Risk Of Hypoglycemia In Patients Research Articles

1,5-Anhydro-D-Glucitol Could Reflect Hypoglycemia Risk in Patients with Type 2 Diabetes Receiving Insulin Therapy.

BackgroundThe identification of a marker for hypoglycemia could help patients achieve strict glucose control with a lower risk of hypoglycemia. 1,5-Anhydro-D-glucitol (1,5-AG) reflects postprandial hyperglycemia in patients with well-controlled diabetes, which contributes to glycemic variability. Because glycemic variability is related to hypoglycemia, we aimed to evaluate the value of 1,5-AG as a marker of hypoglycemia.MethodsWe enrolled 18 adults with type 2 diabetes mellitus (T2DM) receiving insulin therapy and assessed the occurrence of hypoglycemia within a 3-month period. We measured 1,5-AG level, performed a survey to score the severity of hypoglycemia, and applied a continuous glucose monitoring system (CGMS).Results1,5-AG was significantly lower in the high hypoglycemia-score group compared to the low-score group. Additionally, the duration of insulin treatment was significantly longer in the high-score group. Subsequent analyses were adjusted by the duration of insulin treatment and mean blood glucose, which was closely associated with both 1,5-AG level and hypoglycemia risk. In adjusted correlation analyses, 1,5-AG was negatively correlated with hypoglycemia score, area under the curve at 80 mg/dL, and low blood glucose index during CGMS (P=0.068, P=0.033, and P=0.060, respectively).Conclusion1,5-AG level was negatively associated with hypoglycemia score determined by recall and with documented hypoglycemia after adjusting for mean glucose and duration of insulin treatment. As a result, this level could be a marker of the risk of hypoglycemia in patients with well-controlled T2DM receiving insulin therapy.

Fasting for Laboratory Tests Poses a High Risk of Hypoglycemia in Patients with Diabetes: A Pilot Prevalence Study in Clinical Practice

Objective: Fasting for lipid profiles is a deeply-rooted tradition that is being revisited. In patients with diabetes, such fasting poses a risk of hypoglycemia, as observed in recent studies and case reports. This iatrogenic, overlooked, form of hypoglycemia has been referred to as Fasting-Evoked En-route Hypoglycemia in Diabetes (FEEHD). The objective of the study is to determine the prevalence of FEEHD in clinical practice. Methods: A two-page survey was administered to adults with diabetes on anti-diabetic medication(s). Patients were asked if they recalled having experienced hypoglycemia while fasting for laboratory tests (FEEHD) during the preceding 12 months. Results: Of 168 patients enrolled, 166 completed the survey, with a mean age of 55.3 (SD: 15.4) years. Seventy-nine (47.6%) were females. Of these 166 patients, 119 (71 %) had type 2 diabetes. Forty-five patients (27.1%) reported having experienced one or more FEEHD events. Notably, only 31.1% of the patients who experienced a FEEHD event informed their provider of the event, and only 40% of FEEHD events reportedly resulted in any subsequent provider-made medication change(s) to prevent future events. Conclusions: This is the first study of FEEHD prevalence in clinical practice, the results of which serve to increase awareness amongst clinicians about the occurrence of FEEHD. We believe that FEEHD appears to be overlooked by clinicians. The prevalence of FEEHD in clinical practice is strikingly high (27.1%). More concerning is the significant underreporting of FEEHD events by patients to their clinicians (31%). We hope this study will trigger further investigation to confirm these preliminary findings and modify practice guidelines.

Bi-directional interaction between hypoglycaemia and cognitive impairment in elderly patients treated with glucose-lowering agents: a systematic review and meta-analysis.

To examine the bi-directional relationship, whereby hypoglycaemia is a risk factor for dementia, and where dementia increases risk of hypoglycaemia in older patients with diabetes mellitus treated with glucose-lowering agents. We searched MEDLINE and EMBASE over a 10-year span from 2005 to 2015 (with automated PubMed updates to August 2015) for observational studies of the association between hypoglycaemia and cognitive impairment or dementia in participants aged >55 years. Assessment of study validity was based on ascertainment of hypoglycaemia, dementia and risk of confounding. We conducted random effects inverse variance meta-analyses, and assessed heterogeneity using the I(2) statistic. We screened 1177 citations, and selected 12 studies, of which nine were suitable for meta-analysis. There were a total of 1,439,818 participants, with a mean age of 75 years. Meta-analysis of five studies showed a significantly increased risk of dementia in patients who had hypoglycaemic episodes: pooled odds ratio 1.68 [95% confidence interval (CI) 1.45, 1.95]. We also found a significantly increased risk of hypoglycaemia in patients with dementia: pooled odds ratio from five studies 1.61 (95% CI 1.25, 2.06). Limitations of the study were heterogeneity in the meta-analysis, and uncertain ascertainment of dementia and hypoglycaemic outcomes and temporal relationships. Publication bias may have favoured the reporting of more significant findings. Our meta-analysis shows a bi-directional relationship between cognitive impairment and hypoglycaemia in older patients. Glucose-lowering therapy should be carefully tailored and monitored in older patients who are susceptible to cognitive decline.

Utility of Saxagliptin in the Treatment of Type 2 Diabetes: Review of Efficacy and Safety.

IntroductionType 2 diabetes mellitus (T2DM) is a complex disease in which multiple organs and hormones contribute to the pathogenesis of disease. The intestinal hormone, glucagon-like peptide-1 (GLP-1), secreted in response to nutrient ingestion, increases insulin secretion from pancreatic β-cells and reduces glucagon secretion from pancreatic α-cells. GLP-1 is inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme. Saxagliptin is a DPP-4 inhibitor that prevents the degradation of endogenous GLP-1 and prolongs its actions on insulin and glucagon secretion. This article reviews the efficacy and safety of saxagliptin in patients with T2DM.MethodsA PubMed literature search was conducted to identify relevant, peer-reviewed saxagliptin clinical trial articles published between January 2008 and June 2015. Search terms included “saxagliptin” and “DPP-4 inhibitors”.ResultsIn clinical trials, saxagliptin significantly improved glycemic control when used as monotherapy or as add-on therapy to other antidiabetes agents and was associated with a low risk of hypoglycemia. In a large cardiovascular (CV) outcomes trial (SAVOR) in patients with T2DM and with established CV disease or multiple CV risk factors, saxagliptin neither increased nor decreased CV risk compared with placebo as assessed by the composite end point of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. Unexpectedly, more patients in the saxagliptin (3.5%) than in the placebo group (2.8%) were hospitalized for heart failure.ConclusionSaxagliptin demonstrated statistically significant and clinically meaningful improvements in glycemic control and a low risk of hypoglycemia in patients with T2DM. However, this positive profile needs to be tempered by the observation of an increased risk of hospitalization for heart failure in the SAVOR trial. Results from ongoing CV outcome trials with other DPP-4 inhibitors may provide additional data on how best to manage patients with T2DM who are at risk for heart failure.FundingAstraZeneca LP.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0262-9) contains supplementary material, which is available to authorized users.

Glycemic control paradox: Poor glycemic control associated with higher one-year and eight-year risks of all-cause hospitalization but lower one-year risk of hypoglycemia in patients with type 2 diabetes

ObjectiveThe relationship between glycemic control and adverse outcomes found in a population with diabetes has seldom been evaluated in patients with type 2 diabetes. We explored the association between hemoglobin A1c (HbA1c) and hospitalization risks within one-year and eight-year follow-up periods. MethodsWe conducted a retrospective cohort study on 57,061 patients with type 2 diabetes from National Diabetes Case Management Program during 2002–2004 in Taiwan. HbA1c at baseline and in-hospital mortality, all-cause and cause-specific hospitalization over one year and eight years were analyzed. ResultsAfter multivariate adjustment, one-year risk was higher for cases with HbA1c level <6%, 9–10%, ≥10% versus 6-7% for all-cause hospitalization (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.03–1.20; 1.08, 1.01–1.16, and 1.19, 1.12–1.26, respectively) and for ≥10% for diabetes-related hospitalization (1.68, 1.46–1.92). Yet each 1-step increment in HbA1c category (<6.0, 6.0–6.9, 7.0–7.9, 8.0–8.9, 9.0–9.9 and ≥10.0%) showed linkage with lower risk of hypoglycemia hospitalization (0.81, 95% CI: 0.74–0.88). For eight-year risk, subjects with HbA1c level <6%, and ≥10% were more likely to have in-hospitality mortality (1.16, 1.03–1.31, and 1.23, 1.11–1.35, respectively). Each 1-step increment in HbA1c category showed an association with higher risks of all-cause and diabetes-related hospitalization (1.04, 1.03–1.05, and 1.15, 1.14–1.17, respectively). ConclusionsHigher HbA1c level correlated with lower one-year risk due to hypoglycemia hospitalization but increased one-year and eight-year risks due to all-cause and diabetes-specific hospitalization among Chinese people with type 2 diabetes in Taiwan. Future study must ascertain how to meet HbA1c targets and improve outcome without risk to this population.

Dynamic risk factors associated with non-severe hypoglycemia in patients treated with insulin glargine or exenatide once weekly.

Glycemic control in patients with type 2 diabetes is a dynamic process, and changes in risk factors affecting the incidence of hypoglycemia are not well understood. This study explored the association of longitudinal interactive effects of clinical risk factors and concomitant medications on hypoglycemia risk in patients treated with insulin glargine (IG) or exenatide once weekly (EQW). Pooled patient-level 52-week longitudinal data of treatment with EQW (n = 541) or IG (n = 223) from three controlled trials were analyzed. Proportions of patients with at least one episode of hypoglycemia in the EQW and IG groups were 23% and 54%, respectively. Compared with patients with HbA1c ≥7% (53 mmol/mol) over time, patients with HbA1c <7% had significantly higher hypoglycemia risk in both groups (95% confidence intervals [CI] of odds ratios [OR]: EQW-1.21, 2.81; IG- 6.26, 9.84). The patterns of interaction effect of changing body mass index (BMI) and HbA1c on hypoglycemia risk differed in the two treatment groups: patients with with BMI >35 kg/m(2) had a 119% increased hypoglycemia risk in the EQW group, but a 57% reduced risk in the IG group. Sulfonylurea-treated patients in the EQW and IG groups had 4.7- and 3-fold additional hypoglycemia risk, respectively, versus non-sulfonylurea-treated patients. This study revealed differential effects of tight glycemic control and itsinteraction with treatment-induced changes in BMI on hypoglycemia risk its interaction in patients treated with EQW and IG. The residual adverse effect of sulfonylurea was higher in EQW-treated patients.

Relationships among different glycemic variability indices obtained by continuous glucose monitoring

The aim of this study was to assess the relationships among indices of glycemic variability obtained by continuous glucose monitoring (CGM). CGM was performed in 88 patients with diabetes (20 type 1 and 68 type 2 diabetes, age 59±15 years) admitted to our hospital (Keio University Hospital, Tokyo, Japan) between 2010 and 2012. Mean glucose, glucose standard deviation (SDglu) and other glycemic indices such as index of glycemic control (ICG), J-index, mean of daily differences (MODD), continuous overlapping net glycemic action 1 (CONGA1), mean amplitude of glycemic excursions (MAGE) and M value were calculated from CGM data, and the correlations among these indices were assessed. There were strong correlations between SDglu and the indices MAGE, CONGA1, MODD and M value (all r>0.8, P<0.05). On the other hand, mean glucose was strongly correlated with J index and M value (both r>0.8, P<0.05). SDglu and other glycemic variability indices were more strongly correlated with hypoglycemia than was mean glucose, and the combination of mean glucose and SDglu was useful for predicting hypoglycemia in patients with diabetes. In this study, we demonstrated the characteristics of various glycemic variability indices in relation to mean glucose and SDglu. This information will help physicians to understand the characteristics of various glycemic variability indices and to select an appropriate index for their purpose. Our results also underpin the importance of glycemic variability in relation to risk of hypoglycemia in patients with diabetes.

The Traditions and Risks of Fasting for Lipid Profiles in Patients with Diabetes

Fasting overnight has been traditionally recommended by clinicians when ordering laboratory tests for lipid profiles for the purposes of health screening or monitoring of the effects of lipid-lowering medications. Patients with diabetes are tested for lipid profiles at least annually. This deeply rooted tradition of fasting for lipid testing has recently been challenged. Several studies have shown little benefit obtained by testing lipids in fasting compared with postprandial states. Furthermore, recent studies have shown the importance of postprandial lipid spikes in the pathogenesis of cardiovascular disease. At the same time, recent reports have alerted the medical community to the risk of hypoglycemia in patients with diabetes on antidiabetic medications (particularly insulin and sulfonylureas) who are asked to fast for lab tests. This article reviews the literature on these emerging issues in lipid testing in patients with diabetes, and offers recommendations for lipid testing in these patients in view of these emerging discussions.

A Patient-centered Approach to Managing Patients with Type 2 Diabetes

Despite the availability of a number of therapeutic options, management of type 2 diabetes (T2DM) and hyperglycemia remains suboptimal. Evidence shows that physicians are not adequately individualizing incretin-based therapies as there is lack of clear understanding of the similarities and differences between various incretin-based therapies. Additionally, sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors, a very recent addition to the therapeutic armamentarium, are not adequately utilized in managing patients with T2DM due to a lack of awareness or an increased concern regarding their safety, efficacy, and the mechanism of action. Insulin therapy is also not initiated or intensified appropriately due to a lack of clear understanding on when to add and how to intensify them and, more importantly, due to fear of increasing the risk of hypoglycemia in patients. To address these gaps, in the first section of this educational activity, the expert faculty will review the current understanding of the risks associated with hypoglycemia—one of the main factors that limit the successful use of insulin therapy—and when to initiate insulin therapy, as well as the available data on the risk of hypoglycemia with emerging agents. The expert faculty will also provide practical strategies on how to minimize the risk of hypoglycemia in patients. In the second section, the expert faculty will highlight the differences between the various incretin-based therapies in addition to providing strategies for physicians to individualize their choice of incretin-based therapy. The expert faculty will also review the mechanism of action, safety, efficacy, and the appropriate place for this class of therapies in the treatment continuum. In the third section, the expert faculty will discuss the mechanism of action, safety, and efficacy of the currently available SGLT2 inhibitors as well as the appropriate use of these newer agents in T2DM management.This CME Multimedia Activity is also available through the Website of The American Journal of Medicine (www.amjmed.com). Click on the CME Multimedia Activity button in the navigation bar for full access. Or access: www.elseviercme.com/537.

3. Is the Fear of Hypoglycemia Associated with Glycemic Imbalance? (2213-PO)

The fear of hypoglycemia in clinical practice is important, but few practical tools exist to evaluate it. The HFS-II (Hypoglycemia Fear Survey-II) is a validated questionnaire measuring fear of the risk of hypoglycemia in patients with diabetes.

Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial

Insulin analogues have been developed to reduce the risk of hypoglycaemia in patients with diabetes who require insulin-based treatment, but their effect on this endpoint in patients with type 1 diabetes complicated by recurrent severe hypoglycaemia is unknown. We compared the occurrence of severe hypoglycaemic episodes in such patients during treatment with insulin analogues or human insulin. In this investigator-initiated, prospective, randomised, open-label, blinded-endpoint crossover trial at seven medical centres in Denmark, we recruited patients (aged ≥18 years) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint was the number of validated episodes of severe hypoglycaemia (defined by need for treatment assistance from others) reported during the maintenance periods, analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00346996. Between May 9, 2007, and Oct 30, 2009, 159 patients were randomly assigned. 18 patients discontinued during the first run-in period, leaving 141 patients in the intention-to-treat population. 136 severe hypoglycaemic episodes were reported during treatment with human insulin and 105 episodes were reported during treatment with insulin analogues, resulting in an absolute rate reduction of 0.51 episodes (95% CI 0.19-0.84) per patient-year with insulin analogues. This result corresponds to a relative rate reduction of 29% (95% CI 11-48; p=0.010). Treatment with insulin detemir and aspart in patients with type 1 diabetes and recurrent severe hypoglycaemia resulted in a clinically significant reduced rate of severe hypoglycaemia compared with human insulin. Patients with the greatest chance of benefitting from improved insulin therapy should be offered treatment with insulin analogues and be included in future trials of new insulins. Novo Nordisk A/S.

Incidence and predictors of hypoglycemia in Japanese patients with type 2 diabetes treated by insulin glargine and oral antidiabetic drugs in real-life: ALOHA post-marketing surveillance study sub-analysis

BackgroundAdd-on Lantus® to Oral Hypoglycemic Agents (ALOHA), an observational, non-interventional, 24-week post-marketing surveillance study in Japanese patients with type 2 diabetes (T2DM) having uncontrolled glycemic control, demonstrated that basal supported oral therapy (BOT) with insulin glargine was an effective and safe treatment in real-life clinical practice. We performed subgroup analysis to identify incidence and predictors associated with risk of hypoglycemia.MethodsAmong 4219 patients with T2DM, 3732 patients were insulin-naïve and 487 patients were insulin non-naïve who switched from other insulin to insulin glargine. All hypoglycemic episodes were counted by physicians’ documentation based on patients’ reports. Relationships between baseline patient characteristics and glargine-related hypoglycemic episodes were examined by univariate and multivariate analysis.ResultsAmong 4219 patients, 44 (1.0%) patients experienced hypoglycemic episodes (41 insulin-naïve patients; 3 insulin non-naïve patients), with a rate of incidence 0.035 episodes/patient-years. Majority of patients with hypoglycemia (37 of 44) had just one hypoglycemic episode during study period. Among insulin-naïve patients, incidence of hypoglycemia differed significantly depending on age, diabetic complications, estimated glomerular filtration rate (eGFR), and postprandial plasma glucose (P <0.05). In a multivariate adjusted model, poor renal function (eGFR <60 mL/min/1.73 m2) was a statistically significant risk factor (P < 0.05).ConclusionOur results suggest that BOT using insulin glargine is an option of insulin therapy with 1% risk of hypoglycemia in patients with T2DM with inadequate glycemic control. Patients with low renal function might need a careful follow-up.

Long-Term Safety and Efficacy of Empagliflozin, Sitagliptin, and Metformin

OBJECTIVETo investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSIn this randomized, open-label, 78-week extension study of two 12-week, blinded, dose-finding studies of empagliflozin (monotherapy and add-on to metformin) with open-label comparators, 272 patients received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg empagliflozin (166 as add-on to metformin), 56 patients received metformin, and 56 patients received sitagliptin as add-on to metformin.RESULTSChanges from baseline in HbA1c at week 90 were −0.34 to −0.63% (−3.7 to −6.9 mmol/mol) with empagliflozin, −0.56% (−6.1 mmol/mol) with metformin, and −0.40% (−4.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week 90 were −2.2 to −4.0 kg with empagliflozin, −1.3 kg with metformin, and −0.4 kg with sitagliptin. Adverse events (AEs) were reported in 63.2–74.1% of patients on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or moderate in intensity. Hypoglycemic events were rare in all treatment groups, and none required assistance. AEs consistent with genital infections were reported in 3.0–5.5% of patients on empagliflozin, 1.8% on metformin, and none on sitagliptin. AEs consistent with urinary tract infections were reported in 3.8–12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on sitagliptin.CONCLUSIONSLong-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes.

Prognostic implications of DPP-4 inhibitor vs. sulfonylurea use on top of metformin in a real world setting - results of the 1 year follow-up of the prospective DiaRegis registry

DPP-4 inhibitors (DPP4-I) have been shown to provide non-inferior glycaemic control compared with sulfonylureas (SU), but result in a reduction of body weight and a significantly lower risk of hypoglycaemia in patients with type 2 diabetes. We aimed to validate these results in a large real-world sample of patients participating in the prospective DiaRegis registry and to assess prognostic implications. DiaRegis included 3810 patients with type 2 diabetes in which antidiabetic therapy was intensified. We defined two patient subgroups, the first receiving either a DPP4-I or SU on top of prior metformin monotherapy and the second containing patients out of subgroup 1 with unaltered treatment for 1 year. After enrolment 884 patients with prior metformin monotherapy received a dual combination of metformin with either DPP4-I (n = 628; 71%) or SU (n = 256; 29%). Patient characteristics, blood glucose and blood pressure control as well as comorbidity burden were virtually identical. There were neither significant differences in the change of HbA1c over the 12 months treatment period nor in the reduction of body weight, but fasting (p = 0.033) and postprandial glucose levels (p = 0.01) were significantly lower in those receiving DPP4-I. Hypoglycaemia was significantly less frequent in patients receiving DPP4-I (OR 0.32; 95% CI 0.19-0.54). Qualitative changes were robust for subgroup 2 (except of fasting plasma glucose). Patients receiving DPP4-I had significantly less stroke/transitory ischaemic attack (0.2 vs. 2.0; p < 0.05) during the 1 year follow-up, whereas other vascular events (coronary artery bypass graft, percutaneous coronary intervention) were borderline significant. The present results confirm prior randomised controlled trial results in patients with type 2 diabetes from real world clinical practice demonstrating that DPP4-I on top of prior metformin monotherapy result in similar HbA1c reductions within 12 months but a significant reduction in hypoglycaemia compared with sulfonylurea added to metformin. The reduction in vascular events observed has to be verified in larger cohorts.

β2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats

We have previously reported that local activation of β2-adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation. This study examines whether peripheral delivery of a selective B2AR agonist could also promote counter-regulatory responses and thereby has potential therapeutic value to limit hypoglycaemia risk. Conscious male Sprague-Dawley rats received an intra-arterial injection of the B2AR specific agonist, formoterol, or a control solution either before a hyperinsulinaemic-hypoglycaemic clamp study or immediately before recovery from insulin-induced hypoglycaemia. In addition, the capacity of a VMH-targeted microinjection of a B2AR antagonist to limit the anti-insulin effect of the B2AR agonist was assessed. Systemic delivery of B2AR agonist markedly reduced the exogenous glucose infusion rate (GIR) required during the hypoglycaemic clamp study. This effect was mediated by blockade of insulin's inhibitory effect on endogenous glucose production. Local blockade of B2ARs within the VMH using a specific antagonist partially diminished the effect of systemic activation of B2ARs during hypoglycaemia at least in part by diminishing the adrenaline (epinephrine) response to hypoglycaemia. Peripheral B2AR agonist injection also enhanced glucose recovery from insulin-induced hypoglycaemia. Systemic B2AR agonist administration acts to limit insulin-induced hypoglycaemia by offsetting insulin's inhibitory effect on hepatic glucose production. This effect appears to be predominately mediated via a direct effect on liver B2ARs, but a small stimulatory effect on B2ARs within the VMH cannot be excluded. Our data suggest that formoterol may have therapeutic value to limit the risk of hypoglycaemia in patients with diabetes.

Optimizing glycemic control and minimizing the risk of hypoglycemia in patients with type 2 diabetes

Diabetic microvascular and macrovascular complications arise from hyperglycemia, presenting an increasing healthcare burden as the diabetic population continues to grow. Clinical trial evidence indicates that antihyperglycemic medications are beneficial with regard to microvascular disease (retinopathy, renal impairment, and perhaps neuropathy); however, the benefit of aggressive use of these medications with regard to cardiovascular risk has been less clear in recent studies. These studies were confounded by the propensity of the antihyperglycemic medications involved to cause hypoglycemia, which itself presents cardiovascular risk. This article presents additional context for these seemingly discordant results and maintains that the achievement of glycemic targets is warranted in most patients and provides cardiovascular benefit, provided that hypoglycemia is avoided and the treatment regimen is tailored to the needs of the individual patient. A treatment approach that is driven by these principles and emphasizes diet and exercise, a combination of noninsulin antidiabetic agents, not including sulfonylureas and glinides, and judicious use of insulin is also presented.

Efficacy, Safety, and Tolerability of Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus: An Integrated Analysis of the DURATION Trials

Background and Aim: Exenatide is a glucagon-like peptide-1 receptor agonist demonstrated to improve glycemic control with low hypoglycemia risk in patients with type 2 diabetes mellitus. The Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly (DURATION) program comprised 6 randomized, comparator-controlled, 24- to 30-week trials of exenatide once weekly (EQW), an extended-release formulation. This post hoc analysis pooled data from patients taking EQW across 6 trials to assess efficacy and safety in a large, varied patient population. Materials and Methods: The intent-to-treat (ITT) population contained 1379 patients (baseline mean ± standard deviation glycated hemoglobin [HbA1c] levels of 8.4% ± 1.1%) who were treated with EQW over the course of 24 to 30 weeks. Changes from baseline in efficacy parameters for the ITT population and a completer population (1195 patients with ≥ 22 weeks of exposure) were evaluated. Results: The ITT population experienced significant reductions from baseline (least-squares mean [95% CI]) in HbA1c levels (−1.4% [−1.5% to −1.4%]), fasting blood glucose levels (−36 mg/dL [−38.4 mg/dL to −33.8 mg/dL]), and body weight (−2.5 kg [−2.8 kg to −2.3 kg]) after 24 to 30 weeks of EQW treatment. Reductions in HbA1c and fasting blood glucose levels were observed across baseline HbA1c, level strata; patients with higher baseline HbA1c levels experienced greater reductions. Treatment with EQW was associated with modest, significant reductions in blood pressure (systolic blood pressure, −2.8 mm Hg [−3.5 mm Hg to −2.1 mm Hg]; diastolic blood pressure, −0.8 mm Hg [−1.2 mm Hg to −0.4 mm Hg]), and fasting lipid levels (total cholesterol, −6.5 mg/dL [−8.2 mg/dL to −4.7 mg/dL]; low-density lipoprotein cholesterol, −3.9 mg/dL [5.3 mg/dL to −2.5 mg/dL]; and triglyceride [geometric least-squares mean percent change (95% CI)], −6% [−8% to −4%] levels). Similar reductions were observed in the completer population. Exenatide once weekly was generally well tolerated. Transient, mild-to-moderate gastrointestinal treatment-emergent adverse events and injection-site treatment-emergent adverse events were reported most frequently, but were seldom treatment limiting. No major hypoglycemic events were observed; minor hypoglycemic events occurred infrequently in patients not using a sulfonylurea. Conclusion: This post hoc analysis of > 1300 patients demonstrated that EQW was associated with significant reductions in HbA1c levels, body weight, blood pressure, and fasting lipid levels, with minimal hypoglycemia risk. Consistent with established safety profiles, EQW therapy was generally well tolerated., Trial registration: www.ClinicalTrials.gov identifiers: NCT00308139, NCT00637273, NCT00641056, NCT00676338, NCT00877890, NCT01029886

Predictive value of HbA1c and glucose fluctuations in hypoglycemia risk in patients with type 1 diabetes

Predictive value of HbA1c and glucose fluctuations in hypoglycemia risk in patients with type 1 diabetes

Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial

BackgroundManagement of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.MethodsThis was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.ResultsA total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg).ConclusionsDapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone.Trial registrationClinicalTrials.gov: NCT00528879

Overnight automated type 1 diabetes control under MD-logic closed-loop system: a randomized crossover trial

Tight glucose control is needed to prevent long-term diabetes complications; this is hindered by the risk of hypoglycemia, especially at night. To assess the safety and efficacy of the closed-loop MD-Logic Artificial Pancreas (MDLAP), controlling nocturnal glucose levels in patients with type 1 diabetes mellitus (T1DM). This was a randomized, multicenter, multinational, crossover trial conducted in Slovenia, Germany, and Israel. Twelve patients with T1DM (age 23.8 ± 15.6 yr; duration of diabetes 13.5 ± 11.9 yr; A1c 8.1 ± 0.8%, mean ± SD) were randomly assigned to participate in two sequential overnight sessions: one using continuous subcutaneous insulin infusion (CSII) and the other, closed-loop insulin delivery by MDLAP. The primary outcome was the number of hypoglycemic events below 63 mg/dL. Endpoints analyses were based on sensor glucose readings. Three events of nocturnal hypoglycemia occurred during CSII and none during the closed-loop control (p = 0.18). The percentage of time spent in the near normal range of 63-140 mg/dL was significantly higher in the overnight closed-loop sessions [76% (54-85)] than during CSII therapy [29% (11-44)] [p = 0.02, median (interquartile range)]. The mean overnight glucose level was reduced by 36 mg/dL with closed-loop insulin delivery (p = 0.02) with a significantly less glucose variability when compared with the CSII nights (p < 0.001). The results of this study demonstrate the ability of the MDLAP to safely improve overnight glucose control without increased risk of hypoglycemia in patients with T1DM at three different national, geographic, and clinical centers (ClinicalTrials.gov number, NCT 01238406).