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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-naïve patients with type 2 diabetes. Methods: Sixty-eight patients completed the 6-year follow-up and had an end-ofstudy (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 = À0.48, 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

OBJECTIVE To examine the mechanisms responsible for the increase in glucose and ketone production caused by empagliflozin in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Twelve subjects with T2DM participated in two studies performed in random order. In study 1, endogenous glucose production (EGP) was measured with 8-h infusion of 6,6,D2-glucose. Three hours after the start of 6,6,D2-glucose infusion, subjects ingested 25 mg empagliflozin (n = 8) or placebo (n = 4), and norepinephrine (NE) turnover was measured before and after empagliflozin ingestion with 3H-NE infusion. Study 2 was similar to study 1 but performed under pancreatic clamp conditions. RESULTS When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (−34 mg/dL) and insulin (−52%) concentrations and increases in plasma glucagon (+19%), free fatty acid (FFA) (+29%), and β-hydroxybutyrate (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate was greater in subjects receiving empagliflozin (+67%) compared with placebo under both fasting and pancreatic clamp conditions. No difference in plasma NE concentration was observed in either study. CONCLUSIONS The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is likely explained by the increase in NE turnover.

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‐β). 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.

Aim To identify predictors for individualization of antidiabetic therapy in patients with new onset T2DM. Research Design and Methods 261 drug naïve participants in the EDICT study, with new onset diabetes, were randomized in a single-center study to receive: (1) metformin followed by glipizide and then insulin glargine upon failure to achieve HbA1c &lt;6.5%, or (2) initial triple therapy with metformin/pioglitazone/ exenatide. Each patient received 75-gram OGTT prior to start of therapy. Factors that predicted response to therapy were identified using the aROC method. Results 39 patients started and maintained the treatment goal (HbA1c &lt;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 C-Pep120/C-Pep0 ratio during the OGTT was the strongest predictor of response to therapy. Patients with ratio &lt;1.78 were more likely to require insulin for glucose control, while patients with ratio &gt;2.65 were more likely to achieve glucose control with metformin monotherapy. In patients started on initial Triple Therapy the HbA1c decreased independent of C-Pep120/C-Pep0 ratio. Conclusion The increase in plasma C-peptide concentration 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 individualization of antihyperglycemic therapy in patients with new onset diabetes.