Achieving Good Metabolic Control Without Weight Gain with the Systematic Use of GLP-1-RAs and SGLT-2 Inhibitors in Type 2 Diabetes: A Machine-learning Projection Using Data from Clinical Practice

PurposeRecently, the 2022 American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) consensus report stressed the importance of weight control in the management of patients with type 2 diabetes; weight control should be a primary target of therapy. This retrospective analysis evaluated, through an artificial-intelligence (AI) projection of data from the AMD Annals database—a huge collection of most Italian diabetology medical records covering 15 years (2005–2019)—the potential effects of the extended use of sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and of glucose-like peptide 1 receptor antagonists (GLP-1-RAs) on HbA_1c and weight.MethodsData from 4,927,548 visits in 558,097 patients were retrospectively extracted using these exclusion criteria: type 1 diabetes, pregnancy, age >75 years, dialysis, and lack of data on HbA_1c or weight. The analysis revealed late prescribing of SGLT-2is and GLP-1-RAs (innovative drugs), and considering a time frame of 4 years (2014–2017), a paradoxic greater percentage of combined-goal (HbA_1c <7% and weight gain <2%) achievement was found with older drugs than with innovative drugs, demonstrating aspects of therapeutic inertia. Through a machine-learning AI technique, a “what-if” analysis was performed, using query models of two outcomes: (1) achievement of the combined goal at the visit subsequent to a hypothetical initial prescribing of an SGLT-2i or a GLP-1-RA, with and without insulin, selected according to the 2018 ADA-EASD diabetes recommendations; and (2) persistence of the combined goal for 18 months. The precision values of the two models were, respectively, sensitivity, 71.1 % and 69.8%, and specificity, 67% and 76%.FindingsThe first query of the AI analysis showed a great improvement in achievement of the combined goal: 38.8% with prescribing in clinical practice versus 66.5% with prescribing in the “what-if” simulation. Addressing persistence at 18 months after the initial achievement of the combined goal, the simulation showed a potential better performance of SGLT-2is and GLP-1-RAs with respect to each antidiabetic pharmacologic class or combination considered.ImplicationsAI appears potentially useful in the analysis of a great amount of data, such as that derived from the AMD Annals. In the present study, an LLM analysis revealed a great potential improvement in achieving metabolic targets with SGLT-2i and GLP-1-RA utilization. These results underscore the importance of early, timely, and extended use of these new drugs.     

Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus

BackgroundGlucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes.ObjectivesThe aim of this article was to review incretin physiology and studies of incretin therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors that were developed to specifically address the blunted incretin response in patients with T2DM.MethodsRelevant English-language publications between 1995 and 2010 were identified through a search of the MEDLINE and EMBASE databases using the search terms incretin, type 2 diabetes mellitus, GLP-1, glucose-dependent insulinotropic polypeptide, and DPP-4. Review articles and preclinical and clinical trials that described relevant details of the epidemiology of diabetes and incretin physiology in health and in T2DM were selected for review and inclusion. Clinical trials were used to describe the clinical efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. An occasional systematic review article and/or meta-analysis summarizing numerous clinical trials of a particular agent was selected for summarizing key data.ResultsPharmacologic modulation of incretin pathophysiology by GLP-1 receptor agonists and DPP-4 inhibitors significantly improved glycemic control, benefited β-cell function, improved dyslipidemia, and lowered the risk of hypoglycemia compared with insulin and sulfonylureas. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produced weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The most common adverse events with GLP-1 receptor agonist therapy included nausea (28%–44%), vomiting (13%–17%), and diarrhea (11%–17%), which generally reduced in incidence and severity with continued therapy. The tolerability profile of the DPP-4 inhibitors was very good, with the incidence of adverse events similar to that of placebo. There was a suggestion of an increased incidence of nasopharyngitis versus placebo (5%–6% vs 3%–4%) with sitagliptin and urinary tract infection (6.8% vs 6.1% with placebo) and headache with saxagliptin (6.5% vs 5.9% with placebo).ConclusionThe 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term β-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined.     

Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy

OBJECTIVE: This study aimed to assess glycemic response to a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro (Mix 75/25) BID plus metformin versus insulin glargine QD plus metformin in patients with type 2 diabetes mellitus (DM). METHODS: Adults new to insulin therapy were enrolled in a multicenter, randomized, prospective, open-label, crossover study with 16 weeks on each treatment. Variables included glycosylated hemoglobin (HbA(1c)), hypoglycemia rate, fasting blood glucose (FBG), 2-hour postprandial blood glucose (ppBG), and rise in blood glucose after meals. RESULTS: One hundred five patients (mean age, 55 years) were randomized. There was no difference in baseline mean values for either treatment sequence group for body mass index, duration of DM, or HbA(1c). Ninety-five patients completed the study and 67 were included in the efficacy analysis. Mix 75/25 was associated with lower mean (SD) HbA(1c) at end point (7.4% [1.1%] vs 7.8% [1.1%]; P = 0.002). More patients using Mix 75/25 achieved target HbA(1c) < or =7.0% (42% [30/71] vs 18% [13/71]; P < 0.001). With Mix 75/25, the mean (SD) 2-hour ppBG was similar after lunch but lower after breakfast (156.4 [43.6] vs 171.1 [44.9] mg/dL; P = 0.012) and dinner (164.8 [42.5] mg/dL vs 193.8 [51.0] mg/dL; P < 0.001), although FBG was higher (139.3 [36.6] mg/dL vs 123.9 [34.9] mg/dL; P < 0.001). Rise in ppBG was lower with Mix 75/25 after breakfast (16.9 [47.0] mg/dL vs 47.4 [34.8] mg/dL; P < 0.001) and dinner (14.2 [44.1] mg/dL vs 45.9 [41.3] mg/dL; P < 0.001). Gain in mean (SD) body weight was greater with Mix 75/25 than insulin glargine (2.3 [4.0] kg vs 1.6 [4.0] kg; P = 0.006). For all randomized patients, mean (SD) hypoglycemia rates were lower with insulin glargine (0.68 [1.38] vs 0.39 [1.24] episodes/patient per 30 days; P = 0.041), although nocturnal hypoglycemia was similar. CONCLUSION: In this study population, Mix 75/25 plus metformin was associated with lower HbA(1c) than insulin glargine plus metformin, smaller rise in ppBG after breakfast and dinner, and higher proportion of patients achieving HbA(1c) < or =7.0%, with a slight increase in overall (but not nocturnal) hypoglycemia.     

User’s guide to mechanism of action and clinical use of GLP-1 receptor agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are injectable glucose-lowering medications approved for the treatment of adult patients with type 2 diabetes mellitus (T2DM). This article provides practical information to guide primary care physicians on the use of GLP-1RAs in patients with T2DM. Two short-acting (once- or twice-daily administration; exenatide and liraglutide) and three long-acting (weekly administration; albiglutide, dulaglutide and exenatide) GLP-1RAs are currently approved in the US. These drugs provide levels of GLP-1 receptor agonism many times that of endogenous GLP-1. The GLP-1RAs have been shown to significantly improve glycemic parameters and reduce body weight. These agents work by activating GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release—responses that are both glucose-dependent—with a consequent low risk for hypoglycemia. Effects on GLP-1 receptors in the CNS and the gastrointestinal tract cause reduced appetite and delayed glucose absorption due to slower gastric emptying. The most common adverse effects are gastrointestinal, which are transient and less common with the long-acting drugs. GLP-1RAs are recommended as second-line therapy in combination with metformin, sulfonylureas, thiazolidinediones or basal insulin, providing a means of enhancing glucose control while offsetting the weight gain associated with insulin and some oral agents. GLP-1RAs represent a useful tool that the primary care physician can use to help patients with T2DM achieve their therapeutic goals.     

Glucagon-like peptide-1 receptor agonists versus insulin glargine for type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of hypoglycemic drugs, including exenatide, liraglutide, albiglutide, lixisenatide, and taspoglutide. Insulin glargine is a standard agent used to supplement basal insulin in type 2 diabetes mellitus (T2DM).Objective: The aim of this study was to review the efficacy and safety profiles of GLP-1 receptor agonists versus insulin glargine in type 2 diabetic patients who have not achieved treatment goals with oral hypoglycemic agents.Methods: The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and the database of ongoing trials were searched from inception through April 2010. Additional data were sought from relevant Web sites, the American Diabetes Association, reference lists of included trials and related (systematic) reviews, and industry. Randomized controlled trials (RCTs) were selected if they were ≥3 months in duration, compared GLP-1 receptor agonists with insulin glargine in patients with T2DM, and included ≥1 of the following outcomes: mortality, complications of T2DM, glycemie control, weight, lipids, blood pressure, adverse effects, and health-related quality of life. Quasirandomized controlled trials were excluded. The quality of the eligible studies was assessed on the basis of the following aspects: randomization procedure, allocation concealment, blinding, incomplete outcome data (intent-to-treat [ITT] analysis), selective outcome reporting, and publication bias.Results: A total of 410 citations were retrieved; 5 multicenter RCTs that met the inclusion criteria were identified. They were all open-label designs with an insulin glargine arm, predefined outcomes reported, and ITT analysis. One trial had an unclear randomization procedure and allocation concealment. Publication bias was not able to be determined. No data wete found with regard to mortality or diabetes-associated complications, and few data were found on quality of life. The results of the metaanalysis suggest that insulin glargine was significantly better in reducing the fasting blood glucose (mean difference [MD] [95% CI], 1.31 [1.04 to 1.58]; P < 0.001), but exhibits greater incidence of nocturnal hypoglycemia (risk ratio [RR] [95% CI], 0.40 [0.23 to 0.71]; P = 0.002) and influenza (RR [95% CI], 0.56 [0.32 to 0.98]; P = 0.04). GLP-1 receptor agonists are more conducive to reducing weight (MD [95% CI], −3.96 [−5.14 to -2.77]; P < 0.001), postprandial blood glucose (after breakfast, P < 0.001; after dinner, P < 0.001), and LDL-C (MD [95% CI], −0.18 [−0.28 to −0.08]; P < 0.001), but have significantly more gastrointestinal adverse effects (eg, nausea/ vomiting, P < 0.001). There were no significant differences between GLP-1 receptor agonists and insulin glargine in reducing glycosylated hemoglobin (HbA_1c) levels (MD [95% CI], −0.03 [−0.13 to 0.08]) and the overall incidence of hypoglycemia (RR [95% CI], 0.69 [0.42 to 1.14]).Conclusions: Compared with insulin glargine, GLP-1 receptor agonists did not have a significant difference in regard to reducing HbA1c levels and they were significantly associated with decreased weight but increased gastrointestinal adverse events. It remains unclear whether GLP-1 receptor agonists influence mortality or diabetes-associated complications in patients with T2DM. More trials with longer follow-up are needed to determine the exact long-term efficacy and safety profiles of this new class of hypoglycemic drugs.     

Dipeptidyl Peptidase-4 Inhibitors in the Elderly: More Benefits or Risks?

Several studies have shown a high prevalence of type 2 diabetes mellitus (T2DM) in the elderly, characterized by a paucity of symptoms, which represents an obstacle for an early diagnosis. Frequently, T2DM in the elderly is diagnosed when a complication occurs, among which are cognitive disorders and/or affective disturbances. Moreover, hypoglycemia is a frequent side effect of therapeutic treatment with insulin, sulfonylureas or glinides, while other treatments (metformin, acarbose, thiazolidinediones, glucagon-like peptide-1 [GLP-1] receptor agonists, and dipeptidyl peptidase-4 [DPP4] inhibitors) are capable of reducing hyperglycemia without inducing hypoglycemia. Thus, considering that older persons are a very heterogeneous group of individuals, management of T2DM in the elderly is challenging but there are no available specific treatment goals or treatment algorithms for older diabetic patients. Metformin is the recommended first-line therapy in all T2DM patients. When metformin is not sufficient to achieve the desired therapeutic targets, a second drug can be added. Available options include sulfonylureas, meglitinides, alfa-glucosidase inhibitors, pioglitazone, insulin, GLP-1 receptor agonists, and DPP-4 inhibitors. The most intriguing therapy for older patients is the one based on the so-called incretins, i.e., gastrointestinal hormones that, mainly secreted in the postprandial phase, stimulate insulin secretion and inhibit glucagon secretion. The two most important human incretins are GLP-1 and glucose-dependent insulinotropic peptide (GIP). These hormones potentiate the acute effects of glucose on pancreatic alfa and beta cells, thus stimulating insulin secretion, and only GLP-1 inhibits glucagon secretion in a glucose-dependent manner (that is, only when glucose levels are increased); as a result, they reduce hyperglycemia with virtually no hypoglycemic risk. Due to their characteristics, DPP-4 inhibitors seem to be particularly interesting as potential agents for the treatment of older patients with T2DM.     

糖尿病患者胰高血糖素样肽-1在糖耐量试验前后的变化及意义

目的探讨2型糖尿病患者胰高血糖素样肽-1(glucagon-like peptical-1,GLP-1)水平与血糖、胰岛素及胰岛素抵抗的关系。方法 2型糖尿病患者50例(糖尿病组)及体检健康者30例(对照组),2组均禁食10h后行糖耐量试验,采集空腹及餐后2h血标本,分别检测血浆葡萄糖、胰岛素、GLP-1水平。结果糖尿病组空腹及餐后2h血糖明显高于对照组(P<0.05),餐后2hGLP-1水平明显低于对照组(P<0.05),空腹和餐后2h胰岛素水平及空腹GLP-1水平与对照组比较差异无统计学意义(P>0.05)。结论 2型糖尿病患者餐后2hGLP-1水平较正常人明显降低;餐后GLP-1分泌水平可反映2型糖尿病患者胰岛功能受损程度。     

Complementing Insulin Therapy to Achieve Glycemic Control

Introduction

Most patients with type 2 diabetes mellitus (T2DM) will need incrementally more complex therapeutic regimens to control hyperglycemia as the disease progresses. Insulin is very effective in reducing hyperglycemia and may improve β-cell function in patients with T2DM. However, insulin therapy is associated with weight gain and increased risk of hypoglycemia. Adding other antidiabetes medications to insulin can improve glycemic control and potentially lower the required insulin dose, resulting in less weight gain and lower risk for hypoglycemia. This article summarizes the advantages and disadvantages of different classes of commonly used antidiabetes agents, with emphasis on newer classes, for use as add-on therapy to insulin in patients with T2DM inadequately controlled on insulin therapy.

Methods

A PubMed search from July 1, 2003 to April 15, 2013 for peer-reviewed clinical and review articles relevant to insulin combination or add-on therapy in T2DM was conducted. Search terms included “insulin combination therapy,” “add-on therapy diabetes,” “dipeptidyl peptidase-4 (DPP-4) inhibitors,” “glucagon-like peptide-1 (GLP-1) receptor agonist,” “sodium-glucose cotransporter 2 (SGLT2) inhibitors”, “insulin metformin,” “insulin sulfonylurea,” and “insulin thiazolidinedione.” Bibliographies from retrieved articles were also searched for relevant articles. Study design, clinical relevance, and effect on insulin combination therapy were analyzed.

Results

Therapies used as add-on to insulin include agents associated with weight gain (thiazolidinediones and sulfonylureas) and/or hypoglycemia (sulfonylureas), which, therefore, may exacerbate risks already present with insulin. GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when added to insulin and have a low propensity for hypoglycemia and cause no change (DPP-4 inhibitors) or a reduction (GLP-1 receptor agonists, SGLT2 inhibitors) in body weight.

Conclusion

GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when combined with insulin. They also have low propensity for weight gain and hypoglycemia and so may be preferred treatment options for insulin combination when compared with traditional therapies.     

Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT

OBJECTIVETo compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin.RESEARCH DESIGN AND METHODSDrug-naive patients (N = 318) with new-onset T2DM were randomly assigned to receive for 3 years either 1) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or 2) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA_1c at <6.5% (48 mmol/mol). Insulin sensitivity and β-cell function were measured at baseline and 3 years. The primary outcome was the difference in HbA_1c between the groups at 3 years.RESULTSBaseline HbA_1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA_1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21–0.39]; P = 0.001), and the HbA_1c reduction was maintained at 3 years in patients receiving triple therapy compared with conventional therapy (6.4% ± 0.1% and 6.9% ± 0.1%, respectively), despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA_1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39–0.61; P < 0.0001). Triple therapy produced a threefold increase in insulin sensitivity and 30-fold increase in β-cell function. In conventional therapy, insulin sensitivity did not change and β-cell function increased by only 34% (both P < 0.0001 vs. triple therapy).CONCLUSIONSTriple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA_1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.     

Exenatide added to insulin therapy: A retrospective review of clinical practice over two years in an academic endocrinology outpatient setting

Background: Exenatide is an antidiabctic agent currently indicated as adjunctive therapy with oral agents for the treatment of type 2 diabetes mellitus (T2DM). Limited published data exist on the off-label use of exenatide in conjunction with insulin in the treatment of T2DM.Objective: The aim of this retrospective study was to examine the effects of exenatide on glycemic control, weight, and insulin dose in patients with T2DM treated with insulin.Methods: Patients with T2DM receivirg insulin and adjuvant therapy with exenatide at an endocrinology clinic at a university hospital for up to 27 months were eligible for inclusion. Glycosylated hemoglobin (HbA_1c), weight, insulin doses (total, prandial, and basal), concurrent oral antidiabetic medications, and adverse events were ascertained by retrospective review of medical records and were considered the clinical parameters of interest. The last observation in 4 specified time intervals (0–6, 6–12, 12–18, and 18–27 months) for each clinical parameter was used in the analysis.Results: Of the 3397 patients with a confirmed diagnosis of T2DM who were seen at the clinic during the study period, 268 patients met inclusion criteria and were enrolled in the study. Of the 268 patients enrolled, 38 discontinued therapy within the first 2 months, 30 were lost to follow-up, and 12 did not have evaluable data. These latter patients without sufficient data (n = 42) were not included in the primary analysis but were included in the adverse events analysis. Overall, data from 188 patients (mean [SD] age, 56 (9) years; 85 [45%] men; body mass index, 40.4 [8.4] kg/m²; 160 [85%] white) were evaluated (mean duration of treatment, 350 [208] days) and included in all analyses. The mean baseline values for HbA_1c, weight, and total daily insulin dose before exenatide therapy were 8.05% (1.47%), 117.8 (24.7) kg, and 99.9 (90.0) U, respectively. For the 4 time intervals, the mean changes in HbA_1c were: ?0.66% (1.54%) at 0 to 6 months (P < 0.001); ?0.55% (1.4%) at 6 to 12 months (P < 0.001); ?0.54% (1.83%) at 12 to 18 months (P = 0.019); and ?0.54% (1.37%) at 18 to 27 months (P = 0.020). Mean weight significantly declined with increasing treatment duration. Mean changes in weight were: ?2.4 (5.1) kg at 0 to 6 months (P < 0.001); ?4.3 (7.2) kg at 6 to 12 months (P < 0.001); ?6.2 (9.7) kg at 12 to 18 months (P < 0.001); and ?5.5 (10.8) kg at 18 to 27 months (P < 0.01). After 18 months, an increase in weight was observed; but the increase remained lower than baseline. The mean insulin total daily dose (TDD) was decreased in all patients at the 0- to 6-month (?18.0 [49.9] U; P < 0.001) and the 6- to 12-month (?14.8 [35.3] U; P < 0.001) intervals. Mean changes in insulin TDD during the 12- to 18-month and 18- to 27-month intervals were not statistically significant. The mean percent change from baseline in the basal insulin dose at 0 to 6 months, 6 to 12 months, 12 to 18 months, and 18 to 27 months was not statistically significant. For the 4 intervals, the mean percent change from baseline in the prandial insulin dose was ?33.5% (56.2%) at 0 to 6 months (P < 0.001); ?25.9% (59.7%) at 6 to 12 months (P = 0.002); ?29.7% (74.8%) at 12 to 18 months (P = 0.02); and ?55.7% (56.8%) at 18 to 27 months (P = 0.005). Of the 226 patients who were treated with exenatide + insulin for any length of time (including within the first 2 months), 59 (26.1%) discontinued exenatide because of adverse events. The adverse events were largely considered mild and included nausea (n = 51 [22.6% of patients]), vomiting (22 [9.7%]), hypoglycemia (9 [4.0%]), heartburn (2 [0.9%]), diarrhea (1 [0.4%]), constipation (1 [0.4%]), malaise (1 [0.4%]), and generalized edema (1 [0.4%]). Two serious adverse events occurred during the study period: acute renal failure not attributed to exenatide (1 [0.4%]); and pancreatitis (1 [0.4%]), both of which required hospitalization 1 month after the start of exenatide therapy.Conclusion: In this retrospective review of patients with T2DM treated in an outpatient setting, the addition of exenatide to insulin-based therapy was associated with reductions in mean HbA_1c, weight, and prandial insulin requirements for treatment periods of up to 27 months, and in total insulin requirements for treatment periods of up to 12 months.     

Temporal arteritis

Abstract

Objective: To assess rates of diagnosis and antihyperglycemic dose adjustment in patients with moderate to end-stage renal impairment (RI) and type 2 diabetes mellitus (T2DM). Methods: Retrospective database analysis using GE Centricity Outpatient Electronic Medical Records. Patients aged ≥ 18 years with evidence of T2DM (International Classification of Diseases, Ninth Edition, Clinical Modification codes 250.x0 and 250.x2) between January 1, 2000 and June 30, 2009, and ≥ 12 months of data after identification were selected. Moderate to end-stage RI was evaluated using a formula-derived estimated glomerular filtration rate (eGFR) based on serum creatinine (SCr). Patients were classified as moderate (eGFR, 30–59 mL/min/1.73 m²), severe (eGFR, 15–29 mL/min/1.73 m²), or end-stage (eGFR, < 15 mL/min/1.73 m²), per the National Kidney Foundation guidelines, based on the first-observed SCr test. Among patients with a physician diagnosis, the time to diagnosis was reported. Dose adjustment was reported for patients receiving metformin and sitagliptin. Predictors of progression to end-stage RI based on logistic regressions were examined. Results: 35.2% of patients with T2DM had evidence of moderate to end-stage RI. Of these patients, 20% had a chart-documented physician diagnosis (range, 16% [moderate RI] to 66% [end-stage RI]). Patients with moderate or severe RI had a physician diagnosis mean of 253.4 (standard deviation [SD], 584.5) and 86.9 (SD, 417.4) days, respectively, after the eGFR calculation indicating RI. Patients with end-stage RI had a physician diagnosis mean of 83.6 (SD, 399.2) days before the eGFR calculation. After the eGFR calculation, 15.1% and 0.1% of patients with orders for sitagliptin and metformin, respectively, received doses of the drug appropriate for their degree of RI. Among patients with moderate or severe RI, appropriate diagnosis of RI was associated with significantly lower odds of progressing to end-stage RI (odds ratio, 0.200; 95% confidence interval, 0.188–0.213). Conclusions: Renal impairment is common but often undetected in patients with T2DM. Patients with a documented RI diagnosis have lower odds of progression to end-stage RI. Metformin and sitagliptin are frequently used at inappropriate doses in patients with RI. Further analyses to understand the clinical and economic consequences of these findings are needed.     

Early Menopause and Cardiovascular Disease Risk in Women With or Without Type 2 Diabetes: A Pooled Analysis of 9,374 Postmenopausal Women

OBJECTIVEEarly menopause may be associated with higher cardiovascular disease (CVD) risk. Type 2 diabetes mellitus (T2DM), coupled with early menopause, may result in even greater CVD risk in women. We examined CVD risk in women with early compared with normal-age menopause, with and without T2DM overall, and by race/ethnicity.RESEARCH DESIGN AND METHODSWe pooled data from the Atherosclerosis Risk in Communities study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. We included women with data on menopausal status, menopausal age, and T2DM, excluding pre- or perimenopausal women and those with prevalent CVD. Outcomes included incident coronary heart disease (CHD), stroke, heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD) (CHD or stroke). We estimated the risk associated with early (<45 years) compared with normal-age menopause using Cox proportional hazards models. Covariates included age, race/ethnicity, education, BMI, blood pressure, cholesterol, smoking, alcohol consumption, antihypertensive medication, lipid-lowering medication, hormone therapy use, and pregnancy history.RESULTSWe included 9,374 postmenopausal women for a median follow-up of 15 years. We observed 1,068 CHD, 659 stroke, 1,412 HF, and 1,567 ASCVD events. T2DM significantly modified the effect of early menopause on CVD risk. Adjusted hazard ratios for early menopause and the outcomes were greater in women with T2DM versus those without (CHD 1.15 [95% CI 1.00, 1.33] vs. 1.09 [1.03, 1.15]; stroke 1.21 [1.04, 1.40] vs. 1.10 [1.04, 1.16]; ASCVD 1.29 [1.09, 1.51] vs. 1.10 [1.04, 1.17]; HF 1.18 [1.00, 1.39] vs. 1.09 [1.03, 1.16]). The modifying effect of T2DM on the association between early menopause and ASCVD was only statistically significant in Black compared with White women.CONCLUSIONSEarly menopause was associated with an increased risk for CVD in postmenopausal women. T2DM may further augment the risk, particularly in Black women.     

Mechanisms and Clinical Efficacy of Lixisenatide for the Management of Type 2 Diabetes

Introduction

“Incretin-based” therapies, such as the glucagon-like peptide-1 (GLP-1) receptor agonists, represent a major advance in type 2 diabetes mellitus (T2DM) treatment. GLP-1 receptor agonists differ substantially in their duration of action, frequency of administration and clinical profile.

Methods

This article reviews the mechanisms of action and clinical evidence for GLP-1 receptor targeting and discusses differences between GLP-1 therapies, focusing particularly on clinical data for the GLP-1 receptor agonist, lixisenatide.

Results

GLP-1 therapies target islet cell “defects” of insufficient insulin and excessive glucagon secretion in T2DM, in a glucose-dependent manner, with minimal risk of hypoglycemia. Different GLP-1 therapies exert differential effects on fasting and postprandial glycemia (both being major determinants of glycemic control). They also slow gastric emptying to different extents, probably accounting for different effects to reduce postprandial glycemia. The GetGoal phase 3 studies in T2DM have confirmed the efficacy of once-daily lixisenatide in reducing plasma glucose and glycated hemoglobin (HbA_1c), with a pronounced lowering of postprandial plasma glucose (PPG), as monotherapy and as add-on to oral antidiabetic drugs and to basal insulin. Lixisenatide’s ability to diminish PPG is probably partly mediated by its marked ability to delay gastric emptying. Lixisenatide is generally well tolerated, with possibly better gastrointestinal tolerability and lower risk of hypoglycemia than exenatide immediate release. Lixisenatide is associated with a beneficial effect on weight, with either no change or a decrease in body weight when administered as add-on therapy to basal insulin in overweight patients with T2DM.

Conclusions

Lixisenatide improves glycemic control, by primarily affecting PPG, while preventing weight gain or reducing body weight with a low risk of hypoglycemia in T2DM. Lixisenatide is likely to represent a significant advance in the management of T2DM, perhaps particularly in those patients with relatively faster gastric emptying and lower levels of HbA_1c, including those receiving basal insulin.     

Efficacy and tolerability of linagliptin added to a sulfonylurea regimen in patients with inadequately controlled type 2 diabetes mellitus: an 18-week, multicenter, randomized, double-blind, placebo-controlled trial

BackgroundSome patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy.ObjectiveTo assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU.MethodsIn this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A_1c from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview.ResultsMean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA_1c from baseline (8.6%) to 18 weeks of ?0.47% (?0.70 to ?0.24; P < 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA_1c target level of <7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7–24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA_1c reduction of ≥0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7–9.6; P < 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs ?0.01 kg; P = 0.12).ConclusionsThe addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA_1c compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091.     

Effects of glucagon-like peptide 1 (7–36 amide) on whole-body protein metabolism in healthy man

The incretin glucagon-like peptide 1 (GLP-1) shows glucose-dependent insulinotropic activity and may exert anabolic effects. Whole-body protein metabolism was assessed by measuring [1-¹³C]-leucine kinetics in 13 healthy volunteers during hyperglycaemic clamping with or without pancreatic clamping (somatostatin infusion) in order to differentiate between insulin-mediated and direct GLP-1 effects. During intact pancreatic secretion leucine flux and leucine oxidation rate as parameters of whole-body protein breakdown decreased markedly after 180 min of synthetic GLP-1 infusion (GLP-1 vs. placebo: P < 0.003). Indirect calorimetry showed an increase in energy expenditure and CO₂ production during GLP-1 administration (P < 0.0005). Plasma insulin increased after 3 h of GLP-1 infusion to 1486 ± 145 pmol L^?1 vs. 185 ± 12 pmol L^?1 for saline (P < 0.0001). When plasma insulin levels were kept constant (GLP-1 vs. saline, NS) during pancreatic clamping, GLP-1 effects on both protein metabolism and energy expenditure were abolished. Thus, GLP-1 infusion in man exerts protein anticatabolic and thermic effects, which are mediated by GLP-1-induced stimulation of insulin secretion.     

Comparison of insulin detemir and insulin glargine in a basal—bolus regimen,with insulin aspart as the mealtime insulin,in patients with type 1 diabetes: A 52-week,multinational, randomized,open-label,parallel-group,Treat-to-Target noninferiority trial

Objective: The primary study objective was to determine whether insulin detemir (detemir) was noninferior to insulin glargine (glargine) as the basal insulin in a basal—bolus regimen, with insulin aspart as the mealtime insulin, in terms of glycemic control at the end of 52 weeks in patients with type 1 diabetes mellitus (T1DM).Methods: This multinational, open-label, parallel-group, treat-to-target, noninferiority trial enrolled patients aged ≥18 years who had had T1DM for at least 12 months, had been taking a basal—bolus insulin regimen for at least 3 months, and had a glycosylated hemoglobin (HbA_1c) value ≤11.0% at screening. Patients were randomized in a 2:1 ratio to receive either detemir or glargine for 52 weeks. The basal insulin was initially administered once daily (in the evening) in both groups; if patients in the detemir group were achieving the plasma glucose (PG) target before breakfast but not before dinner, they were switched to twice-daily administration. Glargine was administered once daily throughout the trial, according to its approved labeling. Each patient attended 13 study visits and received 16 scheduled telephone calls from the trial site. The primary efficacy end point was glycemic control (HbA_1c) after 52 weeks of treatment. Secondary end points included the number of patients achieving an HbA_1c value ≤7.0%, with or without a major hypoglycemic episode in the last month of treatment; fasting PG (FPG); within-patient variation in self-monitored plasma glucose (SMPG) before breakfast and dinner; and 10-point SMPG profiles. The noninferiority margin was 0.4%, consistent with US Food and Drug Administration guidelines.Results: Four hundred forty-three patients (mean [SD] age, 42 [12] years; body mass index, 26.5 [4.0] kg/m²; duration of diabetes, 17.2 [11.4] years; HbA_1c, 8.1% [1.1%]) received study treatment. After 52 weeks, the estimated mean HbA1c did not differ significantly between the detemir and glargine groups (7.57% and 7.56%, respectively; mean difference, 0.01%; 95% CI, ?0.13 to 0.16), consistent with the noninferiority of detemir to glargine. The corresponding estimated changes in HbA1c were ?0.53% and ?0.54%. In the 90 patients who completed the trial on once-daily detemir and the 173 patients who completed the trial on twice-daily detemir, the estimated changes in HbA1c were ?0.49% and ?0.58%, respectively. After 52 weeks, there were no significant differences in the proportions of those receiving detemir and glargine who achieved an HbA1c value ≤7.0% without major hypoglycemia (31.9% and 28.9%, respectively). In addition, there were no significant differences in estimated mean FPG (8.58 and 8.81 mmol/L; mean difference, ?0.23 mmol/L; 95% CI, ?1.04 to 0.58) or in basal insulin doses. The basal insulin dose was numerically higher in patients receiving detemir twice rather than once daily (0.47 vs 0.33 U/kg, respectively). The relative risks for total and nocturnal hypoglycemia with detemir versus glargine were 0.94 and 1.12, respectively (both, P = NS). Six patients (2.0%) randomized to the detemir group and 4 (2.7%) randomized to the glargine group withdrew due to adverse events.Conclusions: During 52 weeks of basal—bolus therapy in patients with T1DM, detemir was noninferior to glargine in terms of overall glycemic control (HbA_1c). When used according to the approved labeling, detemir and glargine did not differ in tolerability or in terms of the occurrence of hypoglycemia.