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Insulin dosing has been a clinical challenge since the introduction of "islet extract" in the 1920's. Route of administration, insulin preparation and peptide modifications alter clinical effects. With newer insulins, patients and clinicians must clearly understand effective dosing. Technosphere Insulin (TI) is a dry-powder formulation of recombinant human insulin adsorbed onto Technosphere microparticles administered by pulmonary inhalation. TI cartridges are labeled as insulin "units" (4, 8, 12 unit cartridges). With proper dose titration, TI achieves comparable glucose control, improves mealtime glucose, and lowers hypoglycemia risk vs. insulin analogs in T1D. Methods: These analyses compare doses of TI achieved after active titration in 4 randomized trials in individuals with T1D. The ratio of TI inhalation units (based on labeled cartridge content) to SC prandial analog in the comparator group was calculated for each trial at study endpoint. Results: Conclusion: The current analyses across 4 unique studies support the titration of individual patients to TI doses that are approximately 1.3 - 2.5x those of their comparable SC analog insulin doses. These data show that greater "unit doses" of TI should be used to achieve glycemic control in T1D and thus, insulins should be dosed based on glycemic responses rather than "insulin units." Disclosure: D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. J. Manoukian: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company, MannKind Corporation. M. Jones: Employee; Self; MannKind Corporation. R. Abaniel: None. P.M. Morey: Employee; Self; MannKind Corporation. M.L. Grant: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

We investigated non-alcoholic fatty liver disease ( NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes ( T1D), and in insulin-naïve and insulin-treated patients with type 2 diabetes ( T2D). Baseline data from patients who had liver fat content ( LFC) evaluated by magnetic resonance imaging in four phase 3 studies of basal insulin peglispro ( BIL) were analysed. Associations of NAFLD with clinical characteristics, glycaemic control and diabetes therapy were evaluated. The prevalence of NAFLD (defined as LFC ≥ 6%) was low in T1D (8.8%) but high in T2D, with greater prevalence in insulin-naïve (75.6%) vs insulin-treated (61.7%) T2D patients. LFC (mean ± SD) was higher in T2D patients (insulin-naïve, 13.0% ± 8.4%; insulin-treated, 10.2% ± 7.8%) than in T1D patients (3.2% ± 3.2%). In T2D, NAFLD was associated with several markers of insulin resistance. In all three populations, there was an absence of association of HbA1c with LFC, but insulin doses were higher in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Purpose A trade-off exists in most diabetes therapies between the benefits of good glycemic control and the morbidity of hypoglycemia. Balancing these factors to achieve desired outcomes is a key consideration for personalized diabetes therapy. Hypoglycemia at night (nocturnal hypoglycemia [NH]) is a common but often under-reported problem in insulin-treated patients with type 2 diabetes. To better understand the risk for NH, we pooled data from multiple clinical trials of insulin treatment and specifically examined NH risk factors in relation to glycemic goals. Methods Of 53 randomized trials involving insulin treatment, 18 trials that collected NH data were included. Risk factors associated with NH were identified by using gradient-boosting methods. A proportional hazards model was used to quantify the hazard ratio (HR) for risk factors. By modeling with individual patient data, a patient-level NH risk score distribution was created. Finally, results of the model were used to quantify an adjustment to the glycemic goal that would fully offset each risk factor, all other factors being equal. Findings Data pooling resulted in the inclusion of 7341 patients with type 2 diabetes from 18 randomized clinical trials. In the mean 6-month treatment period, 43% of patients experienced at least 1 episode of NH (mean [SD], 1.1 [1.5] events/month). Reduction of glycosylated hemoglobin (HbA 1c ) levels during the trial was a risk factor for NH (HR, 1.40 [95% CI, 1.38-1.43] per –1% of HbA 1c ). Higher baseline HbA 1c level was a protective factor against NH (HR, 0.76 [95% CI, 0.74–0.77] per +1% of HbA 1c ); and the adjustment to HbA 1c goal required to offset 1% higher baseline HbA 1c was –0.825%. Patient characteristics for risk of NH included older age (HR, 1.02 [95% CI, 1.01–1.02]) per 1-year increase), female sex (HR, 1.18 [95% CI, 1.15–1.22]), black or African-American race (HR, 1.41 [95% CI, 1.33–1.50] vs white race), longer diabetes duration (HR, 1.02 [95% CI, 1.01–1.02] per 1-year increase), diabetic nephropathy (HR, 1.40 [95% CI, 1.27–1.54]), and concomitant sulfonylurea use (HR, 1.10 [95% CI, 1.05–1.15]). Asian race was associated with a lower risk of NH (HR, 0.50 [95% CI, 0.48–0.53] vs white race); this finding could be offset with a 2.03% adjustment to the HbA 1c goal. Implications Data on NH are scarce. By pooling multiple clinical trials, this study was able to evaluate patient-level data. A quantitative understanding of the trade-off between individual risk factors for NH and glycemic reduction may help clinicians to personalize patients’ glycemic goals, while effectively managing NH risk. Limitations of the study include that patients were selected through inclusion/exclusion criteria and that patient compliance may be better in a trial setting. Validating the findings in the real world will be helpful. [ABSTRACT FROM AUTHOR]

Abstract: Background: Considerable clinical data on the treatment of type 2 diabetes with incretin-based therapies (glucagon-like peptide 1 receptor agonists [GLP-1RAs] and dipeptidyl-peptidase IV [DPP-4] inhibitors) are available. Objective: This meta-analysis was performed to support the understanding of the overall evidence by summarizing the findings from studies of the incretin-based therapies. Methods: The MEDLINE, EMBASE, BIOSIS, and BIOSIS trial databases were searched for relevant literature published between January 1, 1990, and June 30, 2011. Search terms included GLP-1, DPP-4, the names of drugs that have been approved by the US Food and Drug Administration for the treatment of diabetes, and the names of drugs that have not been approved but are in late-stage research. Studies were included if they were randomized controlled trials of 12 to 52 weeks'' duration and having change from baseline in hemoglobin (Hb) A1c as the primary end point. The random effects meta-analyses models examined HbA1c, fasting plasma glucose (FPG), and body weight for individual therapies, but did not compare effects between therapies. Results: The reviewers identified 362 unique clinical studies, of which 80 were eligible for inclusion in the present meta-analysis. Mean baseline HbA1c values ranged from 7.4% to 10.3% (GLP-1RA studies) and 7.2% to 9.3% (DPP-4 inhibitor studies). The highest maintenance doses of the GLP-1RAs and the DPP-4 inhibitors were associated with changes from baseline in mean HbA1c of −1.1% to −1.6% and −0.6% to −1.1%, respectively. Mean reductions in FPG with exenatide once weekly (QW) or liraglutide once daily were apparently greater than those with exenatide twice daily (BID) and the DPP-4 inhibitors, with the exception of vildagliptin. Mean weight losses with the GLP-1RAs and the DPP-4 inhibitors were >–2.0 and −0.2 to −0.6 kg, respectively. The limitations of the present analysis included a lack of adjustment for placebo use and interstudy heterogeneity associated with differences in methodology (eg, management of concurrent medications, blinding, criteria for treatment discontinuation). Conclusions: All of the incretin-based therapies in the present meta-analysis were associated with significant reductions from baseline in HbA1c and FPG. Further direct comparative studies between the GLP-1RAs and the DPP-4 inhibitors and within the GLP-1RA class are justified. [Copyright &y& Elsevier]

Data have been accumulating on the risk of developing type 2 diabetes in patients receiving statins and on the potential adverse effects of these drugs on glycemic control in patients who already have type 2 diabetes. This article reviews data linking statin use and new-onset diabetes mellitus, the effects of statins on glycemic control in type 2 diabetes, the benefit-risk considerations of statin use and type 2 diabetes, and how these factors affect patient management., (Copyright © 2023 The Cleveland Clinic Foundation. All Rights Reserved.)

Objective: To determine whether the use of an inhaled insulin would improve HbA1c., Methods: This study was performed in 20 type 2 diabetes mellitus (T2DM) participants with HbA1c values ≥7.5 (58) to ≤11.5% (102 mmol/mol) on a variety of glucose-lowering regimens. Prandial Technosphere insulin (TI) was rapidly titrated based on a treatment algorithm using postprandial blood glucose to calculate premeal doses. A 2-week baseline period was followed by 12 weeks of active treatment with TI. The primary outcome was change in HbA1c. Secondary outcomes included glucose time in range (time in range: 70-180 mg/dL) obtained by a blinded continuous glucose monitoring during the baseline period and at the end of 12 weeks. Goals were to assess how to rapidly and safely initiate TI intensification, determine dosing requirements, and establish an effective dose range in uncontrolled T2DM., Results: Mean HbA1c decreased by -1.6% (-17 mmol/mol) from 9.0% (75 mmol/mol) at baseline to 7.4% (57 mmol/mol) at 12 weeks (P < .0001). Mean time in range increased from 42.2% to 65.7% (P < .0002). Mean prandial doses of TI were 18 or 19 units for all meals. Time below range was 1.1% baseline and 2.6% post treatment (P = .01)., Conclusion: Treatment with inhaled TI dosed using a simple algorithm improved glycemic control measured by both HbA1c and time in range, with low rates of hypoglycemia. These data add significantly to understanding TI in the management of T2DM patients for whom prandial insulin is a consideration., (Copyright © 2020 AACE. Published by Elsevier Inc. All rights reserved.)

Objective: To compare glycemic efficacy of Technosphere insulin (TI) versus that of insulin aspart (IA), each added to basal insulin, in type 2 diabetes., Methods: This randomized, 24-week trial included subjects aged from 18 to 80 years who were treated with subcutaneous insulin for 3 months and had glycated hemoglobin (HbA1C) levels of 7.0% to 11.5%. After receiving stabilized insulin glargine doses during a 4-week lead in, the subjects were randomized to TI or IA. The primary end point was an HbA1C change from baseline, with the differences analyzed by equivalence analyses., Results: In the overall cohort (N = 309; males, 23.3%), mean (SD) age was 58.5 (8.4) years, body mass index was 30.8 (4.7) kg/m 2 , weight was 82.2 (13.6) kg, and duration of diabetes was 12.2 (7.1) years. An intention-to-treat cohort had 150 subjects randomized to TI (mean [SD] HbA1C: 8.9% [1.1%]) and 154 randomized to IA (mean [SD] HbA1C: 9.0% [1.3%]). At 24 weeks, mean (SD) HbA1C value declined to 7.9% (1.3%) and 7.7% (1.1%) in the TI and IA cohorts, respectively. A treatment difference of 0.26% was not statistically significant, but the predefined equivalency margin was not met. Subjects receiving TI lost 0.78 kg compared to baseline; subjects receiving IA gained 0.23 kg (P =.0007). The incidence of mild/moderate hypoglycemia was lower for the TI cohort, though not statistically significant., Conclusion: Both TI and IA resulted in significant and clinically meaningful HbA1C reductions. TI also resulted in significant and clinically meaningful weight reductions. These data support the use of inhaled insulin as a treatment option for individuals with type 2 diabetes., (Copyright © 2020 AACE. Published by Elsevier Inc. All rights reserved.)

Hypoglycemia is a serious problem in older patients with diabetes mellitus. This chapter discusses risk factors associated with hypoglycemia and approaches to mitigation of the risk for hypoglycemia. Specific considerations include selection of glucose lowering agents, comorbid conditions and the implications of declining cognitive dysfunction., Competing Interests: Disclosure B.J. Hoogwerf is a former employee and a minor stockholder of Eli Lilly and Co., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: To assess real-world effectiveness of linagliptin in persons with type 2 diabetes mellitus (T2DM) across a range of ages and renal function. Effectiveness was assessed in different races, with a focus on African Americans (AA)., Methods: This was a non-interventional retrospective cohort study using data in the Optum clinical database from adults with T2DM initiating linagliptin. Date of the first linagliptin prescription was the index date. Outcomes included change in glycated hemoglobin (HbA1c) and the percentage of persons achieving an HbA1c < 7% (53 mmol/mol) during the 60-180 days following linagliptin initiation. Analyses of age by renal function were conducted. Multivariate regression analysis was performed to assess change in HbA1c, controlling for an a priori list of covariates., Results: Overall, 11,001 persons were included. Mean pre-index HbA1c value was 8.2% (66 mmol/mol), with higher levels in younger versus older persons and AAs versus other race groups. Persons initiating linagliptin had an average HbA1c reduction of 0.51% (5.6 mmol/mol). Without adjusting for age, renal function, race, and pre-index HbA1c, greater reductions in HbA1c were observed in younger versus older persons, persons with higher versus lower estimated glomerular filtration rate (eGFR), and AAs versus white or Asians. After multivariate analysis, variables significantly associated with a greater HbA1c reduction included higher pre-index HbA1c and older age., Conclusions: These results support the HbA1c-lowering effectiveness of linagliptin across age, race, and renal function categories among a large real-world population of adults with T2DM.

Objective: To examine the clinical effectiveness of concomitant therapy of exenatide twice daily and basal insulin in patients with type 2 diabetes mellitus in the United States., Methods: Data from adults with type 2 diabetes were selected from an electronic medical record database. Concomitant therapy was defined as a basal insulin prescription within 6 months before or after an exenatide prescription between May 2005 and April 2009. Upon initiation, patients were treated with both medications. Clinical effectiveness was measured as mean changes in hemoglobin A1c (primary outcome), body weight, body mass index, blood pressure, and lipid values from a 6-month baseline to mean-adjusted values in a 12-month follow-up period. These changes were assessed by a bootstrapping test., Results: There were 1752 patients (mean age, 57 years) who initiated concomitant therapy (75% added exenatide to basal insulin, 25% added basal insulin to exenatide). Patients achieved significant mean reductions in hemoglobin A1c (0.5%), body weight (1.8 kg), body mass index (0.6 kg/m2), diastolic blood pressure (0.5 mm Hg), and various lipid measures (all P<.05). Hemoglobin A1c reduction was consistent irrespective of the treatment order. However, body weight, body mass index, and blood pressure reductions were observed in only patients who added exenatide to basal insulin., Conclusions: Overall, exenatide and basal insulin concomitant therapy was associated with significant reductions in hemoglobin A1c, body weight, body mass index, diastolic blood pressure, and lipids in a large, diverse patient population treated in ambulatory care settings in the United States. In the subgroup analysis, body weight, body mass index, and diastolic blood pressure reductions were observed in only patients who added exenatide to basal insulin.

Objective: To explore, by post hoc analyses of pooled data, the efficacy and safety of the use of exenatide twice daily (BID) in patients stratified by baseline glucose-lowering therapies., Methods: Patients with type 2 diabetes from long-term randomized controlled trials who were treated with exenatide BID were classified into concomitant medication groups on the basis of background treatment (diet and exercise only, metformin only, sulfonylurea only, thiazolidinedione only, metformin + sulfonylurea, metformin + thiazolidinedione, or insulin with or without other oral antihyperglycemic medications). Seventeen studies were included in the analyses (N = 2,096)., Results: In these analyses of patients treated with exenatide BID for 12 to 30 weeks, there were significant decreases from baseline in hemoglobin A(1c) (A1C) and fasting glucose levels in all groups and significant decreases from baseline in body weight in all groups except the thiazolidinedione-only group. The decrease in A1C appeared to be greater in the insulin group than in the other groups, likely because the insulin dose was titrated whereas doses of concomitant antihyperglycemic medications were generally not titrated. Overall, changes in blood pressure and lipids were small. Across all groups, the most common adverse effects were gastrointestinal events. Hypoglycemia was more common in the sulfonylurea-only, metformin + sulfonylurea, and insulin groups than it was in the other concomitant medication groups., Conclusion: The use of exenatide BID across a wide range of background therapies was associated with reductions in A1C, fasting glucose, and body weight. Gastrointestinal adverse events were common.

This study examined the relationships among health-related quality of life and risk factors of coronary artery disease (CAD) and all-cause mortality in high-risk cardiac patients seen in a cardiology prevention clinic. At baseline, 1785 patients (age, 53.4+/-13.4 years; 58.8% men) had a medical history, physical examination, and laboratory tests. They completed the Medical Outcomes Study Short Form-36-Item Health Survey (SF-36). Analyses were conducted on associations of 2 SF-36 domain scores (overall physical health [OPH] and overall mental health [OMH]) with CAD biomarkers and all-cause mortality. Lower OPH scores were associated with CAD risk factors including smoking; history of hypertension, diabetes, and peripheral artery disease; the metabolic syndrome; and other novel CAD biomarkers. Lower OMH scores showed similar but weaker associations with CAD risk factors. OPH significantly predicted 5-year mortality in multivariable survival analysis. SF-36, especially OPH, was associated with many risk factors of CAD and significantly predicted mortality., ((c) 2009 Wiley Periodicals, Inc.)

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial tested the hypothesis that intensive glucose-lowering (with a hemoglobin A1c target of less than 6.0%) would reduce the incidence of atherosclerotic disease events and death compared with standard treatment (with a hemoglobin A1c target of 7.0% to 7.9%) in more than 10,000 patients with type 2 diabetes at high risk of cardiovascular events. The study was terminated early because more people had died in the intensive-treatment group than in the standard-treatment group (257 vs. 203). The ACCORD results should not substantially alter our usual approach to glucose-lowering, which should still be "as low as we can get it safely" while avoiding hypoglycemia, significant weight gain, complex regimens, and, perhaps, the "stress" of maintaining glycemic control, especially in patients at high risk of coronary heart disease.

DM increases the risk of multiple complications including retinography, nephropathy, and atherosclerotic disease. Management strategies include management of the associated metabolic risk factors such has hyperglycemia, dyslipidemia, and hypertension. Additional management strategies include laser therapy for retinopathy and appropriate footwear to reduce the risk of lower extremity amputations.

Background: Some studies have indicated a decline in patients' cognitive performance after coronary artery bypass graft surgery., Objective: To evaluate cognitive performance before and after coronary artery bypass graft surgery., Methods: Patients' cognitive performance before and after coronary artery bypass graft surgery was evaluated in a prospective observational multicenter study in 5 academic medical centers. A total of 242 men and 123 women were evaluated before surgery; 333 men and 216 women, 5 to 11 months after surgery (197 men and 99 women were evaluated both before and after surgery). Verbal ability, attention/concentration, logical/verbal and visual memory, and facial recognition were measured. Data on demographic, medical, and psychosocial characteristics also were collected., Results: After surgery, patients' overall performance improved (P < .001) for attention/concentration, verbal fluency, and logical/verbal memory. Patients with more education (high school or greater) performed better on each test (P < .001) than did patients with less education. No strong effects of sex or age on cognitive performance were observed before or after surgery, and no important differences in sex, age, or education were associated with changes in scores from before to after surgery., Conclusion: On average, cognitive performance improved rather than declined after coronary artery bypass graft surgery. The improvements were consistent across sex, age, and education.

Insulin is not the only hormone that regulates plasma glucose levels. Glucagon-like peptide 1 (GLP-1), produced in the small intestine, and amylin, produced by beta cells in the pancreas, also have glucose-lowering effects. Synthetic analogues of these hormones are now available for clinical use.

Patients with diabetes mellitus are at higher risk for complications from surgery than their nondiabetic counterparts. Evidence-based guidance on the perioperative management of diabetic patients is still very limited. Management is best guided by careful preoperative and postoperative consideration of diet, antidiabetic medication regimens, and the likelihood of specific complications of diabetes. Good postoperative glucose control reduces the risk of in-hospital death and shortens length of stay. Insulin is the mainstay of perioperative glucose management, and intensive insulin therapy (to a target blood glucose of 110 mg/dL or lower) improves a range of clinical outcomes in critically ill patients relative to less aggressive insulin strategies. There is little role for oral antidiabetic medications in the early postoperative phase.

The 2004 update to the National Cholesterol Education Program guidelines goes farther than the 2001 version in suggesting an optional low-density lipoprotein cholesterol (LDL-C) goal of less than 70 mg/dL for patients at "very high risk." It recommends starting both diet and drug therapy in all patients at high or very high risk whose LDL-C level is above the goal level, with the goal of reducing LDL-C by 30% to 40%. These more aggressive guidelines are based on results of five clinical studies published since 2001.

The National Cholesterol Education Program recognizes the importance of the metabolic syndrome and has published guidelines for its diagnosis. Weight loss, physical activity, and treatment of the individual risk factors constitute the main strategies for treatment. For now, the goals and methods of treating hypertension and dyslipidemia are the same in people with the metabolic syndrome as in the general population. Thiazolidinedione drugs increase insulin sensitivity, but their use in the metabolic syndrome is only speculative at present. We recommend they be used only as indicated to treat diabetes mellitus.