  Article  Google Scholar 

  148. 148.

    Agarwal P, Jindal C, Sapakal V. Efficacy and safety of teneligliptin in Indian patients with inadequately controlled type 2 diabetes mellitus: a randomized, double-blind study. Indian J Endocrinol Metab. 2018;22(1):41–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49(11):2564–71.

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Mohan V, Yang W, Son HY, Xu L, Noble L, Langdon RB, et al. Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract. 2009;83(1):106–16.

    CAS  PubMed  Article  Google Scholar 

  151. 151.

    Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2632–7.

    CAS  PubMed  Article  Google Scholar 

  152. 152.

    Dejager S, Razac S, Foley JE, Schweizer A. Vildagliptin in drug-naive patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Horm Met Res. 2007;39(3):218–23.

    CAS  Article  Google Scholar 

  153. 153.

    Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug-naive patients with type 2 diabetes. Diabetes Res Clin Pract. 2007;76(1):132–8.

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25(10):2401–11.

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13(3):258–67.

    PubMed  Article  Google Scholar 

  156. 156.

    Pan CY, Yang W, Tou C, Gause-Nilsson I, Zhao J. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev. 2012;28(3):268–75.

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetol Metab Syndr. 2012;4(1):36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Yang SJ, Min KW, Gupta SK, Park JY, Shivane VK, Pitale SU, et al. A multicentre, multinational, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15-0444) in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(5):410–6.

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diab Endocrinol. 2013;1(3):208–19.

    CAS  Article  Google Scholar 

  160. 160.

    Inagaki N, Onouchi H, Maezawa H, Kuroda S, Kaku K. Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study. Lancet Diab Endocrinol. 2015;3(3):191–7.

    CAS  Article  Google Scholar 

  161. 161.

    Wu W, Li Y, Chen X, Lin D, Xiang S, Shen F, et al. Effect of Linagliptin on glycemic control in Chinese patients with newly-diagnosed, drug-naive type 2 diabetes mellitus: a randomized controlled trial. Med Sci Monit. 2015;21:2678–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Hong S, Park CY, Han KA, Chung CH, Ku BJ, Jang HC, et al. Efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus: a 24-week multicentre, randomized, double-blind, placebo-controlled phase III trial. Diabetes Obes Metab. 2016;18(5):528–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Ji L, Han P, Wang X, Liu J, Zheng S, Jou YM, et al. Randomized clinical trial of the safety and efficacy of sitagliptin and metformin co-administered to Chinese patients with type 2 diabetes mellitus. J Diab Invest. 2016;7(5):727–36.

    CAS  Article  Google Scholar 

  164. 164.

    Chacra A, Gantz I, Mendizabal G, Durlach L, O'Neill EA, Zimmer Z, et al. A randomised, double-blind, trial of the safety and efficacy of omarigliptin (a once-weekly DPP-4 inhibitor) in subjects with type 2 diabetes and renal impairment. Int J Clin Pract. 2017;71(6):e12955.

  165. 165.

    Home P, Ravi Shankar R, Gantz I, Iredale C, O'Neill EA, Jain L, et al. A randomized, double-blind trial evaluating the efficacy and safety of monotherapy with the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in people with type 2 diabetes. Diabetes Res Clin Pract. 2018;138:253–61.

  166. 166.

    Gantz I, Okamoto T, Ito Y, Okuyama K, O'Neill EA, Kaufman KD, et al. A randomized, placebo- and sitagliptin-controlled trial of the safety and efficacy of omarigliptin, a once-weekly dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017;19(11):1602–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Pratley RE, Fleck P, Wilson C. Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug-naive patients with type 2 diabetes: a randomized, double-blind, 6-month study. Diabetes Obes Metab. 2014;16(7):613–21.

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    Ji L, Li L, Kuang J, Yang T, Kim DJ, Kadir AA, et al. Efficacy and safety of fixed-dose combination therapy, alogliptin plus metformin, in Asian patients with type 2 diabetes: a phase 3 trial. Diabetes Obes Metab. 2017;19(5):754–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Scherbaum WA, Schweizer A, Mari A, Nilsson PM, Lalanne G, Jauffret S, et al. Efficacy and tolerability of vildagliptin in drug-naive patients with type 2 diabetes and mild hyperglycaemia*. Diabetes Obes Metab. 2008;10(8):675–82.

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Ott C, Jumar A, Striepe K, Friedrich S, Karg MV, Bramlage P, et al. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol. 2017;16(1):26.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  171. 171.

    Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(8):721–8.

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Inagaki N, Kondo K, Yoshinari T, Maruyama N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab. 2013;15(12):1136–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2013;15(5):432–40.

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Seino Y, Sasaki T, Fukatsu A, Sakai S, Samukawa Y. Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, placebo-controlled, phase II study. Curr Med Res Opin. 2014;30(7):1219–30.

    CAS  PubMed  Article  Google Scholar 

  175. 175.

    Seino Y, Sasaki T, Fukatsu A, Ubukata M, Sakai S, Samukawa Y. Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study. Curr Med Res Opin. 2014;30(7):1231–44.

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Ikeda S, Takano Y, Cynshi O, Tanaka R, Christ AD, Boerlin V, et al. A novel and selective sodium-glucose cotransporter-2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015;17(10):984–93.

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Sykes AP, Kemp GL, Dobbins R, O'Connor-Semmes R, Almond SR, Wilkison WO, et al. Randomized efficacy and safety trial of once-daily remogliflozin etabonate for the treatment of type 2 diabetes. Diabetes Obes Metab. 2015;17(1):98–101.

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    Sykes AP, O'Connor-Semmes R, Dobbins R, Dorey DJ, Lorimer JD, Walker S, et al. Randomized trial showing efficacy and safety of twice-daily remogliflozin etabonate for the treatment of type 2 diabetes. Diabetes Obes Metab. 2015;17(1):94–7.

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Heerspink HJ, Johnsson E, Gause-Nilsson I, Cain VA, Sjostrom CD. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab. 2016;18(6):590–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217–24.

    PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Bailey CJ, Iqbal N, T'Joen C, List JF. Dapagliflozin monotherapy in drug-naive patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab. 2012;14(10):951–9.

    CAS  PubMed  Article  Google Scholar 

  182. 182.

    Inagaki N, Kondo K, Yoshinari T, Takahashi N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, phase III study. Expert Opin Pharmacother. 2014;15(11):1501–15.

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Kaku K, Watada H, Iwamoto Y, Utsunomiya K, Terauchi Y, Tobe K, et al. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study. Cardiovasc Diabetol. 2014;13:65.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  184. 184.

    Ji L, Ma J, Li H, Mansfield TA, T’Joen CL, Iqbal N, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther. 2014;36(1):84–100 e9.

    CAS  PubMed  Article  Google Scholar 

  185. 185.

    Kashiwagi A, Takahashi H, Ishikawa H, Yoshida S, Kazuta K, Utsuno A, et al. A randomized, double-blind, placebo-controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the long-term ASP1941 safety evaluation in patients with type 2 diabetes with renal impairment (LANTERN) study. Diabetes Obes Metab. 2015;17(2):152–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Kashiwagi A, Kazuta K, Goto K, Yoshida S, Ueyama E, Utsuno A. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2015;17(3):304–8.

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Seino Y, Sasaki T, Fukatsu A, Ubukata M, Sakai S, Samukawa Y. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study. Curr Med Res Opin. 2014;30(7):1245–55.

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Seino Y, Inagaki N, Haneda M, Kaku K, Sasaki T, Fukatsu A, et al. Efficacy and safety of luseogliflozin added to various oral antidiabetic drugs in Japanese patients with type 2 diabetes mellitus. J Diab Invest. 2015;6(4):443–53.

    CAS  Article  Google Scholar 

  189. 189.

    Haneda M, Seino Y, Inagaki N, Kaku K, Sasaki T, Fukatsu A, et al. Influence of renal function on the 52-week efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus. Clin Ther. 2016;38(1):66–88.e20.

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Li FF, Gao G, Li Q, Zhu HH, Su XF, Wu JD, et al. Influence of dapagliflozin on glycemic variations in patients with newly diagnosed type 2 diabetes mellitus. J Diab Res. 2016;2016:5347262.

    Google Scholar 

  191. 191.

    Pollock C, Stefánsson B, Reyner D, et al. Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7(6):429–41.

    CAS  PubMed  Article  Google Scholar 

  192. 192.

    Stenlof K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. 193.

    Terra SG, Focht K, Davies M, Frias J, Derosa G, Darekar A, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab. 2017;19(5):721–8.

    CAS  PubMed  Article  Google Scholar 

  194. 194.

    Aronson R, Frias J, Goldman A, et al. Long-term efficacy and safety of ertugliflozin monotherapy in patients with inadequately controlled T2DM despite diet and exercise: VERTIS MONO extension study. Diab Obes Metab. 2018;20(6):1453.

    CAS  Article  Google Scholar 

  195. 195.

    Lins PE, Lundblad S, Persson-Trotzig E, Adamson U. Glibenclamide improves the response to insulin treatment in non-insulin-dependent diabetics with second failure to sulfonylurea therapy. Acta Med Scand. 1988;223(2):171–9.

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    Stuart CA, Gilkison CR, Carlson RF, Stuart CA, Gilkison CR, Carlson RF. Effect of adding a sulfonylurea in patients with non-insulin-dependent diabetes mellitus previously well controlled with insulin. Endocrine Pract. 1997;3(6):344–8.

    CAS  Article  Google Scholar 

  197. 197.

    Forst T, Uhlig-Laske B, Ring A, Graefe-Mody U, Friedrich C, Herbach K, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diab Med. 2010;27(12):1409–19.

    CAS  Article  Google Scholar 

  198. 198.

    Burant CF, Viswanathan P, Marcinak J, Cao C, Vakilynejad M, Xie B, et al. TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2012;379(9824):1403–11.

    CAS  PubMed  Article  Google Scholar 

  199. 199.

    Schade DS, Mitchell WJ, Griego G. Addition of sulfonylurea to insulin treatment in poorly controlled type II diabetes. A double-blind, randomized clinical trial. Jama. 1987;257(18):2441–5.

    CAS  PubMed  Article  Google Scholar 

  200. 200.

    Stenman S, Groop PH, Saloranta C, Totterman KJ, Fyhrqvist F, Groop L. Effects of the combination of insulin and glibenclamide in type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents. Diabetologia. 1988;31(4):206–13.

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Riddle M, Hart J, Bingham P, Garrison C, McDaniel P. Combined therapy for obese type 2 diabetes: suppertime mixed insulin with daytime sulfonylurea. Am J Med Sci. 1992;303(3):151–6.

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Feinglos M, Dailey G, Cefalu W, Osei K, Tayek J, Canovatchel W, et al. Effect on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM. Diabetes Res Clin Pract. 2005;68(2):167–75.

    CAS  PubMed  Article  Google Scholar 

  203. 203.

    Lewitt MS, Yu VK, Rennie GC, Carter JN, Marel GM, Yue DK, et al. Effects of combined insulin-sulfonylurea therapy in type II patients. Diabetes Care. 1989;12(6):379–83.

    CAS  PubMed  Article  Google Scholar 

  204. 204.

    Riddle MC, Schneider J. Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Glimepiride Combination Group. Diabetes Care. 1998;21(7):1052–7.

    CAS  PubMed  Article  Google Scholar 

  205. 205.

    Roberts VL, Stewart J, Issa M, Lake B, Melis R. Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2005;27(10):1535–47.

    CAS  PubMed  Article  Google Scholar 

  206. 206.

    Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Karlander SG, Gutniak MK, Efendic S. Effects of combination therapy with glyburide and insulin on serum lipid levels in NIDDM patients with secondary sulfonylurea failure. Diabetes Care. 1991;14(11):963–7.

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    Camerini-Davalos RA, Bloodworth JM Jr, Velasco CA, Reddi AS. Effect of insulin-glipizide combination on skeletal muscle capillary basement membrane width in diabetic patients. Clin Ther. 1994;16(6):952–61.

    CAS  PubMed  Google Scholar 

  209. 209.

    Willms B, Ruge D. Comparison of acarbose and metformin in patients with type 2 diabetes mellitus insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study. Diabetic Med. 1999;16(9):755–61.

    CAS  PubMed  Article  Google Scholar 

  210. 210.

    Aviles-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;131(3):182–8.

    CAS  PubMed  Article  Google Scholar 

  211. 211.

    Hermann LS, Kalen J, Katzman P, Lager I, Nilsson A, Norrhamn O, et al. Long-term glycaemic improvement after addition of metformin to insulin in insulin-treated obese type 2 diabetes patients. Diabetes Obes Metab. 2001;3(6):428–34.

    CAS  PubMed  Article  Google Scholar 

  212. 212.

    Douek IF, Allen SE, Ewings P, Gale EA, Bingley PJ. Continuing metformin when starting insulin in patients with type 2 diabetes: a double-blind randomized placebo-controlled trial. Diabetic Med. 2005;22(5):634–40.

    CAS  PubMed  Article  Google Scholar 

  213. 213.

    Gram J, Henriksen JE, Grodum E, Juhl H, Hansen TB, Christiansen C, et al. Pharmacological treatment of the pathogenetic defects in type 2 diabetes: the randomized multicenter South Danish Diabetes Study. Diabetes Care. 2011;34(1):27–33.

    PubMed  Article  Google Scholar 

  214. 214.

    Kooy A, de Jager J, Lehert P, Bets D, Wulffele MG, Donker AJ, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169(6):616–25.

    CAS  PubMed  Article  Google Scholar 

  215. 215.

    Nemoto M, Tajima N, Kawamori R. Efficacy of combined use of miglitol in type 2 diabetes patients receiving insulin therapy-placebo-controlled double-blind comparative study. Acta Diabetol. 2011;48(1):15–20.

    CAS  PubMed  Article  Google Scholar 

  216. 216.

    Hwu CM, Ho LT, Fuh MM, Siu SC, Sutanegara D, Piliang S, et al. Acarbose improves glycemic control in insulin-treated Asian type 2 diabetic patients: results from a multinational, placebo-controlled study. Diabetes Res Clin Pract. 2003;60(2):111–8.

    CAS  PubMed  Article  Google Scholar 

  217. 217.

    Schnell O, Mertes G, Standl E. Acarbose and metabolic control in patients with type 2 diabetes with newly initiated insulin therapy. Diabetes Obes Metab. 2007;9(6):853–8.

    CAS  PubMed  Article  Google Scholar 

  218. 218.

    Kelley DE, Bidot P, Freedman Z, Haag B, Podlecki D, Rendell M, et al. Efficacy and safety of acarbose in insulin-treated patients with type 2 diabetes. Diabetes Care. 1998;21(12):2056–61.

    CAS  PubMed  Article  Google Scholar 

  219. 219.

    Lam KS, Tiu SC, Tsang MW, Ip TP, Tam SC. Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study. Diabetes Care. 1998;21(7):1154–8.

    CAS  PubMed  Article  Google Scholar 

  220. 220.

    Mitrakou A, Tountas N, Raptis AE, Bauer RJ, Schulz H, Raptis SA. Long-term effectiveness of a new alpha-glucosidase inhibitor (BAY m1099-miglitol) in insulin-treated type 2 diabetes mellitus. Diab Med. 1998;15(8):657–60.

    CAS  Article  Google Scholar 

  221. 221.

    Standl E, Baumgartl HJ, Fuchtenbusch M, Stemplinger J. Effect of acarbose on additional insulin therapy in type 2 diabetic patients with late failure of sulphonylurea therapy. Diabetes Obes Metab. 1999;1(4):215–20.

    CAS  PubMed  Article  Google Scholar 

  222. 222.

    Standl E, Schernthaner G, Rybka J, Hanefeld M, Raptis SA, Naditch L. Improved glycaemic control with miglitol in inadequately-controlled type 2 diabetics. Diabetes Res Clin Pract. 2001;51(3):205–13.

    CAS  PubMed  Article  Google Scholar 

  223. 223.

    Lin BJ, Wu HP, Huang HS, Juang JH, Sison A, Bin Abdul Kadir DK, et al. Efficacy and tolerability of acarbose in Asian patients with type 2 diabetes inadequately controlled with diet and sulfonylureas. J Diabetes Complicat. 2003;17(4):179–85.

    CAS  PubMed  Article  Google Scholar 

  224. 224.

    Phillips P, Karrasch J, Scott R, Wilson D, Moses R. Acarbose improves glycemic control in overweight type 2 diabetic patients insufficiently treated with metformin. Diabetes Care. 2003;26(2):269–73.

    CAS  PubMed  Article  Google Scholar 

  225. 225.

    Hsieh SH, Shih KC, Chou CW, Chu CH. Evaluation of the efficacy and tolerability of miglitol in Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylureas. Acta Diabetol. 2011;48(1):71–7.

    CAS  PubMed  Article  Google Scholar 

  226. 226.

    Halimi S, Le Berre MA, Grange 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.

    CAS  PubMed  Article  Google Scholar 

  227. 227.

    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):326–31.

    PubMed  Article  Google Scholar 

  228. 228.

    Johnston PS, Feig PU, Coniff RF, Krol A, Kelley DE, Mooradian AD. Chronic treatment of African-American type 2 diabetic patients with alpha-glucosidase inhibition. Diabetes Care. 1998;21(3):416–22.

    CAS  PubMed  Article  Google Scholar 

  229. 229.

    Johnston PS, Feig PU, Coniff RF, Krol A, Davidson JA, Haffner SM. Long-term titrated-dose alpha-glucosidase inhibition in non-insulin-requiring Hispanic NIDDM patients. Diabetes Care. 1998;21(3):409–15.

    CAS  PubMed  Article  Google Scholar 

  230. 230.

    Bachmann W, Petzinna D, Raptis SA, Wascher T, Westermeier T. Long-term improvement of metabolic control by acarbose in type 2 diabetes patients poorly controlled with maximum sulfonylurea therapy. Clin Drug Invest. 2003;23(10):679–86.

    CAS  Article  Google Scholar 

  231. 231.

    Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effect of combination therapy of troglitazone and sulphonylureas in patients with type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabetic Med. 1996;13(4):365–70.

    CAS  PubMed  Article