Estimation of glucose absorption, insulin sensitivity, and glucose effectiveness from the oral glucose tolerance test.

CONTEXT: Glucose tolerance during an oral glucose tolerance test (OGTT) is affected by variations in glucose effectiveness (GE) and glucose absorption and thus affects minimal model calculations of insulin sensitivity (SI). The widely used OGTT SI by Dalla Man et al. does not account for variances in GE and glucose absorption. OBJECTIVE: To develop a novel model that concurrently assesses SI, GE, and glucose absorption. DESIGN: Cross-sectional. SETTING: Academic Medical Center. PARTICIPANTS: Eighteen subjects without abnormalities on OGTT (controls) and 88 subjects with diabetes. INTERVENTION: All subjects underwent 75-gram 120-minute 6-timepoint OGTT. MAIN OUTCOMES: SI from the Dalla Man model was validated with the novel model Si using Bland Altman limits of agreement methodology. Comparisons of SI, GE, and gastrointestinal glucose half-life (GIGt1/2); a surrogate measure for glucose absorption were made between subjects with diabetes and controls. RESULTS: In controls and diabetes, the novel model SI was higher than the current OGTT model. SI from both controls (ƿ=0.90, p < 0.001) and diabetes (ƿ=0.77, p < 0.001) has high agreement between models. GE was higher in diabetes (median:0.021 1/min, IQR [interquartile range]: 0.020-0.022) compared to controls (median:0.016 1/min, IQR: 0.015-0.017), p = 0.02. GIGt1/2 was shorter in diabetes (median: 48.404 min, IQR: 54.424-39.426) than in controls (median: 55.086 min, IQR: 61.368-48.502) without statistical difference. CONCLUSIONS: Our novel model SI has a good correlation with SI from the widely used Dalla Man's model while concurrently calculating GE and GIGt1/2. Thus, besides estimating SI, our novel model can quantify differences in insulin-independent glucose disposal mechanisms important for diabetes pathophysiology.

1-h Glucose During Oral Glucose Tolerance Test Predicts Hyperglycemia Relapse-Free Survival in Obese Black Patients With Hyperglycemic Crises.

Objective: Approximately 50% of obese Black patients with unprovoked diabetic ketoacidosis (DKA) or severe hyperglycemia (SH) at new-onset diabetes achieve near-normoglycemia remission with intensive insulin treatment. Despite the initial near-normoglycemia remission, most DKA/SH individuals develop hyperglycemia relapse after insulin discontinuation. Traditional biomarkers such as normal glucose tolerance at the time of remission were not predictive of hyperglycemia relapse. We tested whether 1-h plasma glucose (1-h PG) at remission predicts hyperglycemia relapse in Black patients with DKA/SH. Methods: Secondary analysis was performed of two prospective randomized controlled trials in 73 patients with DKA/SH at the safety net hospital with a median follow-up of 408 days. Patients with DKA/SH underwent a 5-point, 2-h 75-g oral glucose tolerance test after hyperglycemia remission. Hyperglycemia relapse is defined by fasting blood glucose (FBG) > 130 mg/dl, random blood glucose (BG) >180 mg/dl, or HbA1c > 7%. Results: During the median 408 (interquartile range: 110-602) days of follow-up, hyperglycemia relapse occurred in 28 (38.4%) participants. One-hour PG value ≥199 mg/dl discriminates hyperglycemia relapse (sensitivity: 64%; specificity: 71%). Elevated levels of 1-h PG (≥199 mg/dl) were independently associated with hyperglycemia relapse (adjusted hazard ratio: 2.40 [95% CI: 1.04, 5.56]). In a multivariable model with FBG, adding 1-h PG level enhanced the prediction of hyperglycemia relapse, with significant improvements in C-index (Δ: +0.05; p = 0.04), net reclassification improvement (NRI: 48.7%; p = 0.04), and integrated discrimination improvement (IDI: 7.8%; p = 0.02) as compared with the addition of 2-h PG (NRI: 20.2%; p = 0.42; IDI: 1.32%; p = 0.41) or HbA1c (NRI: 35.2%; p = 0.143; IDI: 5.8%; p = 0.04). Conclusion: One-hour PG at the time of remission is a better predictor of hyperglycemia relapse than traditional glycemic markers among obese Black patients presenting with DKA/SH. Testing 1-h PG at insulin discontinuation identifies individuals at high risk of developing hyperglycemia relapse.

Long-term changes in carbohydrate tolerance, insulin secretion and action in African-American patients with obesity and history of hyperglycemic crises.

INTRODUCTION: Many African-Americans (AA) with obesity with newly diagnosed diabetes presenting with diabetic ketoacidosis (DKA) or severe hyperglycemia (SH) discontinue insulin therapy and achieve near-normoglycemia remission (hemoglobin A1c (HbA1c) <7%, fasting blood glucose (FBG) <130 mg/dL) and able to be managed on oral antidiabetic agents (OAD) during follow-up. Using combined data from two randomized controlled trials, we assessed long-term carbohydrate tolerance and changes in insulin sensitivity and insulin secretion. RESEARCH DESIGN AND METHODS: Seventy-five participants with DKA (n=33) and SH (n=42) underwent 2-hour 75 g oral glucose tolerance test (OGTT) after insulin discontinuation and every 6 months until hyperglycemia relapse (FBG ≥130 mg/dL, HbA1c >7% or two random BG ≥180 mg/dL) while treated with OAD (metformin, sitagliptin or pioglitazone) or placebo. Glucose tolerance status was defined as per the American Diabetes Association. Sensitivity index (Si) was calculated by oral minimal model, insulin secretion as the incremental area under the curve of insulin (IncreAUCi) and disposition index (DI) as Si×IncreAUCi. RESULTS: During remission, OGTT showed normal glucose tolerance (NGT) (n=9 (12%)), prediabetes (n=34 (45%)) and diabetes (n=32 (43%)). DI and Si were higher in patients with NGT versus prediabetes versus diabetes (p<0.001), while IncreAUCi was not significantly different among NGT, prediabetes and diabetes (p=0.14). Achieving NGT status did not prolong near-normoglycemia remission. OAD treatment significantly prolonged hyperglycemia relapse-free survival (log-rank p=0.0012) compared with placebo and was associated with lower hyperglycemia relapse (HR: 0.45, 95% CI: (0.21 to 0.96), p=0.04). CONCLUSIONS: In AA patients with obesity with history of DKA and SH, near-normoglycemia remission is associated with improved insulin secretion and action with half of patients achieving NGT or prediabetes, and only half having diabetes on OGTT. NGT and prediabetes on OGTT were not associated with prolonged hyperglycemia relapse-free survival. TRIAL REGISTRATION NUMBER: NCT01099618, NCT00426413.

A Comparison of Inpatient Cost Per Day in General Surgery Patients with Type 2 Diabetes Treated with Basal-Bolus versus Sliding Scale Insulin Regimens.

BACKGROUND: The identification of cost-effective glycaemic management strategies is critical to hospitals. Treatment with a basal-bolus insulin (BBI) regimen has been shown to result in better glycaemic control and fewer complications than sliding scale regular insulin (SSI) in general surgery patients with type 2 diabetes mellitus (T2DM), but the effect on costs is unknown. OBJECTIVE: We conducted a post hoc analysis of the RABBIT Surgery trial to examine whether total inpatient costs per day for general surgery patients with T2DM treated with BBI (n = 103) differed from those for patients with T2DM treated with SSI (n = 99) regimens. METHODS: Data were collected from patient clinical and hospital billing records. Charges were adjusted to reflect hospital costs. General linearized models were used to estimate the risk-adjusted effects of BBI versus SSI treatment on average total inpatient costs per day. RESULTS: Risk-adjusted average total inpatient costs per day were $US5404. Treatment with BBI compared with SSI reduced average total inpatient costs per day by $US751 (14%; 95% confidence interval [CI] 20-4). Being treated in a university medical centre, being African American or having a bowel procedure or higher-volume pharmacy use significantly reduced costs per day. CONCLUSIONS: In general surgery patients with T2DM, a BBI regimen significantly reduced average total hospital costs per day compared with an SSI regimen. BBI has been shown to improve outcomes in a randomized controlled trial. Those results, combined with our findings regarding savings, suggest that hospitals should consider adopting BBI regimens in patients with T2DM undergoing surgery.

Impact of obesity on hospital complications and mortality in hospitalized patients with hyperglycemia and diabetes.

OBJECTIVE: Obesity is associated with increased risk of diabetes, hypertension and cardiovascular mortality. Several studies have reported increased length of hospital stay and complications; however, there are also reports of obesity having a protective effect on health, a phenomenon coined the 'obesity paradox'. We aimed to investigate the impact of overweight and obesity on complications and mortality in hospitalized patients with hyperglycemia and diabetes. RESEARCH DESIGN AND METHODS: This retrospective analysis was conducted on 29 623 patients admitted to two academic hospitals in Atlanta, Georgia, between January 2012 and December 2013. Patients were subdivided by body mass index into underweight (body mass index <18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)) and obese (>30 kg/m(2)). Hyperglycemia was defined as a blood glucose >10 mmol/L during hospitalization. Hospital complications included a composite of pneumonia, acute myocardial infarction, respiratory failure, acute kidney injury, bacteremia and death. RESULTS: A total of 4.2% were underweight, 29.6% had normal weight, 30.2% were overweight, and 36% were obese. 27.2% of patients had diabetes and 72.8% did not have diabetes (of which 75% had hyperglycemia and 25% had normoglycemia during hospitalization). A J-shaped curve with higher rates of complications was observed in underweight patients in all glycemic groups; however, there was no significant difference in the rate of complications among normal weight, overweight, or obese patients, with and without diabetes or hyperglycemia. CONCLUSIONS: Underweight is an independent predictor for hospital complications. In contrast, increasing body mass index was not associated with higher morbidity or mortality, regardless of glycemic status. There was no evidence of an obesity paradox among inpatients with diabetes and hyperglycemia.

Randomized Controlled Study of Metformin and Sitagliptin on Long-term Normoglycemia Remission in African American Patients With Hyperglycemic Crises.

OBJECTIVE: After intensive insulin treatment, many obese African American patients with new-onset diabetic ketoacidosis (DKA) and severe hyperglycemia are able to achieve near-normoglycemia remission. The optimal treatment to prevent hyperglycemic relapses after remission is not known. RESEARCH DESIGN AND METHODS: This prospective, 4-year, placebo-controlled study randomly assigned 48 African American subjects with DKA and severe hyperglycemia to metformin 1,000 mg daily (n = 17), sitagliptin 100 mg daily (n = 16), or placebo (n = 15) after normoglycemia remission. Hyperglycemic relapse was defined as fasting glucose >130 mg/dL (7.2 mmol/L) and HbA1c >7.0% (53 mmol/mol). Oral glucose tolerance tests were conducted at randomization and at 3 months and then every 6 months for a median of 331 days. Oral minimal model and incremental area under the curve for insulin (AUCi) were used to calculate insulin sensitivity (Si) and ß-cell function, respectively. Disposition index (DI) was calculated as a product of Si and incremental AUCi. RESULTS: Relapse-free survival was higher in sitagliptin and metformin (P = 0.015) compared with placebo, and mean time to relapse was significantly prolonged in the metformin and sitagliptin groups compared with the placebo group (480 vs. 305 days, P = 0.004). The probability of relapse was significantly lower for metformin (hazard ratio 0.28 [95% CI 0.10-0.81]) and sitagliptin (0.31 [0.10-0.98]) than for placebo. Subjects who remained in remission had a higher DI (P = 0.02) and incremental AUCi (P < 0.001) than those with hyperglycemia relapse without significant changes in Si. CONCLUSIONS: This study shows that near-normoglycemia remission was similarly prolonged by treatment with sitagliptin and metformin. The prolongation of remission was due to improvement in ß-cell function.

Report on Racial Disparities in Hospitalized Patients with Hyperglycemia and Diabetes.

CONTEXT: A higher prevalence of diabetes-related complications is reported in minority populations; however, it is not known if there are racial disparities in diabetes care and outcomes in hospitalized patients. OBJECTIVE: Our objective was to determine the association between hyperglycemia, in patients with and without diabetes mellitus (non-DM), and complications among different racial groups. DESIGN: This observational study compared the frequency of hyperglycemia (blood glucose ≥ 180 mg/dL; 10 mmol/L) and DM and hospital complications between Black and White patients hospitalized patients between January 2012 and December 2013. SETTING AND PARTICIPANTS: Adults admitted to medical and surgery services in two academic hospitals were included in this study. RESULTS: Among 35 866 patients, there were 14 387 Black (40.1%) and 21 479 White patients (59.9%). Blacks had a higher prevalence of hyperglycemia (42.3% vs 36.7%, P < .0001) and DM (34.5% vs 22.8%, P < .0001) and a higher admission rate and mean daily blood glucose (P < .001). Blacks also had higher rates of complications (22.2% vs 19.2%, P < .0001), both in patients with DM (24.7 vs 22.9%, P = .0413) and non-DM with hyperglycemia (41.2% vs 37.2%, P = .0019). Using sequential modelling adjusted for age, gender, body mass index, comorbidities, and insurance coverage, non-DM Blacks with normoglycemia (odds ratio, 1.22; 95% confidence interval, 1.10-1.35) and non-DM Blacks with hyperglycemia (odds ratio, 1.18; 95% confidence interval, 1.04-1.33) had higher number of complications compared to Whites. CONCLUSIONS: Black patients have higher rates of hyperglycemia and diabetes, worse inpatient glycemic control, and greater frequency of hospital complications compared to Whites. Non-DM Blacks with hyperglycemia are a particularly vulnerable group. Further investigation is needed to better understand factors contributing the racial disparities in the hospital.

A randomized controlled trial comparing treatment with oral agents and basal insulin in elderly patients with type 2 diabetes in long-term care facilities.

BACKGROUND: Managing hyperglycemia and diabetes is challenging in geriatric patients admitted to long-term care (LTC) facilities. METHODS: This randomized control trial enrolled patients with type 2 diabetes (T2D) with blood glucose (BG) >180 mg/dL or glycated hemoglobin >7.5% to receive low-dose basal insulin (glargine, starting dose 0.1 U/kg/day) or oral antidiabetic drug (OAD) therapy as per primary care provider discretion for 26 weeks. Both groups received supplemental rapid-acting insulin before meals for BG >200 mg/dL. Primary end point was difference in glycemic control as measured by fasting and mean daily glucose concentration between groups. RESULTS: A total of 150 patients (age: 79±8 years, body mass index: 30.1±6.5 kg/m(2), duration of diabetes mellitus: 8.2±5.1 years, randomization BG: 194±97 mg/dL) were randomized to basal insulin (n=75) and OAD therapy (n=75). There were no differences in the mean fasting BG (131±27 mg/dL vs 123±23 mg/dL, p=0.06) between insulin and OAD groups, but patients treated with insulin had greater mean daily BG (163±39 mg/dL vs 138±27 mg/dL, p<0.001) compared to those treated with OADs. There were no differences in the rate of hypoglycemia (<70 mg/dL) between insulin (27%) and OAD (31%) groups, p=0.58. In addition, there were no differences in the number of hospital complications, emergency room visits, and mortality between treatment groups. CONCLUSIONS: The results of this randomized study indicate that elderly patients with T2D in LTC facilities exhibited similar glycemic control, hypoglycemic events and complications when treated with either basal insulin or with oral antidiabetic drugs. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01131052.

COMPARISON OF BASAL INSULIN REGIMENS ON GLYCEMIC VARIABILITY IN NONCRITICALLY ILL PATIENTS WITH TYPE 2 DIABETES.

OBJECTIVE: To evaluate the impact of different subcutaneous basal insulin regimens on glycemic variability (GV) and hospital complications in non-intensive care unit (ICU) patients with type 2 diabetes (T2D). METHODS: This study is a post hoc analysis of 279 general medicine and surgery patients treated with either a "Basal Bolus" insulin regimen using glargine once daily and glulisine before meals or a "Basal Plus" regimen using glargine once daily plus correction doses of glulisine before meals for glucose >140 mg/dL. GV was calculated as mean delta (Δ) daily glucose, mean SD, and mean amplitude of glycemic excursions (MAGE). RESULTS: Treatment with Basal Bolus and Basal Plus regimens resulted in similar mean daily glucose, hypoglycemia, length of stay (LOS), and hospital complications (all P>.05). There were no differences in GV between treatment groups by Δ change (72.5 ± 36 vs. 69.3 ± 34 mg/dL), SD (38.5 ± 18 vs. 37.1 ± 16 mg/dL) and MAGE (67.5 ± 34 vs. 66.1 ± 39 mg/dL) (all P>.05). Surgery patients treated with Basal Bolus had higher GV compared to those treated with Basal Plus (Δ daily glucose and SD: P = .02, MAGE: P = .009), but no difference in GV was found between treatment groups for the general medicine patients (P>.05). Patients with hypoglycemia events had higher GV compared to subjects without hypoglycemia (P<.05), but no association was found between GV and hospital complications (P>.05). CONCLUSION: Treating hospitalized, non-ICU, diabetic patients with Basal Plus insulin regimen resulted in similar glucose control and GV compared to the standard Basal Bolus insulin regimen. Higher GV was not associated with hospital complications.

Randomized controlled trial of insulin supplementation for correction of bedtime hyperglycemia in hospitalized patients with type 2 diabetes.

OBJECTIVE: Clinical guidelines recommend point-of-care glucose testing and the use of supplemental doses of rapid-acting insulin before meals and at bedtime for correction of hyperglycemia. The efficacy and safety of this recommendation, however, have not been tested in the hospital setting. RESEARCH DESIGN AND METHODS: In this open-label, randomized controlled trial, 206 general medicine and surgery patients with type 2 diabetes treated with a basal-bolus regimen were randomized to receive either supplemental insulin (n = 106) at bedtime for blood glucose (BG) >7.8 mmol/L or no supplemental insulin (n = 100) except for BG >19.4 mmol/L. Point-of-care testing was performed before meals, at bedtime, and at 3:00 a.m. The primary outcome was the difference in fasting BG. In addition to the intention-to-treat analysis, an as-treated analysis was performed where the primary outcome was analyzed for only the bedtime BG levels between 7.8 and 19.4 mmol/L. RESULTS: There were no differences in mean fasting BG for the intention-to-treat (8.8 ± 2.4 vs. 8.6 ± 2.2 mmol/L, P = 0.76) and as-treated (8.9 ± 2.4 vs. 8.8 ± 2.4 mmol/L, P = 0.92) analyses. Only 66% of patients in the supplement and 8% in the no supplement groups received bedtime supplemental insulin. Hypoglycemia (BG <3.9 mmol/L) did not differ between groups for either the intention-to-treat (30% vs. 26%, P = 0.50) or the as-treated (4% vs. 8%, P = 0.37) analysis. CONCLUSIONS: The use of insulin supplements for correction of bedtime hyperglycemia was not associated with an improvement in glycemic control. We conclude that routine use of bedtime insulin supplementation is not indicated for management of inpatients with type 2 diabetes.

Hospital discharge algorithm based on admission HbA1c for the management of patients with type 2 diabetes.

OBJECTIVE: Effective treatment algorithms are needed to guide diabetes care at hospital discharge in general medicine and surgery patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a prospective, multicenter open-label study aimed to determine the safety and efficacy of a hospital discharge algorithm based on admission HbA1c. Patients with HbA1c <7% (53.0 mmol/mol) were discharged on their preadmission diabetes therapy, HbA1c between 7 and 9% (53.0-74.9 mmol/mol) were discharged on a preadmission regimen plus glargine at 50% of hospital daily dose, and HbA1c >9% were discharged on oral antidiabetes agents (OADs) plus glargine or basal bolus regimen at 80% of inpatient dose. The primary outcome was HbA1c concentration at 12 weeks after hospital discharge. RESULTS: A total of 224 patients were discharged on OAD (36%), combination of OAD and glargine (27%), basal bolus (24%), glargine alone (9%), and diet (4%). The admission HbA1c was 8.7 ± 2.5% (71.6 mmol/mol) and decreased to 7.3 ± 1.5% (56 mmol/mol) at 12 weeks of follow-up (P < 0.001). The change of HbA1c from baseline at 12 weeks after discharge was -0.1 ± 0.6, -0.8 ± 1.0, and -3.2 ± 2.4 in patients with HbA1c <7%, 7-9%, and >9%, respectively (P < 0.001). Hypoglycemia (<70 mg/dL) was reported in 22% of patients discharged on OAD only, 30% on OAD plus glargine, 44% on basal bolus, and 25% on glargine alone and was similar in patients with admission HbA1c ≤7% (26%) compared with those with HbA1c >7% (31%, P = 0.54). CONCLUSIONS: Measurement of HbA1c on admission is beneficial in tailoring treatment regimens at discharge in general medicine and surgery patients with type 2 diabetes.

Glucose variability is an independent predictor of mortality in hospitalized patients treated with total parenteral nutrition.

OBJECTIVE: Hyperglycemia is associated with increased mortality in critically ill patients treated with total parenteral nutrition (TPN). The role of glucose variability (GV) in predicting outcomes in these patients is not known. METHODS: This retrospective study included medical and surgical patients receiving TPN in a community teaching hospital. GV was calculated by standard deviation (SD) of blood glucose (BG) values and by mean BG daily (Δ) change (daily max - daily minimum). RESULTS: A total of 276 medical and surgical patients (mean age: 51 ± 18 years), 19% with a history of diabetes mellitus (DM), and 74% with intensive care unit (ICU) admission were treated with TPN. During TPN, the mean daily BG was 142.9 ± 33 mg/dL; frequencies of hypoglycemia < 70 and < 40 mg/dL were 41% and 3%, respectively; and hospital mortality was 27.2%. The mean GV by SD was 38 ± 21 mg/dL and by mean (D) change 58 ± 34 mg/dL. GV was significantly higher in deceased patients (SD: 48 ± 25 vs. 34 ± 18 mg/dL and Δ change: 75 ± 39 vs. 51 ± 29 mg/dL, both P < .01) than surviving patients. Multivariate analysis adjusted for age, DM status, gender, APACHE (Acute Physiology and Chronic Health Evaluation) score, mean daily glucose, and hypoglycemia revealed that GV was an independent predictor of hospital mortality (P < .05). The association between GV and mortality was limited to patients without a history of DM and was not present in patients with DM. CONCLUSION: High GV is associated with increased hospital mortality independent of the presence and severity of hyperglycemia or hypoglycemia during TPN therapy. Prospective randomized trials are needed to determine if reduction in GV with intensive glycemic control improves clinical outcomes in patients treated with TPN.

Prevalence, quality of care, and complications in long term care residents with diabetes: a multicenter observational study.

BACKGROUND: Few studies have reported on the quality of diabetes care and glycemic control adjusted for medication use in long term care (LTC) facilities. METHODS: This observational study analyzed diabetes prevalence and management and the impact of glycemic control on clinical outcome in elderly subjects admitted to 3 community LTC facilities. RESULTS: Among 1409 LTC residents (age 79.7 ± 12 years), the prevalence of diabetes was 34.2%. Subjects with diabetes were either on no pharmacological agents (10%) or were treated with sliding scale regular insulin (SSI, 25%), oral antidiabetic drugs (OAD, 5%), insulin (34%), or with combination of OAD and insulin (26%). Patients with diabetes had a mean daily BG of 156 ± 39 mg/dL and a mean admission HbA1c of 6.7% ± 1.1%. Compared with nondiabetes, residents with diabetes had higher number of complications (54% vs 45%, P < .001), infections (26% vs 21%, P = .036), emergency room (ER) and hospital transfers (37% vs 30%, P = .003), but similar mortality (15% vs 14%, P = .56). A total of 43% of residents with diabetes had a BG less than 70 mg/dL, and those with hypoglycemia had longer median length of stay (LOS, 52 vs 29 days, P < .001), more ER or hospital transfers (56% vs 69%, P = .005), and mortality (20% vs 10%, P = .002) compared with residents without hypoglycemia. CONCLUSION: Diabetes is common in LTC residents and is associated with higher resource utilization and complications. Hypoglycemia is common and is associated with increased need of emergency room visits and hospitalization and higher mortality. Our findings emphasize the need for randomized trials evaluating the impact of different approaches to glycemic management on clinical outcome in LTC residents with diabetes.

Differences in inpatient glycemic control and response to subcutaneous insulin therapy between medicine and surgery patients with type 2 diabetes.

OBJECTIVE: To determine differences in inpatient glycemic control and response to two different glargine-based insulin regimens in general medicine and surgery patients with type 2 diabetes (T2D). METHODS: This is a post-hoc analysis of a prospective, multicenter, randomized trial of 298 non-ICU medicine and surgery patients with T2D treated with Basal Bolus regimen with glargine once daily and glulisine before meals and with Basal Plus regimen with glargine once daily and supplemental doses of glulisine before meals for blood glucose (BG)>140mg/dl. Major study outcomes included differences in mean daily BG, frequency of treatment failures (defined as >2 consecutive BG>240mg/dl or a mean daily BG>240mg/dl), and hypoglycemia between the medicine and surgery cohorts. RESULTS: Patients treated with Basal Bolus or with Basal Plus experienced similar improvement in mean daily BG after 1st day of therapy (p=0.16), number of treatment failures (p=0.11) and hypoglycemic events (p=0.50). Compared to surgery patients (n=130), medicine patients (n=168) had higher admission BG (p=0.01) and HbA1c levels (p<0.01); however, they had similar response to either treatment regimen without differences in mean daily BG after 1st day of therapy (p=0.18), number of treatment failures (p=0.58), daily insulin requirements (p=0.36), or in the frequency of hypoglycemia (p=0.79). CONCLUSION: The Basal Plus regimen with glargine once daily and correction doses with glulisine before meals resulted in similar glycemic control to basal bolus regimen. We observed no differences in response to either basal insulin regimen between medicine and surgery patients with type 2 diabetes.

Safety and efficacy of sitagliptin therapy for the inpatient management of general medicine and surgery patients with type 2 diabetes: a pilot, randomized, controlled study.

OBJECTIVE: This study investigated the safety and efficacy of sitagliptin (Januvia) for the inpatient management of type 2 diabetes (T2D) in general medicine and surgery patients. RESEARCH DESIGN AND METHODS: In this pilot, multicenter, open-label, randomized study, patients (n = 90) with a known history of T2D treated with diet, oral antidiabetic agents, or low total daily dose of insulin (≤0.4 units/kg/day) were randomized to receive sitagliptin alone or in combination with glargine insulin (glargine) or to a basal bolus insulin regimen (glargine and lispro) plus supplemental (correction) doses of lispro. Major study outcomes included differences in daily blood glucose (BG), frequency of treatment failures (defined as three or more consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL), and hypoglycemia between groups. RESULTS: Glycemic control improved similarly in all treatment groups. There were no differences in the mean daily BG after the 1st day of treatment (P = 0.23), number of readings within a BG target of 70 and 140 mg/dL (P = 0.53), number of BG readings >200 mg/dL (P = 0.23), and number of treatment failures (P > 0.99). The total daily insulin dose and number of insulin injections were significantly less in the sitagliptin groups compared with the basal bolus group (both P < 0.001). There were no differences in length of hospital stay (P = 0.78) or in the number of hypoglycemic events between groups (P = 0.86). CONCLUSIONS: Results of this pilot indicate that treatment with sitagliptin alone or in combination with basal insulin is safe and effective for the management of hyperglycemia in general medicine and surgery patients with T2D.

Clinical effects of once-weekly exenatide for the treatment of type 2 diabetes mellitus.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, administration, dosage, place in therapy, and cost of extended-release exenatide are reviewed. SUMMARY: Regular-release exenatide has a half-life of 2.4 hours and is administered twice daily. In order to allow for once-weekly administration, exenatide was encapsulated in poly(lactic-co-glycolic acid) microspheres, a biodegradable polymer. After subcutaneous injection, the microspheres slowly degrade, and the drug is released. A single injection of extended-release exenatide reaches maximum plasma concentration after 4-8 hours and remains at therapeutic levels for 8-16 hours, depending on the dosage. Based on the pharmacokinetics of a single dose, researchers determined that 0.8- and 2-mg once-weekly doses were likely to maintain therapeutic levels in the serum. Patients who used extended-release exenatide monotherapy had significantly lower glycosylated hemoglobin (HbA1c) levels and lost more weight than those receiving sitagliptin or pioglitazone (p < 0.05). In combination with metformin, extended-release exenatide reduced HbA1c levels more than did insulin glargine. This new formulation reduced HbA1c levels by 1.5-1.9%, fasting blood glucose concentrations by 31-42 mg/dL, and weight by 2.3-3.7 kg. The most common adverse events were injection-site reactions and transient nausea. Postmarketing reports have described acute pancreatitis and acute necrotizing or hemorrhagic pancreatitis in patients treated with exenatide. The published average wholesale price for a one-month supply of extended-release exenatide 2 mg is $388. CONCLUSION: Extended-release exenatide taken once weekly is an effective second-line therapy for patients with type 2 diabetes who have not achieved glycemic goals with metformin alone.

Randomized study comparing a Basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: basal plus trial.

OBJECTIVE: Effective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This multicenter trial randomized 375 patients with T2D treated with diet, oral antidiabetic agents, or low-dose insulin (≤ 0.4 units/kg/day) to receive a basal-bolus regimen with glargine once daily and glulisine before meals, a basal plus regimen with glargine once daily and supplemental doses of glulisine, and sliding scale regular insulin (SSI). RESULTS: Improvement in mean daily blood glucose (BG) after the first day of therapy was similar between basal-bolus and basal plus groups (P = 0.16), and both regimens resulted in a lower mean daily BG than did SSI (P = 0.04). In addition, treatment with basal-bolus and basal plus regimens resulted in less treatment failure (defined as >2 consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL) than did treatment with SSI (0 vs. 2 vs. 19%, respectively; P < 0.001). A BG <70 mg/dL occurred in 16% of patients in the basal-bolus group, 13% in the basal plus group, and 3% in the SSI group (P = 0.02). There was no difference among the groups in the frequency of severe hypoglycemia (<40 mg/dL; P = 0.76). CONCLUSIONS: The use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal-bolus regimen. The basal plus approach is an effective alternative to the use of a basal-bolus regimen in general medical and surgical patients with T2D.

The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes.

Thiazolidinedione (TZD) therapy has been associated with an increased risk of bone fractures. Studies in rodents have led to a model in which decreased bone quality in response to TZDs is due to a competition of lineage commitment between osteoblasts (OBs) and adipocytes (ADs) for a common precursor cell, resulting in decreased OB numbers. Our goal was to investigate the effects of TZD exposure on OB-AD lineage determination from primary human bone marrow stromal cells (hBMSCs) both in vitro and in vivo from nondiabetic subjects and patients with type 2 diabetics. Our experimental design included 2 phases. Phase 1 was an in vitro study of TZD effects on the differentiation of hBMSCs into OBs and ADs in nondiabetic subjects. Phase 2 was a randomized, placebo-controlled trial to determine the effects of 6-month pioglitazone treatment in vivo on hBMSC differentiation using AD/OB colony forming unit assays in patients with type 2 diabetes. In vitro, TZDs (pioglitazone and rosiglitazone) enhanced the adipogenesis of hBMSCs, whereas neither altered OB differentiation or function as measured by alkaline phosphatase activity, gene expression, and mineralization. The ability of TZDs to enhance adipogenesis occurred at a specific time/stage of the differentiation process, and pretreating with TZDs did not further enhance adipogenesis. In vivo, 6-month TZD treatment decreased OB precursors, increased AD precursors, and increased total colony number in patients with type 2 diabetes. Our results indicate that TZD exposure in vitro potently stimulates adipogenesis but does not directly alter OB differentiation/mineralization or lineage commitment from hBMSCs. However, TZD treatment in type 2 diabetic patients results in decreased osteoblastogenesis from hBMSCs compared with placebo, indicating an indirect negative effect on OBs and suggesting an alternative model by which TZDs might negatively regulate bone quality.

Risk factors for inpatient hypoglycemia during subcutaneous insulin therapy in non-critically ill patients with type 2 diabetes.

OBJECTIVE: We aimed to determine risk factors associated with hypoglycemia during subcutaneous insulin therapy in non-critically ill patients with type 2 diabetes. METHODS: We conducted an analysis of three randomized control trials using basal/bolus regimen and regular sliding scale insulin (SSI) in patients with diabetes admitted to medical and surgical settings. RESULTS: We analyzed medical records of 261 general medicine and 211 noncardiac surgery patients treated with basal/bolus regimen with glargine/glulisine (n = 169), detemir/aspart (n = 67), neutral protamine Hagedorn/regular (n = 63), or with SSI (n = 173). The overall frequency of mild and severe hypoglycemia (<70 and <40 mg/dl) was 19% and 2%, respectively. During treatment, medical patients experienced a higher number of hypoglycemia than surgical patients (23% versus 13%; p = .005), but the rate of severe hypoglycemia was similar between groups (1.9% versus 1.9%; p = not significant). Increasing age, impaired kidney function (glomerular filtration rate < 60 ml/min), total daily insulin dose, and type of insulin regimen (basal/bolus versus SSI) during hospitalization were important contributors for hypoglycemia in both medical and surgical patients. Among these variables, increasing age and type of insulin regimen (basal/bolus versus SSI) were found to be independent predictors of hypoglycemic events. CONCLUSIONS: Mild hypoglycemic events are common during subcutaneous insulin therapy in medical and surgical patients with type 2 diabetes. Increasing age, impaired renal function, daily insulin dose, and insulin regimen (basal/bolus versus SSI) are important predictors of hypoglycemia during insulin therapy in patients with type 2 diabetes mellitus.

A double-blind, randomized clinical trial comparing soybean oil-based versus olive oil-based lipid emulsions in adult medical-surgical intensive care unit patients requiring parenteral nutrition.

OBJECTIVE: Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions, the only Food and Drug Administration-approved lipid formulation for clinical use. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Medical-surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital. PATIENTS: Adult medical-surgical intensive care unit patients. INTERVENTION: Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid emulsions. MEASUREMENTS: Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups. RESULTS: A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil-based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients received olive oil-based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6 [±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups. CONCLUSION: The administration of parenteral nutrition containing soybean oil-based and olive oil-based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults.