Introduction To compare carotid intima–media thickness (cIMT) and liver fat content in subjects who maintained good glycemic control for 6 years on initial triple therapy with metformin/exenatide/pioglitazone versus sequential add-on therapy with metformin followed with glipizide and basal insulin in subjects with new-onset diabetes.Research design and methods Liver fat content and cIMT were compared among patients with T2DM who received initial triple therapy with metformin/pioglitazone/exenatide (n=29) versus metformin, followed by stepwise addition of glipizide and then insulin glargine (n=26) and who maintained HbA1c<6.5% for 6 years in Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes.Results After 6 years in subjects receiving initial triple therapy with metformin/pioglitazone/exenatide and subjects receiving sequential addition of metformin followed by glipizide and insulin glargine had a mean HbA1c of 5.7% vs 6.0%, respectively, p=NS. Nonetheless, subjects receiving sequential add-on therapy experienced a greater increase in cIMT and manifested greater liver fat content and fibrosis than subjects receiving initial triple therapy.Conclusions Including pioglitazone plus exenatide in the glucose-lowering regimen slows the progression of cIMT and was associated with lower hepatic fat content and fibrosis compared with subjects receiving sequential add-on therapy without pioglitazone and exenatide despite comparable optimal glycemic control.Trial registration number NCT01107717.

Beta cell failure is the key pathophysiologic determinant in progression from PreDM to type 2 diabetes (T2D). Lifestyle modifications frequently are insufficient to prevent T2D onset and drugs that modify disease progression by targeting pathophysiologic defects in PreDM may be required. Methods: EPIC seeks to answer whether a specific drug provides greater benefit to prevent PreDM progression and to assess the effect of two years of treatment with antidiabetic drugs in 200 individuals with IFG and/or IGT on insulin sensitivity (IS) and beta cell function (BCF). At baseline, participants received 2h-OGTT and two-step hyperglycemic clamp (HC) (+125 and +400 mg/dl) with GLP-1RA infusion. Subjects then were randomized to metformin (MET), pioglitazone (PIO), saxagliptin (SAXA) or dapagliflozin (DAPA). 55 participants have completed the intervention (35F/20M; age = 51 ± 3 ys) Matsuda Index of IS was quantitated from OGTT. Beta Cell Function (BCF) was quantitated: (i) from OGTT as (ΔC-Pep/ΔG) x (Matsuda) and (ii) from HC as ΔC-Pep (First Phase, AIR x Matsuda; ΔC-Pep (Second Phase, +400 mg/dL x Matsuda; and (Second Phase + Exenatide) x Matsuda. Results: A1c did not change significantly in any group, while FPG (106 ±4 to 100 ± 3 mg/dl) and 2h PG (150 ±8 to 141 ± 11) decreased significantly in all groups (p<0.05 for PIO > SAXA). Matsuda Index increased in all groups (p<0.01 for PIO vs all other groups). Weight increased significantly in PIO (+2.5kg p<0.05), did not change with SAXA, decreased with DAPA and MET (both p = NS). BCF during OGTT tended to increase in all groups (p<0.10 for trend). No significant changes in AIR, second phase (+400 mg/dl), and second phase (+400) + Exenatide were seen for MET, SAXA, DAPA, but significantly increased with PIO (AIR 7.1 to 22.8; 2ND STEP 10 to 45.4; 2nd STEP + Exenatide 19 to 79 (all p <0.01). Conclusion: Early drug intervention in prediabetes with pioglitazone preserves beta cell function and improves insulin sensitivity better than MET, SAXA, and DAPA. Disclosure A. Chavez: None. A. Merovci: None. S. Neppala: None. L. A. Cruz Moreno: None. G. Baskoy: None. F. M. Acosta: None. A. A. Hansis-Diarte: None. C. L. Puckett: None. J. M. Adams: None. M. Abdul-Ghani: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. E. Cersosimo: None. R. A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc. Funding National Institutes of Health (R01DK024092-3AZ, ISSDAPA0002)

Aim To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin -> glipizide -> glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naive patients with type 2 diabetes. Methods Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat. Results At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = -0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS. Conclusions At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy.

Aim To examine the efficacy of glucose-lowering medications in subgroups of patients with type 2 diabetes mellitus (T2DM). Research design and methods Cluster analysis was performed in participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study and the Qatar study using age, body mass index (BMI), glycated haemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta). Participants also underwent an oral glucose tolerance test with measurement of plasma glucose, insulin and C-peptide concentrations to derive independent measures of insulin secretion and insulin sensitivity. The response to glucose-lowering therapies (change in HbA1c) was measured in each participant cluster for 3 years. Results Three distinct and comparable clusters/groups of T2DM patients were identified in both the EDICT and Qatar studies. Participants in Group 1 had the highest HbA1c and manifested severe insulin deficiency. Participants in Group 3 had comparable insulin sensitivity to those in Group 1 but better beta-cell function and better glucose control. Participants in Group 2 had the highest BMI with severe insulin resistance accompanied by marked hyperinsulinaemia, which was primarily attributable to decreased insulin clearance. Unexpectedly, participants in Group 1 had better response to combination therapy with pioglitazone plus exenatide than with insulin therapy or metformin sequentially followed by glipizide and basal insulin, while participants in Group 2 responded equally well to both therapies despite very severe insulin resistance. Conclusion Distinct metabolic phenotypes characterize different T2DM clusters and differential responses to glucose-lowering therapies. Participants with severe insulin deficiency respond better to agents that preserve beta-cell function, while, surprisingly, patients with severe insulin resistance did not respond favourably to insulin sensitizers.

To identify predictors of response to glucose‐lowering therapy in patients with new‐onset diabetes and very high HbA1c (>10%).

CONTEXT:The results of the present study demonstrate that beta cell function in newly diagnosed T2DM patients is the key predictor of response to glucose lowering medications and provides a practical tool (C-Pep120 /C-Pep0) to guide the choice of glucose lowering agent. OBJECTIVE:This work aims to identify predictors for individualization of antidiabetic therapy in patients with new-onset type 2 diabetes mellitus (T2DM). METHODS:A total of 261 drug-naive participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study, with new-onset diabetes, were randomly assigned in a single-center study to receive 1) metformin followed by glipizide and then insulin glargine on failure to achieve glycated hemoglobin A1c (HbA1c) less than 6.5%, or 2) initial triple therapy with metformin/pioglitazone/exenatide. Each patient received a 75-g oral glucose tolerance test (OGTT) prior to start of therapy. Factors that predicted response to therapy were identified using the area under the receiver operating characteristic curve method. RESULTS:Thirty-nine patients started and maintained the treatment goal (HbA1c < 6.5%) on metformin only, and did not require intensification of antihyperglycemic therapy; 54 patients required addition of glipizide to metformin; and 47 patients required insulin addition to metformin plus glipizide for glucose control. The plasma C-peptide concentration (C-Pep)120/C-Pep0 ratio during the OGTT was the strongest predictor of response to therapy. Patients with a ratio less than 1.78 were more likely to require insulin for glucose control, whereas patients with a ratio greater than 2.65 were more likely to achieve glucose control with metformin monotherapy. In patients started on initial triple therapy, the HbA1c decreased independently of the C-Pep120/C-Pep0 ratio. CONCLUSION:The increase in C-Pep above fasting following glucose load predicts the response to antihyperglycemic therapy in patients with new-onset diabetes. C-Pep120/C-Pep0 provides a useful tool for the individualization of antihyperglycemic therapy in patients with new-onset T2DM.

Objective: To compare the long term efficacyof initiating therapy with metformin/pioglitazone/exenatide in new onset T2DMpatients versus sequential addition of metformin followed by glipizide andinsulin. Research Design and Methods: 318 drug naïve,new onset T2DM were randomized to receive for 3 years: (1) combination therapywith metformin/pioglitazone/ exenatide (Triple Therapy) or (2) sequential addition of metformin followed by glipizideand insulin (Conventional Therapy) to maintain HbA1c <6.5% (48 mmol/mol). Insulinsensitivity and beta cell function were measured at baseline and at 3 years.The primary outcome was the difference in HbA1c between the groups at 3years. Results: Baseline HbA1c was 9.0±0.2% and8.9±0.2% in the Triple Therapy and Conventional Therapy groups. The decrease inHbA1c produced by Triple Therapy was greater at 6 months than ConventionalTherapy (0.30%, 95% CI=0.21-0.39) (p=0.001), and the HbA1c reduction wasmaintained at 3 years in subjects receiving Triple Therapy compared toConventional Therapy (6.4±0.1% and 6.9±0.1%, respectively) despiteintensification of antihyperglycemic therapy in the latter. Thus, thedifference in HbA1c between the two treatment groups at 3 years was 0.50% (95%CI=0.39-0.61, P<0.0001). Triple Therapy produced 3-fold increasein insulin sensitivity and 30-fold increase in beta cell function. In Conventional Therapy insulin sensitivity did not change and betacell function increased by only 34% (both p<0.0001 versus Triple Therapy). Conclusion: Triple Therapy with agents that improve insulinsensitivity and beta cell function in new onset T2DM patients produce greater,more durable HbA1c reduction, than agents that lower glucose without correctingthe underlying metabolic defects.

Patients with NAFLD and T2DM are at high risk of liver fibrosis. Pioglitazone(Pio) and GLP-1RAs have shown efficacy against NAFLD. The EDICT trial assessed Triple (pio/exenatide/metformin(met)) vs. Conventional(Conv) (met/SU/insulin) Therapy. Aim: Evaluate the effect of these approaches on liver fibrosis scores and hepatic fibrosis, steatosis (FibroScan). Methods: 144 newly diagnosed T2DM were randomized to receive Triple or Conv Therapy to maintain HbA1c <6.5%. After 2 yrs baseline measurements were repeated and liver fibrosis scores (AST/ALT ratio, APRI, FIB-4, NFS) were calculated. Results: Patients were well matched for age, BMI, HbA1c (8.8%), LFTs. Neither therapy reduced any liver fibrosis score. Triple, but not Conv, reduced AST/ALT (p<0.001). The greatest AST/ALT reductions with Triple Therapy occurred in subjects in highest AST/ALT tertile at baseline. Only 1 subject receiving Triple Therapy had fibrosis score >0, while 43% of Conv Therapy subjects had fibrosis score of F3/F4 (p<0.0001). 87% of Conv Therapy subjects had steatosis score of S2/S3 vs. to 38% of Triple Therapy (p<0.001) (Table). Conclusion: Both Triple (6.0%) and Conventional Therapy (6.7%) markedly reduced HbA1c after 2 yrs, but only Triple Therapy reduced AST/ALT. Fibrosis scores did not change in either group and are not useful in predicting response to therapy. Triple Therapy completely prevented fibrosis and reduced steatosis by >50 % vs. Conventional Therapy. Disclosure O. Lavrynenko: None. M. Alatrach: None. M. Abdul-Ghani: None. E. Cersosimo: None. N. Alkhouri: Research Support; Self; Allergan plc. C.L. Puckett: None. R.A. DeFronzo: None. J.M. Adams: None. J.A. Vasquez: None. G.D. Clarke: None.

Background: Patients with NAFLD and T2DM are at high risk of developing liver fibrosis. Pioglitazone and GLP1 RAs have shown some efficacy against NAFLD. EDICT is an interventional trial assessing Triple Therapy (pioglitazone/ exenatide/ metformin) versus Conventional Therapy (metformin/ glimepiride/ glargine insulin). Aim: To evaluate the effect of these two approaches on liver fibrosis scores after two years. Methods: 144 newly diagnosed T2DM patients were enrolled. Blood was drawn for plasma glucose, HbA1c and LFTs. Subjects were randomized to receive Triple Therapy or Conventional Therapy to maintain HbA1c <6.5%. After 2 years baseline measurements were repeated and liver fibrosis scores (AST/ALT ratio, APRI, FIB-4, NFS) were calculated. Results: At baseline patients were well matched for age, gender, BMI, HbA1c, LFTs. The ratio between the 2-year values of liver fibrosis scores to baseline values was compared between groups. Neither therapy significantly reduced any of the liver fibrosis scores. Triple, but not Conventional, Therapy reduced both AST and ALT (p<0.001). The greatest reductions in AST and ALT in the Triple Therapy group were observed in diabetic subjects in the highest tertile of AST and ALT at baseline. Conclusion: In patients with new-onset T2DM, both Triple Therapy and Conventional Therapy markedly reduced HbA1c after 2 years, but only Triple Therapy reduced AST and ALT. Fibrosis scores did not change in either group and are unlikely to be useful in predicting response to therapeutic interventions. Measurement of hepatic fibrosis (Fibroscan) and liver fat content (MRI PDFF) showed marked progression in Conventional versus Triple Therapy.

Background: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study has enrolled a racially and ethnically diverse population with type 2 diabetes, performed extensive phenotyping, and randomly assigned the participants to one of four second-line diabetes medications. The continuous glucose monitoring (CGM) substudy has been added to determine whether there are racial/ethnic differences in the relationship between average glucose (AG) and hemoglobin A1c (HbA1c). CGM will also be used to compare time in target range, glucose variability, and the frequency and duration of hypoglycemia across study groups. Methods: The observational CGM substudy will enroll up to 1800 of the 5047 GRADE study participants from the four treatment groups, including as many as 450 participants from each of 4 racial/ethnic minority groups to be compared: Hispanic White, non-Hispanic White, non-Hispanic African American, and non-Hispanic Other. CGM will be performed for 2 weeks in proximity to a GRADE annual visit, during which an oral glucose tolerance test will be performed and HbA1c and glycated albumin measured. Indicators of interindividual variation in red blood cell turnover, based on specialized erythrocyte measurements, will also be measured to explore the potential causes of interindividual HbA1c variations. Conclusions: The GRADE CGM substudy will provide new insights into whether differences exist in the relationship between HbA1c and AG among different racial/ethnic groups and whether glycemic profiles differ among frequently used diabetes medications and their potential clinical implications. Understanding such differences is important for clinical care and adjustment of diabetes medications in patients of different races or ethnicities.

Background: We previously have shown that initial combination therapy with metformin/pioglitazone/exenatide (Triple Therapy) produced greater reduction in A1c than sequential add-on therapy in subjects with new onset of type 2 diabetes (T2D). Research Design and Methods: The EDICT study is a randomized open-label study in which newly diagnosed drug-naïve T2D subjects with new onset diabetes were randomized to receive Triple Therapy (n=132) or escalating dose of metformin followed by sequential addition of glipizide and then glargine insulin (Conventional Therapy) (n=146) to maintain A1c< 6.5. Here, we report the 6-year follow-up results. Results: Subjects receiving Triple Therapy experienced a significantly greater reduction in A1c after a mean follow-up of 6 years vs. Conventional Therapy (5.8% vs. 6.7%, p<0.001) (Figure 1). Further, more subjects maintained HbA1c <6.5% in the Triple Therapy group (25%) than in the Conventional Therapy (52%). Progression of carotid IMT (read blindly) was reduced by >50% (P<0.001) in Triple Therapy vs. Insulin Therapy. Conclusion: The results of this study demonstrate that combination therapy with metformin/pioglitazone/ exenatide in newly diagnosed T2DM patients produces greater and more reduction in A1c than sequential add-on therapy with metformin, sulfonylurea, and basal insulin. Disclosure M. Abdul-Ghani: None. C.L. Puckett: None. C.L. Triplitt: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc. D. Maggs: Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Employee; Self; Fractyl Laboratories, Inc.. Stock/Shareholder; Spouse/Partner; Gelesis. Employee; Spouse/Partner; Gelesis. J.M. Adams: None. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..

AIM:To test our hypothesis that initiating therapy with a combination of agents known to improve insulin secretion and insulin sensitivity in subjects with new-onset diabetes would produce greater, more durable reduction in glycated haemoglobin (HbA1c) levels, while avoiding hypoglycaemia and weight gain, compared with sequential addition of agents that lower plasma glucose but do not correct established pathophysiological abnormalities. METHODS:Drug-naïve, recently diagnosed subjects with type 2 diabetes mellitus (T2DM) were randomized in an open-fashion design in a single-centre study to metformin/pioglitazone/exenatide (triple therapy; n = 106) or an escalating dose of metformin followed by sequential addition of sulfonylurea and glargine insulin (conventional therapy; n = 115) to maintain HbA1c levels at <6.5% for 2 years. RESULTS:Participants receiving triple therapy experienced a significantly greater reduction in HbA1c level than those receiving conventional therapy (5.95 vs. 6.50%; p < 0.001). Despite lower HbA1c values, participants receiving triple therapy experienced a 7.5-fold lower rate of hypoglycaemia compared with participants receiving conventional therapy. Participants receiving triple therapy experienced a mean weight loss of 1.2 kg versus a mean weight gain of 4.1 kg (p < 0.01) in those receiving conventional therapy. CONCLUSION:The results of this exploratory study show that combination therapy with metformin/pioglitazone/exenatide in patients with newly diagnosed T2DM is more effective and results in fewer hypoglycaemic events than sequential add-on therapy with metformin, sulfonylurea and then basal insulin.

Background: In UKPDS stepwise addition of metformin, sulfonylurea, and basal insulin reduced microvascular complications, but A1c rose progressively to > 8.5% and ~ 65% of individuals required insulin therapy aft er 10.5 years. Yet metformin, add SU, add insulin remains the most frequently employed therapeutic recommendation in the US and other countries.