Post Hoc Analysis Evaluating the Impact of Antihyperglycemic Background Therapies on Attainment of A1C Targets Without Hypoglycemia in the ACHIEVE Control Pragmatic, Real-Life Study.

BACKGROUND: ACHIEVE Control, a prospective, open-label, randomized, pragmatic, real-life study in insulin-naive people with type 2 diabetes (A1C 8.0-11.0%), demonstrated superiority of insulin glargine 300 units/mL (Gla-300) versus first-generation standard-of-care basal insulin (SOC-BI; glargine 100 units/mL or insulin detemir) in achieving individualized A1C targets without documented symptomatic (glucose ≤3.9 mmol/L [≤70 mg/dL] or <3.0 mmol/L [<54 mg/dL]) or severe hypoglycemia (American Diabetes Association level 3) at 6 months. Noninsulin antihyperglycemic background therapies are commonly used; however, sulfonylureas may increase hypoglycemia risk. This post hoc analysis assessed outcomes according to background therapy. METHODS: Subgroup analyses were performed per concomitant use/nonuse of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase 4 inhibitors, or sodium-glucose cotransporter 2 (SGLT2) inhibitors. End points (6 and 12 months) included A1C target attainment without documented symptomatic or severe hypoglycemia, A1C target attainment, and absence of documented symptomatic or severe hypoglycemia. RESULTS: Odds ratios (ORs) at 12 months mostly favored Gla-300 versus SOC-BI across subgroups except in analysis of SGLT2 inhibitors, in which ORs were similar. Among sulfonylurea users, ORs at 12 months strongly favored Gla-300 versus SOC-BI for all end points, particularly A1C target achievement without documented symptomatic hypoglycemia (glucose ≤3.9 mmol/L [≤70 mg/dL]; OR 1.25, 95% CI 1.02-1.53) or severe hypoglycemia and achievement of no documented symptomatic hypoglycemia (glucose <3.0 mmol/L [<54 mg/dL]; OR 1.25, 95% CI 1.02-1.52) or severe hypoglycemia. CONCLUSION: The results suggest that, in insulin-naive people with type 2 diabetes, Gla-300 is effective with a risk of hypoglycemia that is lower than or similar to that of SOC-BI regardless of background medication. Individuals receiving concomitant sulfonylureas were more likely to remain without symptomatic or severe hypoglycemia with Gla-300.

Application of Machine Learning Models to Evaluate Hypoglycemia Risk in Type 2 Diabetes.

INTRODUCTION: To identify predictors of hypoglycemia and five other clinical and economic outcomes among treated patients with type 2 diabetes (T2D) using machine learning and structured data from a large, geographically diverse administrative claims database. METHODS: A retrospective cohort study design was applied to Optum Clinformatics claims data indexed on first antidiabetic prescription date. A hypothesis-free, Bayesian machine learning analytics platform (GNS Healthcare REFS™: Reverse Engineering and Forward Simulation) was used to build ensembles of generalized linear models to predict six outcomes defined in patients' 1-year post-index claims history, including hypoglycemia, antidiabetic class persistence, glycated hemoglobin (HbA1c) target attainment, HbA1c change, T2D-related inpatient admissions, and T2D-related medical costs. A unified set of 388 variables defined in patients' 1-year pre-index claims history constituted the set of predictors for all REFS models. RESULTS: The derivation cohort comprised 453,487 patients with a T2D diagnosis between 2014 and 2017. Patients with comorbid conditions had the highest risk of hypoglycemia, including those with prior hypoglycemia (odds ratio [OR] = 25.61) and anemia (OR = 1.29). Other identified risk factors included insulin (OR = 2.84) and sulfonylurea use (OR = 1.80). Biguanide use (OR = 0.75), high blood glucose (> 125 mg/dL vs. < 100 mg/dL, OR = 0.47; 100-125 mg/dL vs. < 100 mg/dL, OR = 0.53), and missing blood glucose test (OR = 0.40) were associated with reduced risk of hypoglycemia. Area under the curve (AUC) of the hypoglycemia model in held-out testing data was 0.77. Patients in the top 15% of predicted hypoglycemia risk constituted 50% of observed hypoglycemic events, 26% of T2D-related inpatient admissions, and 24% of all T2D-related medical costs. CONCLUSIONS: Machine learning models built within high-dimensional, real-world data can predict patients at risk of clinical outcomes with a high degree of accuracy, while uncovering important factors associated with outcomes that can guide clinical practice. Targeted interventions towards these patients may help reduce hypoglycemia risk and thereby favorably impact associated economic outcomes relevant to key stakeholders.

Switching to insulin glargine 300 units/mL in real-world older patients with type 2 diabetes (DELIVER 3).

AIM: To compare the second-generation basal insulin glargine 300 units/mL (Gla-300) and first-generation basal insulins on glycaemic control and hypoglycaemia risk in older adults with type 2 diabetes (T2D). MATERIALS AND METHODS: DELIVER 3 was a retrospective observational cohort study of electronic medical records. A total of 1176 older adults (aged ≥ 65 years) with T2D and ≥1 HbA1c value during 6 month baseline and 3 to 6 month follow-up who switched from basal insulin to Gla-300 were propensity score-matched to 1176 older adults who switched to a first-generation basal insulin [insulin detemir (IDet) or insulin glargine 100 units/mL (Gla-100)]. Outcomes were follow-up HbA1c, achievement of HbA1c <7% and <8%, hypoglycaemia incidence and event rates, and healthcare resource utilization. RESULTS: Following basal insulin switching, HbA1c reductions were greater/similar with Gla-300 versus IDet/Gla-100 (variable follow-up: -0.45% ± 1.40% vs. -0.29% ± 1.57%; P = .021; fixed follow-up: -0.48% ± 1.49% vs. -0.38% ± 1.59%; P = .114), while HbA1c goal attainment was similar in both cohorts. Gla-300 was associated with less hypoglycaemia [event rate: adjusted rate ratio (aRR): 0.63, 95% CI: 0.53-0.75; P < .001] and inpatient/emergency department-associated hypoglycaemia (adjusted hazard ratio: 0.58, 95% CI: 0.37-0.90; P = .016; aRR: 0.43, 95% CI: 0.31-0.60; P < .001) by variable follow-up. By fixed follow-up, hypoglycaemia results significantly or numerically favoured Gla-300. CONCLUSION: Among older adults with T2D, switching to Gla-300 versus Gla-100/IDet was associated with greater/similar improvements in glycaemic control, and generally less hypoglycaemia.

Glycaemic goal attainment and hypoglycaemia outcomes in type 2 diabetes patients initiating insulin glargine 300 units/mL or 100 units/mL: Real-world results from the DELIVER Naïve cohort study.

AIMS: To compare HbA1c and hypoglycaemia in insulin-naïve patients with type 2 diabetes (T2D) who initiated insulin glargine 300 units/mL (Gla-300) or 100 units/mL (Gla-100). MATERIALS AND METHODS: This retrospective cohort study examined electronic medical records of insulin-naïve adults with T2D who initiated Gla-300 or Gla-100 during March 2015 through to December 2016 with active records for ≥12 months before and ≥6 months after initiation, and ≥1 valid HbA1c value during 6-month baseline and 90-180-day follow-up. Outcomes included HbA1c and hypoglycaemia. Cohorts were propensity score-matched (1:2) on baseline demographic and clinical characteristics. Sensitivity analyses were conducted using broader inclusion criteria. RESULTS: The matched cohorts included 1004 Gla-300 and 2008 Gla-100 initiators (mean age 60.4 years; 53.2% male). During 6-month follow-up, Gla-300 versus Gla-100 initiators had a greater mean HbA1c decrease (-1.52 ± 2.08% vs. -1.30 ± 2.12%; P = 0.003) and more patients achieved HbA1c <7% (25.0% vs. 21.5%; P = 0.029) and <8% (55.0% vs. 49.2%; P = 0.002); and HbA1c <7% (21.9% vs. 17.4%; P = 0.003) and <8% (49.1% vs. 41.8%; P < 0.001) without hypoglycaemia. Gla-300 initiators were similarly or less likely to have any or inpatient/emergency department-associated hypoglycaemia during 3- and 6-month follow-up (e.g. any hypoglycaemia to 6 months: 9.7% vs. 12.5%; adjusted odds ratio 0.61; P = 0.057). CONCLUSIONS: Among insulin-naïve adults with T2D, Gla-300 was associated with significantly better HbA1c reductions (latest value during 90-180-day follow-up) and similar or improved hypoglycaemia outcomes (3- and 6-month follow-up) than Gla-100.

Impact of a structured patient support program on adherence and persistence in basal insulin therapy for type 2 diabetes.

OBJECTIVE: Treatment adherence and persistence are essential to achieving therapeutic goals in diabetes and may be improved by patient support programs (PSPs). The COACH Program was launched in 2015 with the goal of supporting patients with diabetes who are prescribed insulin glargine 300 U/mL (Gla-300). The study objective was to assess the program's impact on persistence and adherence with therapy among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A retrospective 12-month analysis was conducted to compare treatment adherence and persistence in patients treated with Gla-300 who actively participated in the COACH PSP versus those who did not enroll using COACH engagement and claims data for the identification period from February 1, 2016 to July 31, 2016. COACH (n=544) and non-COACH (n=544) participants were matched on selected baseline characteristics. RESULTS: COACH participants were more likely to be adherent to (68.0% vs 61.4%, p= 0.0201; OR: 1.81, p=0.0002) and persistent (48.5% vs 42.1%, p= 0.0309; discontinuation HR: 0.60, p<0.0001) with Gla-300 than non-COACH patients during the 12-month follow-up after controlling for clinical confounders. Additionally, both insulin-naive and basal insulin switcher COACH participants, respectively, were more likely to be adherent (OR: 2.25, p=0.0082 and OR: 1.662, p=0.0364) and persistent (discontinuation HR: 0.53, p=0.0054 and HR: 0.67, p=0.0492) than non-COACH patients. Finally, COACH participants with greater level of engagement showed better persistence. CONCLUSION: These data demonstrate that participation and engagement with COACH PSPs are associated with improved persistence and adherence to Gla-300 among patients with type 2 diabetes.

Real-world evidence concerning clinical and economic outcomes of switching to insulin glargine 300 units/mL vs other basal insulins in patients with type 2 diabetes using basal insulin.

This retrospective cohort study compared real-world clinical and healthcare-resource utilization (HCRU) data in patients with type 2 diabetes using basal insulin (BI) who switched to insulin glargine 300 units/mL (Gla-300) or another BI. Data from the Predictive Health Intelligence Environment database 12 months before (baseline) and 6 months after (follow-up) the switch date (index date, March 1, 2015 to May 31, 2016) included glycated haemoglobin A1c (HbA1c), hypoglycaemia, HCRU and associated costs. Baseline characteristics were balanced using propensity score matching. Change in HbA1c from baseline was similar in both matched cohorts (n = 1819 in each). Hypoglycaemia incidence and adjusted event rate were significantly lower with Gla-300. Patients switching to Gla-300 had a significantly lower incidence of HCRU related to hypoglycaemia. All-cause and diabetes-related hospitalization and emergency-department HCRU were also favourable for Gla-300. Lower HCRU translated to lower costs in patients using Gla-300. In this real-world study, switching to Gla-300 reduced the risk of hypoglycaemia in patients with type 2 diabetes when compared with those switching to another BI, resulting in less HCRU and potential savings of associated costs.

Improved glycaemic control and lower hypoglycaemia risk with reduced prior oral antidiabetes drug therapy in patients with type 2 diabetes treated with insulin glargine 300 U/mL.

AIMS: Data from the EDITION 3 randomized study and the Clinformatics claims database were analysed to determine whether insulin glargine 300 U/mL (Gla-300) could provide insulin-naive patients with type 2 diabetes (T2D) on oral antidiabetes drugs (OADs) with reductions in prior OAD therapy without compromising glycaemic control, and while preserving its known low incidence of hypoglycaemia compared with insulin glargine 100 U/mL (Gla-100). METHODS: Patient-level data from EDITION 3 and de-identified data from the Clinformatics real-world claims database were analysed. RESULTS: At baseline, 70% of patients in EDITION 3 were on a background of ≥2 OADs. Among the 435 and 437 patients who initiated basal insulin with Gla-300 and Gla-100, respectively, at Month 6, 336 (77%) and 338 (77%) were using ≤1 OAD. Adding Gla-300 or Gla-100 similarly allowed for a reduction in background OAD medication in the Clinformatics dataset (N = 6430), such that, at 6 months postbasal insulin initiation, 14% of patients were no longer taking any OADs. In the analysis of the EDITION 3 study, reduction in OAD burden did not compromise glycaemic benefit, and the low incidence of hypoglycaemia associated with Gla-300 compared with Gla-100 was also preserved. Documented symptomatic hypoglycaemia (blood glucose ≤70 mg/dL) occurred in 30.5% vs 41.0% of patients treated with Gla-300 and Gla-100, respectively (P = 0.0442). CONCLUSION: Patients with T2D who initiate basal insulin with Gla-300 could potentially reduce their prior OAD use without compromising glycaemic control and with less hypoglycaemia than with Gla-100.

Idiopathic hypoparathyroidism presenting with severe hypocalcemia and asymptomatic basal ganglia calcification followed by acute intracerebral bleed.

OBJECTIVE: To report a case of idiopathic hypoparathyroidism presenting with severe hypocalcemia and intracerebral calcifications that resulted in a spontaneous intracerebral bleed. METHODS: We present the clinical, laboratory, and radiologic findings in a woman with idiopathic hypoparathyroidism who developed spontaneous intracerebral bleed in the setting of chronic intracerebral calcifications. RESULTS: A 37-year-old woman presented with vague symptoms of hypocalcemia. Clinical evaluation revealed brisk deep tendon reflexes and positive Chvostek's and Trousseau's signs. The serum calcium level was 3.7 mg/dL (reference range, 8.0 to 10.6 mg/dL) and the phosphorus level was 8.2 mg/dL (reference range, 2.3 to 5.0 mg/dL). Serum intact parathyroid hormone was undetectable. Computed tomography of the head showed extensive bilateral symmetrical calcification of basal ganglia and dentate nucleus in the cerebellum and centrum semiovale. Fluid and electrolytes were replaced appropriately, and calcium and calcitriol were prescribed. While in the hospital, the patient developed an acute intracerebral bleed confirmed by computed tomography. The patient recovered without neurologic sequelae and was discharged from the hospital on calcium supplementation and calcitriol. Repeated computed tomography of the head 3 years later demonstrated complete resolution of the bleed. CONCLUSION: This case suggests that patients with severe hypoparathyroidism and intracerebral calcification may be at risk for spontaneous intracerebral bleed and should be monitored accordingly.

Profile of diabetic ketoacidosis in a predominantly African American urban patient population.

The occurrence of diabetic ketoacidosis (DKA), a serious but largely preventable acute complication of diabetes mellitus, has been declining in recent years. However, empiric observations indicate that DKA continues to have a major effect on ethnic minority patients in inner-city settings. In this study, we conducted a retrospective analysis of five-year hospital admission data for DKA at a single inner-city hospital that serves a largely uninsured adult African American population. A computer-assisted search of the International Classification of Diseases, Ninth Revision, Clinical Modification codes for DKA revealed 847 admissions for confirmed DKA in 630 patients. Of these, 592 (94%) were African Americans, 22 (3.5%) were Whites, and 16 (2.5%) were Hispanics. The mean age was 43.4 +/- .4 years. Five hundred seventy-one (90.6%) of the patients had type 1 diabetes, and 59 (9.4%) had type 2 diabetes. One hundred forty-five patients (23%) were newly diagnosed with diabetes. Ninety-four (14.9%) of the patients had multiple admissions, ranging from 2 to 23 admissions per patient during the five-year period, while the remaining 391 (62.1%) patients were single admissions. Half of the patients (52%) did not have health insurance. Major precipitating factors for DKA included discontinuation of insulin, infection, and other medical illness in 501 (59.1%), 136 (16.1%), and 30 (3.5%) of the admissions, respectively. In conclusion, these data demonstrate that DKA continues to have a major effect in urban African American patients with diabetes. Therefore, multiple targeted interventions are needed in this population to improve diabetes care and thereby decrease the frequency of DKA.

Human insulin receptor juxtamembrane domain independent insulin signaling.

The exon 16-encoded juxtamembrane (JM) domain of human insulin receptor (hIR) harbors the NPEY motif which couples the insulin-activated hIR kinase to downstream signal transduction molecules. We sought to determine if signal transduction requires the entire exon 16-encoded 22-amino acid JM domain. Transfected CHO cells were generated stably expressing either the wild-type hIR (hIR-WT) or two mutant hIRs (hIRDeltaEx16 in which the JM domain was deleted, and hIRrosJM in which the deleted segment was replaced by the corresponding domain of v-ros protein). The mutant hIRDeltaEx16 and hIRrosJM exhibited similar insulin-binding as the hIRWT. Insulin internalization and insulin dose-response experiments toward activation of downstream signal transduction molecules demonstrated that: i) the presence of intact hIR-JM domain which harbors the NPEY motif is essential for Shc phosphorylation but not for IRS-1 phosphorylation; ii) insulin signal transduction can occur independent of the JM domain of hIR and without participation of the NPEY motif; iii) engagement of this putative alternative downstream signal transduction is Shc independent and is dependent on insulin concentration; and iv) insulin internalization does not necessarily require the hIR specific aa sequence of the JM domain which can be partially substituted by the JM domain of the v-ros tyrosine kinase.

Exercise capacity is a predictor of cardiovascular events in patients with type 2 diabetes mellitus.

Peak exercise oxygen consumption (peak VO2), as measured by expired gas analysis, is an accurate, reproducible and reliable method for determining exercise capacity. In this study, a cohort of 468 patients with type 2 diabetes underwent graded exercise testing to measure peak VO2 at baseline; the cohort was followed for five years for the occurrence of cardiovascular disease (CVD) events. Patients who developed CVD events during the five-year follow-up period were found to have significantly lower baseline peak VO2, as compared to those who did not (p = 0.02). Analysis by gender showed that the mean peak VO2 in male patients who developed CVD events was significantly lower than the peak VO2 in those who did not (p < 0.03). Multiple Cox regression analysis also showed low peak VO2 to be an independent factor. In conclusion, patients with type 2 diabetes mellitus with reduced peak VO2 during exercise have a greater tendency to develop future CVD events.

Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy.

The aim of this study was to evaluate changes in lipid profiles in patients with type 2 diabetes after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin and other lipid-altering therapies. A total of 305 patients were enrolled in this open-label study. Patients had been taking stable dosages of rosiglitazone and statins for > 90 days. At baseline, patients discontinued rosiglitazone and started pioglitazone 30 mg/day, but continued statins and other lipid-altering therapies. The primary end point was change from baseline in fasting triglyceride levels. At 17 weeks after treatment conversion, patients had significant reductions in triglycerides (-15.2%), total cholesterol (-9.0%), and low-density lipoprotein (LDL) particle concentration (-189 nmol/L), and increases in LDL cholesterol (+2.2%), high-density lipoprotein (HDL) cholesterol (+1.8%), and LDL particle diameter (+0.23 nm). In conclusion, after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin therapy, patients with type 2 diabetes had marked improvements in lipid profiles along with stable glycaemic control.

Analysis of serum lipids and lipoproteins in Ethiopian diabetic patients.

Serum lipids and lipoproteins were determined in 302 randomly selected diabetic patients attending the Tikur Anbessa Hospital diabetic clinic. The main objective of the study was to analyse lipid levels in type 1 and type 2 diabetic patients. Lipid measurement was done by cholesterol pap method. The mean age was 41.4 +/- 14.4 years (range 14-85 years). One hundred sixty (53%) were males and 142 (47%) were females. There were 140 (46.4%) type 1 and 162 (53.6%) type 2 patients. The mean duration of diabetes mellitus, haemoglobin A1c, fasting blood glucose and random blood glucose were 9.4 +/- 5.4 years, 10.4 +/- 2.2%, 195.5 +/- 79.9 mg/dl and 273.1 +/- 114.5 mg/dl respectively. The mean cholesterol, triglycerides, LDL, VLDL and HDL were 166.5 +/- 45.5 mg/dl, 129.9 +/- 92.4 mg/dl, 94.5 +/- 36.4 mg/dl, 24.4 +/- 15.1 mg/dl and 44.3 +/- 11.5 mg/dl respectively. Hypercholesterolemia and Hypertriglyceridemia were seen in 18.5% and 14.2% of the patients. Total cholesterol was significantly higher in females than in males and in type 2 than in type 1 patients (179.3 +/- 48.4 mg/dl versus 154.1 +/- 38.2 mg/dl, P < 0.01 and 183.2 +/- 43.7 mg/dl versus 145.9 +/- 37.6 mg/dl, P < 0.001) respectively. Triglycerides and LDL cholesterol were also significantly higher in type 2 diabetic patients than in type 1 diabetic patients (162.7 +/- 10.5 mg/dl versus 91.5 +/- 53.3 mg/dl, P < 0.001 and 105.6 +/- 36.2 mg/dl versus 81.9 +/- 32.2 mg/dl, P < 0.001), but HDL cholesterol was the same in both types of diabetic patients. Similarly, hyperlipidemia was associated with obesity and hypertension. The study confirms that lipid values are high particularly in type 2 diabetic patients. Hence our patients are at increased risk of developing atherosclerosis therefore periodic check up of lipids in diabetic patients and effective treatment of the dyslipidemia along with a tight metabolic control was recommended.