Goal achievement of HbA1c and LDL-cholesterol in a randomized trial comparing colesevelam with ezetimibe: GOAL-RCT.

AIM: To compare the efficacy and safety of colesevelam and ezetimibe as second-line low density lipoprotein-cholesterol (LDL-c)-lowering options in type 2 diabetes (T2D). MATERIALS AND METHODS: GOAL-RCT is a 24-week, open-label, randomized, pragmatic clinical trial. Subjects with T2D with uncontrolled HbA1c (7.1%-10%) and LDL-c (>2.0 mmol/L) were randomized 1:1 to colesevelam 3.75 g or ezetimibe 10 mg daily. The primary composite outcome was the proportion of participants achieving an LDL-c target of ≤2.0 mmol/L and HbA1c target of ≤7.0%. Intention to treat analysis was performed. RESULTS: Two hundred subjects were enrolled: mean age 59 ± 10 years; mean HbA1c 8.0%; mean LDL-c 2.5 mmol/L; 97% on statin therapy. The primary composite outcome was achieved by similar proportions of participants with colesevelam (14.6%) and ezetimibe (10.5%) (Pnon-inferiority < .001, Psuperiority = .41). LDL-c reduction from baseline was less with colesevelam compared with ezetimibe (14.0% vs. 23.2%, P < .01), as was the proportion of subjects achieving an LDL-c target of ≤2.0 mmol/L (47.6% and 67.0%, respectively; P = .007). Mean HbA1c was reduced with colesevelam (-0.26 ± 0.10%), while no change was observed with ezetimibe (difference P = .06). Adverse events and discontinuation rates were higher for colesevelam (20.2% and 31.1%) compared with ezetimibe (7.2% and 6.2%), respectively. CONCLUSIONS: Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL-c and HbA1c within target), with ezetimibe recording a greater LDL-c reduction and better tolerability than colesevelam.

Glycemic Improvement with a Fixed-dose combination of DPP-4 inhibitor + metformin in patients with Type 2 diabetes (GIFT study).

This study investigates changes in A1C following a switch from dual therapy of metformin and DPP-4 inhibitor to a fixed-dose combination (FDC) of metformin + DPP-4 inhibitor following the introduction of the FDC in the provincial formulary. The LMC Diabetes Registry was queried retrospectively for patients with type 2 diabetes, aged between 18 and 80 years with at least one A1C recorded prior and ≥3 months post-switch. Five hundred and sixty-eight subjects with mean age 64 ± 12 years and mean A1C 7.7% ± 1.2% met study criteria. Overall, A1C was 0.3% lower post-switch to FDC (P < .01). In stratified analysis, subjects with baseline A1C between 7% and 10% had 0.4% lower A1C (P < .01), with 31% of these subjects reaching target A1C ≤7%, post-switch. A1C reduction was greater among patients with a higher baseline pill burden: 0.4% among those using ≥10 pills/day vs. 0.1% for those with <10 pills/day (P = .02). In this real-world study, switching to FDC of metformin + DPP-4 inhibitor was associated with a significant improvement in A1C. Switching to FDC, especially in patients with high pill burden, can improve A1C goal achievement in clinical practice.

Randomized Comparison of Initiating the Fixed-Ratio Combination of iGlarLixi or Biosimilar Insulin Glargine Together With Gliclazide in Participants of South Asian Origin With Type 2 Diabetes: VARIATION 2 SA Trial.

OBJECTIVES: The objective of this study was to compare initiation of a fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) vs insulin glargine U100 (iGlar) along with gliclazide, exclusively in people of South Asian origin with type 2 diabetes (T2D). METHODS: The Variability of glucose Assessed in a Randomized trial comparing the Initiation of A Treatment approach with biosimilar basal Insulin analog Or a titratable iGlarLixi combinatioN in type 2 diabetes among South Asian participants (VARIATION 2 SA) trial (ClinicalTrials.gov identifier: NCT03819790) randomized insulin-naïve adults with T2D having glycated hemoglobin (A1C) 7.1% to 11% to initiate either iGlarLixi or iGlar + gliclazide. Insulin doses were titrated similarly to a prebreakfast glucose target of 4.0 to 5.5 mmol/L. Average time in range (TIR) on a masked continuous glucose monitor (CGM), A1C, fasting plasma glucose (FPG) and weight were assessed at the end of the 12-week treatment period. RESULTS: Mean baseline characteristics for the 104 randomized participants were similar between treatment groups, including the following: age, 59±11 years; diabetes duration, 13.7±7.3 years; and A1C, 8.5%±1.2%. Coprimary outcomes of average TIRs within 24- and 12-h (6 am to 6 pm) periods at the end of trial were 70.5%±16.8% and 72.9%±17.6% for iGlarLixi, whereas these TIRs were 65.6%±21.6% and 67.3%±20.7% for the iGlar + gliclazide regimen, respectively, with no significant differences between groups (p=0.35 for 24-h TIR and p=0.14 for 12-h TIR). No significant difference in secondary outcomes was observed between treatment groups. Self-reported hypoglycemic events throughout the trial period and CGM-reported hypoglycemia (<4 and <3 mmol/L) were similar between randomized treatments. CONCLUSIONS: Initiation of iGlarLixi resulted in similar TIR, A1C, FPG, weight and hypoglycemia compared with the more affordable option of starting iGlar + gliclazide in adults of South Asian origin with T2D.

Lowest Glucose Variability and Hypoglycemia Are Observed With the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study).

OBJECTIVE: There is a dearth of published literature comparing glucose variability (GV) between different insulin regimens in type 2 diabetes. This cohort study compares GV using continuous glucose monitoring (CGM) in patients with well-controlled type 2 diabetes using four common insulin regimens: basal insulin + oral drugs (BO), basal insulin + glucagon-like peptide 1 receptor agonist (GLP-1 RA) (BGLP), premixed insulin (PM), and basal-bolus insulin (BB). RESEARCH DESIGN AND METHODS: Consecutive patients from three endocrinology clinics who met study criteria-type 2 diabetes, age 18 to 80 years, BMI ≤ 45 kg/m2, stable insulin regimen for a minimum of 6 months, and stable A1C value ≤7.5% (58 mmol/mol) before study enrollment-underwent 6-day masked CGM. Hypoglycemia was defined as a sensor glucose concentration <70 mg/dL on CGM. RESULTS: A total of 160 patients with comparable baseline characteristics formed four equal insulin regimen cohorts. The daily glucose SD (the primary outcome) was significantly lower in the BGLP cohort versus the BO, PM, and BB cohorts (P = 0.03, P = 0.01, and P < 0.01, respectively), and remained so after adjusting for age, BMI, type 2 diabetes duration, and A1C. Similarly, daily hypoglycemia outcomes on CGM were least for the BGLP cohort. CONCLUSIONS: The lowest GV and lowest hypoglycemia were observed in patients using the combination of basal insulin with a GLP-1 RA, supporting the complementary glycemic action of these agents in type 2 diabetes. These observed benefits in GV and hypoglycemia may contribute to the cardiovascular outcome reduction seen with GLP-1 RA therapy and should be investigated further.

Randomized Trial of Long-Acting Insulin Glargine Titration Web Tool (LTHome) Versus Enhanced Usual Therapy of Glargine Titration (INNOVATE Trial).

BACKGROUND: Basal insulin titration in the real world is often unsuccessful. LTHome, a web tool, applies a rules engine-based algorithm providing insulin titration advice directly to the patient. METHODS: This pilot, randomized trial evaluates basal insulin glargine titration by LTHome compared to enhanced usual therapy ([EUT]-diabetes education program) over 12 weeks. Important inclusion criteria: 18-75 years, type 2 diabetes, computer literacy, and HbA1c >7.0%. Trial protocol was approved by ethics board. RESULTS: We randomized 139 subjects. The achievement of primary composite outcome (four out of seven fasting plasma glucose [FPG] within 5-7.2 mmol/L + mean for three consecutive FPG within 5-7.2 mmol/L + no severe hypoglycemia) was 15% in LTHome versus 41% in EUT (noninferiority not met, P-value = 0.92). Other outcomes were similar between the LTHome and EUT arms: alternate composite outcome achievement (last five FPG mean within the range of 5-7.2 mmol/L + no hypoglycemia, 47% and 51%, P = 0.73); A1c reduction (-1.0% and -1.1%, P = 0.66); proportion achieving A1c ≤7% (14% and 20%, P = 0.36); and hypoglycemia incidence (31% and 37%, P = 0.4), respectively. Patient satisfaction score improvements were greater in LTHome versus EUT (change in fear of hypoglycemia score P = 0.04 and change in diabetes distress score P = 0.04). The mean number of additional healthcare provider visits was 0.13 for LTHome and 1.22 for EUT (P < 0.01). CONCLUSION: INNOVATE trial suggests clinical utility of LTHome compared to EUT in real-life settings. Further research is needed to evaluate the efficacy and safety of automated insulin titration algorithms.

The Need Associated with Diabetes Primary Care and the Impact of Referral to a Specialist-Centered Multidisciplinary Diabetes Program (the NADIR Study).

OBJECTIVE: The impact of specialist care on glycemia and cardiovascular risk factors in patients with diabetes is uncertain. This observational cohort study investigated metabolic risk factors in patients referred to LMC Diabetes & Endocrinology for diabetes management. METHODS: The cohort included 306 consecutive patients with diabetes referred to LMC in Ontario between January and June 2010. Sources of prereferral data included consultation notes, records from primary care physicians and the Ontario Lab Information System. Postreferral data were obtained from LMC's patients' records. RESULTS: The mean duration of diabetes before referral was 11 years, and the mean baseline glycated hemoglobin (A1C) level was 8.8%. Among patients with uncontrolled A1C levels at baseline, 73% had had no A1C values ≤7% for up to 6 years before referral. Following referral, mean A1C levels decreased to 7.8% at 6 and 12 months (both p<0.001 vs. baseline). Attendance at diabetes education programs improved from 28% to 67% postreferral, and attendees achieved significantly greater A1C reductions than nonattendees (mean 1.1% vs. 0.7%, respectively). Mean low-density lipoprotein levels declined from 2.3 mmol/L at referral to 1.8 mmol/L at 12 months (p<0.05). Mean blood pressure was similar, at 128/75 before and 129/75 mm Hg after referral; however, following referral, blood pressure improved from 143/89 to 134/80 (p<0.001) in patients with previously uncontrolled blood pressure. Use of guideline-recommended medications increased significantly following referral. CONCLUSION: Referral to specialist care should be considered early in the course of diabetes in order to optimize management of glycemia and cardiovascular risk factors.