Re-examining insulin compared to non-insulin therapies for type 2 diabetes: when in the disease trajectory is insulin preferable?

In patients with type 2 diabetes secondary to excess nutrients and energy balance, relative - not absolute - insulin deficiency plays a key role in disease development and progression. Although patients with type 2 diabetes who have features of insulin resistance would usually have hyperinsulinemia, insulin therapy remains recommended by guidelines particularly when patients fail to achieve glycemic goals. This approach does not prevent complications particularly macrovascular complications. This raises a controversial question regarding the benefit of using exogenous insulin for glycemic control in patients with type 2 diabetes who have features of insulin resistance. To address this concern, the authors performed a literature search looking for either randomized trials or meta-analyses directly comparing exogenous insulin to non-insulin therapy in the treatment of patients with type 2 diabetes. Our main outcomes of interest were effect on glycemic control and insulin resistance at various time points in the usual trajectory of type 2 diabetes. In trials investigating early short-term initiation of intensive insulin therapy, insulin therapy was beneficial in rapidly achieving glycemic control and reversing glucotoxicity. Following the initial 2 weeks to 3 months of adequate glycemic control in patients on intensive insulin therapy, there is little evidence that continuing insulin therapy provides greater glycemic control or improves insulin resistance beyond what can be achieved with other therapies. In conclusion, long-term insulin use appears neutral if not potentially harmful with respect to insulin resistance and cardiovascular outcomes. While this review has limitations and should be dealt cautiously, it raises questions regarding the benefit of insulin in patients with type 2 diabetes with features of insulin resistance. Further research is needed to confirm these findings.

Diabetes Fellowship in Primary Care: A Survey of Graduates.

CONTEXT: The diabetes pandemic has outpaced the US supply of diabetes specialists and has overwhelmed primary care providers (physicians, physician assistants, and nurse practitioners). Primary care diabetes fellowships can be used to address this workforce shortage. OBJECTIVES: To determine the skills obtained during 2 diabetes fellowship programs, the barriers encountered in practice, the impact of the programs on career paths, and perceived acceptance by patients and colleagues. METHODS: A Qualtrics link to a 26-item survey was sent via email to all graduates of the Ohio University Heritage College of Osteopathic Medicine and East Carolina University Brody School of Medicine diabetes fellowship programs. Items included demographic information, comfort level with different clinical diabetes skills, and current system barriers encountered in their practices. RESULTS: Of 39 graduates, 36 completed the survey. The most beneficial skills acquired during the fellowship were insulin pump management (13 [36%]), insulin management (10 [29%]), and diabetes pharmacology (6 [17%]). The most common barrier was the lack of board certification as a diabetologist, which affected time with patients and insurance reimbursement. The perceived acceptance by patients was high (25 [69%]), and the perceived receptiveness by colleagues was mostly neutral (7 [19%]) or positive (10 [29%]). The most common postfellowship career path was primary care medicine (15) followed by hospitalist (7) and diabetologist (5). CONCLUSION: Physicians who completed the diabetes fellowship training reported high comfort levels with treating patients with diabetes, but they also reported the barriers faced in an unrecognized specialty.

Endocrinologists' Opinions of Diabetology as a Primary Care Subspecialty.

IN BRIEF This study was conducted to ascertain the opinions of endocrinologists about diabetes care as it relates to the health care provider workforce. A survey was administered to endocrinologists in the Planning Research in Inpatient Diabetes and Planning Research in Outpatient Diabetes (PRIDE/PROUD) group and given to attendees of the American Diabetes Association (ADA) Scientific Sessions special interest group whose focus was primary care. The majority of respondents agreed that there is a need for more providers to be trained to take care of patients with diabetes and that more trained providers are needed, and almost half agreed that primary care providers (PCPs) with advanced training in diabetes should be part of the workforce for managing the diabetes pandemic. Expanding diabetes fellowship programs for PCPs remains an important potential solution for addressing workforce development needs in diabetes care.

Switching basal insulins in type 2 diabetes: practical recommendations for health care providers.

Basal insulin remains the mainstay of treatment of type 2 diabetes when diet changes and exercise in combination with oral drugs and other injectable agents are not sufficient to control hyperglycemia. Insulin therapy should be individualized, and several factors influence the choice of basal insulin; these include pharmacological properties, patient preferences, and lifestyle, as well as health insurance plan formularies. The recent availability of basal insulin formulations with longer durations of action has provided further dosing flexibility; however, patients may need to switch agents throughout therapy for a variety of personal, clinical, or economic reasons. Although a unit-to-unit switching approach is usually recommended, this conversion strategy may not be appropriate for all patients and types of insulin. Glycemic control and risk of hypoglycemia must be closely monitored by health care providers during the switching process. In addition, individual changes in care and formulary coverage need to be adequately addressed in order to enable a smooth transition with optimal outcomes.

The Time Is Now: Diabetes Fellowships in the United States.

PURPOSE OF REVIEW: Diabetes is a complex and costly chronic disease that is growing at an alarming rate. In the USA, we have a shortage of physicians who are experts in the care of patients with diabetes, traditionally endocrinologists. Therefore, the majority of patients with diabetes are managed by primary care physicians. With the rapid evolution in new diabetes medications and technologies, primary care physicians would benefit from additional focused and intensive training to manage the many aspects of this disease. Diabetes fellowships designed specifically for primary care physicians is one solution to rapidly expand a well-trained workforce in the management of patients with diabetes. RECENT FINDINGS: There are currently two successful diabetes fellowship programs that meet this need for creating more expert diabetes clinicians and researchers outside of traditional endocrinology fellowships. We review the structure of these programs including funding and curriculum as well as the outcomes of the graduates. The growth of the diabetes epidemic has outpaced current resources for readily accessible expert diabetes clinical care. Diabetes fellowships aimed for primary care physicians are a successful strategy to train diabetes-focused physicians. Expansion of these programs should be encouraged and support to grow the cadre of clinicians with expertise in diabetes care and improve patient access and outcomes.

The role of the new basal insulin analogs in addressing unmet clinical needs in people with type 1 and type 2 diabetes.

BACKGROUND: Despite improvements in anti-hyperglycemic therapies, there are many unmet clinical needs that hinder successful glycemic control in people being treated with current basal insulin analogs. OBJECTIVE: This paper reviews the unmet needs associated with current basal insulin therapy and describes the most recent basal insulins for the treatment of diabetes. METHODS: PubMed was searched for articles on basal insulin analogs published between 2000 and April 2016. RESULTS: Although long-acting insulin analogs, such as insulin glargine 100 units/mL and insulin detemir, have come towards approximating physiologic basal insulin levels, limitations such as hypoglycemia and intra- and inter-individual variability are associated with their use resulting in glycemic fluctuations. Some basal insulins lack 24 hour coverage, requiring some patients to split their dose, increasing the number of injections required to maintain glycemic control. Fear of hypoglycemia and the need for additional injections often leads to poor compliance and suboptimal glycemic control. Long-acting insulin analogs, such as insulin glargine 300 units/mL and insulin degludec, have improved upon the shortcomings of the current basal insulin analogs. Improved pharmacodynamic/pharmacokinetic profiles afford lower intra-patient variability and an extended duration of action, providing full and stable 24 hour basal insulin coverage with once daily dosing, and comparable efficacy to insulin glargine with lower rates of hypoglycemia. CONCLUSION: The improved pharmacodynamic/pharmacokinetic profiles of new long-acting insulin formulations provide greater glycemic control with once daily dosing. With the growing number of therapeutic choices available, physicians have more scope to individualize patient options for basal insulin therapy.

USE OF A COMPUTER-GUIDED GLUCOSE MANAGEMENT SYSTEM TO IMPROVE GLYCEMIC CONTROL AND ADDRESS NATIONAL QUALITY MEASURES: A 7-YEAR, RETROSPECTIVE OBSERVATIONAL STUDY AT A TERTIARY CARE TEACHING HOSPITAL.

OBJECTIVE: Inpatient hyperglycemia, hypoglycemia, and glucose variability are associated with increased mortality. The use of an electronic glucose management system (eGMS) to guide intravenous (IV) insulin infusion has been found to significantly improve blood glucose (BG) control. This retrospective observational study evaluated the 7-year (January 2009-December 2015) impact of the EndoTool® eGMS in intensive and intermediate units at Vidant Medical Center, a 900-bed tertiary teaching hospital. METHODS: Patients assigned to eGMS had indications for IV insulin infusion, including uncontrolled diabetes, stress hyperglycemia, and/or postoperative BG levels >140 mg/dL. This study evaluated time required to achieve BG control (<180 mg/dL; <140 mg/dL for cardiovascular surgery patients); hypoglycemia incidence (<70 and <40 mg/dL); glucose variability (assessed by SD and coefficient of variation percentage [CV%]); excursions (BG levels >180 mg/dL after control attained); and the impact of eGMS on hospital-acquired condition (HAC)-8 rates. RESULTS: Data were available for all treated patients (492,078 BG readings from 16,850 patients). With eGMS, BG levels were brought to target within 1.5 to 2.3 hours (4.5 to 4.8 hours for cardiovascular patients). Minimal hypoglycemia was observed (BG values <70 mg/dL, 0.93%; <40 mg/dL, 0.03%), and analysis of variance of BG values <70 mg/dL showed significant reductions over time in hypoglycemia frequency, from 1.04% in 2009 to 0.46% in 2015 (P<.0001). The CV% per patient visit was 26.5 (±12.9)%, and 4% of patients experienced glucose excursions (defined as BG levels >180 mg/dL once control was attained). HAC-8 rates were reduced from 0.083 per 1,000 patients (2008) to 0.032 per 1,000 patients (2011). CONCLUSION: The use of eGMS resulted in rapid, effective control of inpatient BG levels, including significantly reduced hypoglycemia rates. ABBREVIATIONS: BG = blood glucose CMS = Centers for Medicare and Medicaid Services CV = coefficient of variation CV% = coefficient of variation percentage eGMS = electronic glucose management system GV = glycemic variability HAC = Hospital-Acquired Condition ICU = intensive care unit IU = intermediate unit IV = intravenous LOS = length of stay VMC = Vidant Medical Center.

Managing diabetes in hospitalized patients with chronic kidney disease.

Because few randomized trials have been done, little is known about appropriate glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus. These patients are at high risk of hypoglycemia. It is prudent to monitor glucose closely, set less-stringent blood sugar goals, avoid oral antidiabetic agents, and possibly reduce insulin dosage.

Interdisciplinary Diabetes Care: A New Model for Inpatient Diabetes Education.

A patient-centered interdisciplinary diabetes care model was implemented at Vidant Medical Center in Greenville, N.C., a 909-bed tertiary care teaching hospital, for the purpose of providing all patients with diabetes clear and concise instructions on diabetes survival skills. Survival skills education during hospitalization is needed for safe transition to community resources for continued and expanded diabetes self-management education. This article describes the process used to develop, implement, and evaluate the model. This initiative achieved substantial cost savings, with no significant changes in length of stay (LOS) or diabetes readmission rates. This patient-centered model demonstrates how a team of interdisciplinary health care professionals can integrate services in providing care for a large population of patients with chronic disease.

The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on therapy to metformin in patients with Type 2 diabetes: A systematic review and meta-analysis.

There is no consensus on the selection of specific drug therapies when metformin fails in Type 2 diabetes (T2D). This meta-analysis was performed to determine the efficacy and safety of Dipeptidyl peptidase-4 inhibitors (DPP4-I) compared to sulfonylurea (SU) as add-on therapy to metformin in inadequately controlled T2D patients. We searched MEDLINE, CENTRAL, EMBASE, and CINAHL for randomized trials comparing DPP4-I to SU as add-on therapy to metformin and reported a change in hemoglobin A1c (HbA1c). Sixteen articles were included. There was a significantly greater reduction in HbA1c from baseline to 12 weeks with SU versus DPP4-I (MD[95% CI]=0.21%(2 mmol/mol) [0.06, 0.35]) but no significant difference at 52 and 104 weeks (MD[95% CI]=0.06%(-1 mmol/mol) [-0.03, 0.15] and 0.02%(-1 mmol/mol) [-0.13,0.18] respectively). SU was associated with weight gain and DPP4-I with weight loss at all time-points. The incidence of hypoglycemia at 12, 52, and 104 weeks was significantly greater with SU (20%, 24%, and 27% respectively) compared to DPP4-I (6%, 3%, and 4% respectively). The proportion of patients with HbA1c<7%(53 mmol/mol) without hypoglycemia was significantly higher at 52 and 104 weeks among patients on DPP4-I (RR[95% CI]=1.20 [1.05, 1.37] and 1.53 [1.16, 2.02] respectively). There was no significant difference between the two groups in the incidence of other side effects. While both SU and DPP4-I can be considered as options for add-on therapy to metformin in inadequately controlled T2D, SU results in a significantly increased risk of hypoglycemia and weight gain. By contrast, DPP4-I produce 0.4-0.6% (4-7 mmol/mol) reduction in HbA1c, lower risk of hypoglycemia, and weight loss.

Patient behaviors associated with optimum glycemic outcomes with sensor-augmented pump therapy: insights from the STAR 3 study.

OBJECTIVE: The purpose of this analysis was to identify patient behaviors that led to optimum glycemic outcomes in subjects with type 1 diabetes (T1DM) who transitioned from multiple daily injections (MDI) therapy to sensor-augmented pump (SAP) therapy. METHODS: Sensor-augmented pump Therapy for A1C Reduction (STAR 3), a randomized controlled trial, assigned 485 suboptimally controlled T1DM subjects to either MDI therapy (n = 241) or SAP therapy (n = 244). We categorized subjects in the latter group according to age at enrollment and glycated hemoglobin (A1C) value after using the SAP system for 12 months. Pairwise comparisons of how the pump features were used between SAP subjects with the highest and lowest end-of-study A1C values were made via t tests. RESULTS: Larger decreases in A1C values were significantly correlated with increasing sensor use in both the adult and pediatric age groups. Subjects in the low-A1C cohorts of both pediatric and adult age groups gave themselves smaller and more frequent boluses and used the Bolus Wizard bolus estimation calculator more frequently than subjects in age-matched high-A1C cohorts. Children in the low-A1C cohort used less insulin than children in the high-A1C cohort. There was no additional hypoglycemia in either the adult or pediatric low-A1C cohorts versus their high-A1C counterparts. CONCLUSIONS: Both adult and pediatric patients with T1DM on SAP who use CGM sensors more often will have a greater decrease in their A1C values than those who do not demonstrate these behaviors. Routine use of CGM may lead to smaller and more frequent bolus dosing, enabling this population to safely reach their A1C goals.

Postmortem Diagnosis of Diabetic Ketoacidosis Presenting as the "Dead-in-Bed Syndrome".

OBJECTIVE: To report a case of a young male with type 1 diabetes mellitus found dead in his bed, initially assumed to have died from hypoglycemia (i.e., the "dead in bed" syndrome). However, his autopsy findings revealed that diabetic ketoacidosis (DKA) was the cause of death. METHODS: We present the laboratory and autopsy findings of the patient, highlighting the importance of laboratory analyses of the vitreous humor and microscopy of kidney tissue when investigating the cause of sudden death in patients with type 1 diabetes. RESULTS: A 25-year-old healthy male with type 1 diabetes on continuous subcutaneous insulin infusion therapy was found dead in his undisturbed bed. An autopsy included vitreous humor analyses. His results were as follows: glucose of 755 mg/dL (reference range 70-105 mg/dL), anion gap >36 mEq (reference range 4-12 mEq/L), elevated acetone at 66 mg/dL (reference range negative), which were consistent with DKA. Renal microscopy demonstrated subnuclear vacuoles in the proximal tubules, 1 of 2 lesions were described as an Armanni-Ebstein lesion, which is a postmortem finding in patients who die from diabetic coma. CONCLUSION: The most likely cause of death at home in young patients with type 1 diabetes is severe hypoglycemia. However, an autopsy of the present case confirmed DKA based on vitreous humor biochemistry and microscopic examination of the kidneys, which demonstrated the Armanni-Ebstein phenomenon. Analysis of the vitreous fluid and microscopic examination of the kidneys for the presence of Armanni-Ebstein lesion can be used to help determine the cause of death in patients with type 1 diabetes mellitus.

Duloxetine Compared with Pregabalin for Diabetic Peripheral Neuropathic Pain Management in Patients with Suboptimal Pain Response to Gabapentin and Treated with or without Antidepressants: A Post Hoc Analysis.

OBJECTIVE: To examine the efficacy of duloxetine vs. pregabalin in the treatment for diabetic peripheral neuropathic pain (DPNP), comparing patient subgroups with and without concomitant antidepressant use. METHODS: This post hoc analysis assessed data from a randomized 12-week study that confirmed the noninferiority of duloxetine to pregabalin. In the previously published study, patients with DPNP with inadequate response to gabapentin were switched to duloxetine monotherapy, combination therapy of duloxetine plus gabapentin, or pregabalin monotherapy. Current, stable antidepressant use was allowed; 79 patients were concomitantly treated with antidepressants and 328 without antidepressants. In this post hoc analysis, improvement in the weekly mean of diary-based average daily pain ratings (numerical rating scale: 0-10) in antidepressant users and nonusers was analyzed using a longitudinal mixed-models repeated-measures (MMRM) analysis, including a test of the 3-way interaction (antidepressant subgroup by treatment by week) to assess whether the differences among treatment groups over 12 weeks differ between the antidepressant-use subgroups. RESULTS: The 3-way interaction was significant (P = 0.035), demonstrating that treatment-group differences in pain reduction over time differ between the subgroups. Among patients without antidepressant use, patients treated with duloxetine had significantly greater pain reduction than pregabalin at Week 4 and at each successive week up to the 12-week endpoint (-2.8 for duloxetine and -2.1 for pregabalin; P = 0.031); patients treated with duloxetine plus gabapentin had greater pain reduction than pregabalin at Weeks 2, 3, 5, and 7 to 9 (P ≤ 0.05) but not at endpoint (-2.4; P = 0.222). Among concomitant antidepressant users, no treatment-group differences were found. CONCLUSIONS: In patients with DPNP inadequately treated with gabapentin without the concomitant use of antidepressants, switching to duloxetine instead of pregabalin may provide better pain reduction. Conversely, in nonresponders to gabapentin who are concomitantly using an antidepressant, switching to duloxetine or pregabalin may provide similar pain reductions.

Increased glycemic variability is independently associated with length of stay and mortality in noncritically ill hospitalized patients.

OBJECTIVE: To investigate the association between glycemic variability (GV) and both length of stay (LOS) and 90-day mortality in noncritically ill hospitalized patients. RESEARCH DESIGN AND METHODS: This study retrospectively analyzed 4,262 admissions to the general medicine or surgery services during a 2 year period. Patients with point-of-care glucose monitoring and a minimum of two glucose values per day on average were selected. GV was assessed by SD and coefficient of variation (CV). Data were analyzed with linear and logistic multivariate regression analysis in separate models for SD and CV. Analysis was performed with generalized estimating equations to adjust for correlation between multiple admissions in some individual cases. RESULTS: After exclusions, 935 admissions comprised the sample. Results of adjusted analysis indicate that for every 10 mg/dL increase in SD and 10-percentage point increase in CV, LOS increased by 4.4 and 9.7%, respectively. Relative risk of death in 90 days also increased by 8% for every 10-mg/dL increase in SD. These associations were independent of age, race, service of care (medicine or surgery), previous diagnosis of diabetes, HbA1c, BMI, the use of regular insulin as a sole regimen, mean glucose, and hypoglycemia occurrence during the hospitalization. CONCLUSIONS: Our results indicate that increased GV during hospitalization is independently associated with longer LOS and increased mortality in noncritically ill patients. Prospective studies with continuous glucose monitoring are necessary to investigate this association thoroughly and to generate therapeutic strategies targeted at decreasing GV.

Pharmacologic management of diabetic peripheral neuropathic pain.

INTRODUCTION: Diabetic peripheral neuropathic pain (DPNP) is a debilitating and distressing complication that occurs in patients with diabetes mellitus. This article provides an overview of diabetic peripheral neuropathy focusing on DPNP. AREAS COVERED: This article reviews the diagnosis, pathogenesis, prevention and treatment of diabetic neuropathy and neuropathic pain. A comprehensive and systematic Medline search of the published literature for treatment of diabetic peripheral neuropathy was done from 1965 to December 2012. Studies not in English language were excluded. EXPERT OPINION: Neuropathic pain is difficult to treat, and patients rarely experience complete pain relief. Despite several pharmacological agents being used in the treatment of DPNP, only duloxetine and pregabalin have evidence-based support for controlling DPNP.

Improved outcomes in diabetes care for rural African Americans.

PURPOSE: Rural low-income African American patients with diabetes have traditionally poorer clinical outcomes and limited access to state-of-the-art diabetes care. We determined the effectiveness of a redesigned primary care model on patients' glycemic, blood pressure, and lipid level control. METHODS: In 3 purposively selected, rural, fee-for-service, primary care practices, African American patients with type 2 diabetes received point-of-care education, coaching, and medication intensification from a diabetes care management team made up of a nurse, pharmacist, and dietitian. In 5 randomly selected control practices matched for practice and patient characteristics, African American patients received usual care. Using univariate and multivariate adjusted models, we evaluated the effects of the intervention on intermediate (median 18 months) and long-term (median 36 months) changes in glycated hemoglobin (hemoglobin A1c) levels, blood pressure, and lipid levels, as well as the proportion of patients meeting target values. RESULTS: Among 727 randomly selected rural African American diabetic patients (368 intervention, 359 control), intervention patients had a significantly greater reduction in mean hemoglobin A1c levels at intermediate (-0.5 % vs -0.2%; P <.05) and long-term (-0.5% vs -0.10%; P <.005) follow-up in univariate and multivariate models. The proportion of patients achieving a hemoglobin A1c level of less than 7.5% (68% vs 59%, P <.01) and/or a systolic blood pressure of less than 140 mm Hg (69% vs 57%, P <.01) was also significantly greater in intervention practices in multivariate models. CONCLUSION: Redesigning care strategies in rural fee-for-service primary care practices for African American patients with established diabetes results in significantly improved glycemic control relative to usual care.

GLP-1 response to a mixed meal: what happens 10 years after Roux-en-Y gastric bypass (RYGB)?

BACKGROUND: Oral meal consumption increases glucagon-like peptide 1 (GLP-1) release which maintains euglycemia by increasing insulin secretion. This effect is exaggerated during short-term follow-up of Roux-en-y gastric bypass (RYGB). We examined the durability of this effect in patient with type 2 diabetes (T2DM) >10 years after RYGB. METHODS: GLP-1 response to a mixed meal in the 10-year post-RYGB group (n = 5) was compared to lean (n = 9), obese (n = 6), and type 2 diabetic (n = 10) controls using a cross-sectional study design. Analysis of variance (ANOVA) was used to evaluate GLP-1 response to mixed meal consumption from 0 to 300 min, 0-20 min, 20-60 min, and 60-300 min, respectively. Weight, insulin resistance, and T2DM were also assessed. RESULTS: GLP-1 response 0-300 min in the 10-year post-RYGB showed a statistically significant overall difference (p = 0.01) compared to controls. Furthermore, GLP-1 response 0-20 min in the 10-year post-RYGB group showed a very rapid statistically significant rise (p = 0.035) to a peak of 40 pM. GLP-1 response between 20 and 60 min showed a rapid statistically significant (p = 0.041) decline in GLP-1 response from ~40 pM to 10 pM. GLP-1 response in the 10-year post-RYGB group from 60 to 300 min showed no statistically significant difference from controls. BMI, HOMA, and fasting serum glucose before and >10 years after RYGB changed from 59.9 → 40.4, 8.7 → 0.88, and 155.2 → 87.6 mg/dl, respectively, and were statistically significant (p < 0.05). CONCLUSIONS: An exaggerated GLP-1 response was noted 10 years after RYGB, strongly suggesting a durability of this effect. This phenomenon may play a key role in maintaining type 2 diabetes remission and weight loss after RYGB.