Risk Of Serious Hypoglycemia Research Articles

Application of the U.S. Food and Drug Administration's Sentinel Routine Querying Tools to the Taiwan Sentinel Data Model-formatted National Health Insurance Research Database.

The U.S. Food and Drug Administration's Sentinel System is a leading distributed data network for drug safety surveillance in the world. The National Health Insurance Research Database (NHIRD) in Taiwan was converted into the Taiwan Sentinel Data Model (TSDM) based on the Sentinel Common Data Model (SCDM) version 6.0.2. The goal of this study was to investigate the feasibility of applying the same study designs, analytic choices, and analytic tools as used by the U.S. Sentinel System to examine the same drug-outcome associations in the TSDM-formatted NHIRD. Four known drug-outcome associations previously examined by the U.S. Sentinel System were selected as the use cases: (1) use of angiotensin-converting enzyme inhibitors (ACEIs) and risk of angioedema, (2) use of warfarin and risk of gastrointestinal bleeding, (3) use of oral clindamycin and risk of Clostridioides difficile infection (CDI), and (4) use of glyburide and risk of serious hypoglycemia. We followed the same study designs and analytic choices used by the U.S. Sentinel System and applied the Sentinel Routine Querying Tools to answer the same study questions within the TSDM-formatted NHIRD. The results showed that ACEIs were associated with a non-significant increase in risk of angioedema compared to beta-blockers (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.89-1.64); warfarin was associated with a higher risk of gastrointestinal bleeding compared to statins (HR: 1.72; 1.50-1.98); glyburide was associated with an increased risk of hypoglycemia compared to glipizide (HR: 1.61, 1.30-2.00). We were unable to evaluate the association between oral clindamycin and risk of CDI due to the low event number. Our study demonstrated that it was feasible to directly apply the publicly available Sentinel Routine Querying Tools within the TSDM-formatted NHIRD. However, sources of heterogeneity other than design and analytic differences should be carefully considered when comparing the results between the two systems.

Ambient Heat and Risk of Serious Hypoglycemia in Older Adults With Diabetes Using Insulin in the U.S. and Taiwan: A Cross-National Case-Crossover Study.

To measure the association between ambient heat and hypoglycemia-related emergency department visit or hospitalization in insulin users. We identified cases of serious hypoglycemia among adults using insulin aged ≥65 in the U.S. (via Medicare Part A/B/D-eligible beneficiaries) and Taiwan (via National Health Insurance Database) from June to September, 2016-2019. We then estimated odds of hypoglycemia by heat index (HI) percentile categories using conditional logistic regression with a time-stratified case-crossover design. Among ∼2 million insulin users in the U.S. (32,461 hypoglycemia case subjects), odds ratios of hypoglycemia for HI >99th, 95-98th, 85-94th, and 75-84th percentiles compared with the 25-74th percentile were 1.38 (95% CI, 1.28-1.48), 1.14 (1.08-1.20), 1.12 (1.08-1.17), and 1.09 (1.04-1.13) respectively. Overall patterns of associations were similar for insulin users in the Taiwan sample (∼283,000 insulin users, 10,162 hypoglycemia case subjects). In two national samples of older insulin users, higher ambient temperature was associated with increased hypoglycemia risk.

Increased Risk of Serious Hypoglycemia with Insulin Glargine in Veterans with Type 2 Diabetes: An Emulated Clinical Trial Observational Study

Increased Risk of Serious Hypoglycemia with Insulin Glargine in Veterans with Type 2 Diabetes: An Emulated Clinical Trial Observational Study

Risk of serious hypoglycemia in patients with atrial fibrillation and diabetes concurrently taking antidiabetic drugs and oral anticoagulants: A nationwide cohort study.

Evidence regarding the risks of serious hypoglycemia for patients with atrial fibrillation (AF) and diabetes mellitus (DM) taking antidiabetic medications with concurrent non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin is limited. This study aimed to investigate this knowledge gap. This retrospective cohort study used nationwide data from Taiwan's National Health Insurance Research Database and included a total of 56,774 adult patients treated with antidiabetic medications and oral anticoagulants between January 1, 2012 and December 31, 2020. The incidence rate ratios (IRRs) of serious hypoglycemia were estimated for patients taking antidiabetic drugs with NOACs versus warfarin. Poisson regression models with generalized estimating equations accounting for intra-individual correlation across follow-up periods were used. Stabilized inverse probability of treatment weighting was used to create treatment groups with balanced characteristics for comparisons. Compared to concurrent use of antidiabetic drugs with warfarin, those with NOACs showed a significantly lower risk of serious hypoglycemia (IRR = 0.73, 95% CI: 0.63-0.85, p<0.001). In the analyses of each NOAC, patients taking dabigatran (IRR = 0.76, 95% CI: 0.63-0.91, p = 0.002), rivaroxaban (IRR = 0.72, 95% CI: 0.61-0.86, p<0.001), and apixaban (IRR = 0.71, 95% CI: 0.57-0.89, p = 0.003) showed a significantly lower risk of serious hypoglycemia than those taking warfarin. In patients with AF and DM taking antidiabetic drugs, concurrent use of NOACs was associated with a lower risk of serious hypoglycemia than concurrent use of warfarin.

Hypoglycemia and cardiac arrhythmias in diabetes mellitus

The article provides an assessment of cardiovascular risks associated with episodes of hypoglycemia in patients with diabetes mellitus. The analysis has been performed for the experimental and clinical data on cardiac arrhythmias during induced hypoglycemia in animal models and in patients with diabetes. The pathogenetic mechanisms of the development of life‑threatening heart rhythm disorders during hypoglycemic states (in particular, changes in autonomic nervous system activation and in the serum level of potassium) have been considered. The nature of electrocardiographic changes preceding the development of arrhythmias during hypoglycemia is described and factors affecting QT interval duration during hypoglycemia are given. The authors highlight the results of clinical studies of spontaneous hypoglycemia in terms of the arrhythmias’ specific features in daytime and nocturnal hypoglycemia, and different mechanisms of the cardiac arrhythmias’ development at different periods of the day. Clinical data have been presented as regards the drug‑induced hypoglycemia during administration beta‑adrenergic receptor blockers, angiotensin‑converting enzyme inhibitors, fluoroquinolones, as well as mechanisms of dysglycemic effects of these drugs. It has been noted that β‑blockers can mask symptoms of catecholamine‑mediated hypoglycemia. It has been established that among hypoglycemic agents, insulin secretion stimulators (sulfonylureas, meglinides) and insulin have the highest risk of serious hypoglycemia. However, the use of basal and prandial insulin analogues was associated with a lower frequency of hypoglycemia compared to human insulin. It was emphasized that hypoglycemia should be avoided in clinical practice to improve prognosis and prevent arrhythmias. For this, it is necessary to individualize target glycemic values with their mitigation in high‑risk patients, to use the safest insulin and non‑insulin hypoglycemic agents, and to implement new technologies (pumps, continuous glucose monitoring) more widely. It is extremely important to take into account comorbidity and the effects on hypoglycemia risk of drugs used for the treatment of concomitant diseases.

Comparative risk of serious hypoglycemia among persons dispensed a fluoroquinolone versus a non-fluoroquinolone antibiotic

AimFluoroquinolone antibiotics have been implicated in cases of metabolic adverse events. This study investigated the causal association between fluoroquinolones and serious hypoglycemia in those with and without diabetes. MethodsWe conducted a propensity score-matched cohort study using Optum claims data. We included adults dispensed an oral fluoroquinolone or comparator antibiotic between January 2000 and September 2015 for specific infections of interest. The outcome was serious hypoglycemia, defined using a validated algorithm. Conditional logistic regression was used to estimate odds ratios (ORs) in diabetes and non-diabetes cohorts after matching on propensity scores fitted using confounding variables of interest. ResultsOur cohort contained 119,112 individuals with diabetes and 917,867 individuals without diabetes exposed to a fluoroquinolone, matched 1:1 with a comparator. Matching produced balance (standardized mean difference < 0.1) on all variables included in the propensity score. The OR for the association between fluoroquinolones and serious hypoglycemia was 1.28 (95% confidence interval [CI]: 1.04–1.57) in the entire cohort, 1.30 (95% CI: 1.05–1.62) in individuals with diabetes, and 1.06 (95% CI: 0.53–2.13) in individuals without diabetes. ConclusionFluoroquinolone users are at an increased risk of serious hypoglycemia relative to comparator antibiotic users. This association was evident only among persons diagnosed with diabetes.

Angiotensin-Converting Enzyme Inhibitors Used Concomitantly with Insulin Secretagogues and the Risk of Serious Hypoglycemia.

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.

925-P: Risk of Cardiovascular Events and Serious Hypoglycemia Comparing Patients with Type 2 Diabetes Initiating a GLP-1 Receptor Agonist or Basal Insulin: A Propensity-Score Matched Cohort Study

Prior head-to-head open label trials comparing selected GLP-1RA(s) versus basal insulin(s) did not evaluate cardiovascular outcomes. Using 2 large U.S. commercial claims databases (Optum and Truven MarketScan) from 01/2012 to 12/2017, we assessed the risk of a composite cardiovascular outcome (MI, stroke) and serious hypoglycemia defined by validated claims-based algorithms comparing 26,308 patients with type 2 diabetes (mean age 58, mean HbA1c 8.6%) with prior or concurrent metformin therapy newly initiating an injectable GLP-1RA or basal insulin (Table). We estimated pooled incidence rates, meta-analyzed hazard ratios and 95% CI adjusting for &amp;gt;140 baseline clinical characteristics, including HbA1c. Baseline clinical characteristics were well-balanced in the two groups after 1:1 propensity score matching. In an as-treated analysis, the median follow-up was 148 days. Compared to basal insulin, initiating a GLP-1RA was associated with a lower risk of MI or stroke (HR 0.68 [95% confident interval (CI), 0.51 to 0.90]) and lower risk of serious hypoglycemia (HR 0.38 [95% CI, 0.25 to 0.57]). These results support recent clinical treatment guidelines that recommend starting a GLP-1RA before basal insulin for patients with type 2 diabetes with inadequate glycemic control despite metformin. Disclosure J. Luo: Consultant; Self; Alosa Health. A. Pawar: None. D.J. Wexler: Other Relationship; Self; Novo Nordisk A/S. D.H. Kim: None. S.C. Kim: Research Support; Self; AbbVie Inc., Bristol-Myers Squibb. E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH. Funding Brigham and Women’s Hospital

Risk of severe hypoglycemic events from amiodarone-sulfonylureas interactions: A population-based nested case-control study.

To evaluate whether concomitant use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia. We conducted two nested case-control studies by analyzing the Taiwan National Health Insurance Research Database from 2008 to 2013 among diabetic patients continuously receiving sulfonylureas. Cases were defined as patients with severe hypoglycemia and those with a composite outcome of severe hypoglycemia, altered consciousness, and fall-related fracture in the first and second study, respectively. In both studies, each case was individually matched up to 10 randomly-selected controls. Conditional logistic regressions were employed to estimate odds ratios (ORs). We identified 1343 cases and 11 597 controls as well as 2848 cases of composite events and 24 808 controls among 46 317 sulfonylurea users. Concurrent use of amiodarone with sulfonylureas was associated with a 1.56-fold (95% CI: 0.98-2.46) increased risk of severe hypoglycemia, despite not statistically significant. Notably, an approximately 2-fold increased risk of severe hypoglycemia was observed with amiodarone therapy lasting for >180 days (adjusted OR: 2.08; 95% CI: 1.01-4.30) or at a daily dose greater than 1 defined daily dose (adjusted OR: 2.21; 95% CI: 1.25-3.91) when concurrently administrating sulfonylureas. A significantly increased risk of hypoglycemia-related composite events was also found with amiodarone concurrently used with sulfonylureas (adjusted OR: 1.59; 95% CI: 1.13-2.24). Concurrent use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia among diabetic patients, with an elevated risk for amiodarone used in a long-term or at a high daily dose.

Body Weight Considerations in the Management of Type 2 Diabetes.

Obesity is one of the main risk factors for type 2 diabetes (T2D), representing a major worldwide health crisis. Modest weight-loss (≥ 5% but < 10%) can minimize and reduce diabetes-associated complications, and significant weight-loss can potentially resolve disease. Treatment guidelines recommend that intensive lifestyle interventions, pharmacologic therapy, and/or metabolic surgery be considered as options for patients with T2D and obesity. The benefits and risks of such interventions should be evaluated in the context of their weight-loss potential, ability to sustain weight change, side effect profile, and costs. Antihyperglycemia therapies have considerable effects on patient weight, prompting careful consideration of weight-loss or weight-neutral therapies for patients with T2D who also have obesity. Metformin, sodium glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), α-glucosidase inhibitors, and amylin mimetics promote weight-loss. Dipeptidyl peptidase-4 inhibitors and fixed-ratio insulin/GLP-1 RA combination therapies (IDegLira, iGlarLixi) appear to be weight-neutral. Thiazolidinediones, insulin secretagogues (sulfonylureas, meglitinides), and insulins are associated with weight gain. Sulfonylureas are additionally associated with a higher risk of serious hypoglycemia from hyperinsulinemia, making them less suitable for the treatment of patients who are overweight or have obesity. Patients are often overtitrated on basal insulin, resulting in an increased risk of hypoglycemia and weight gain without achieving glycemic goals. Given these observations, the effects of antihyperglycemia agents on weight should be considered when individualizing T2D therapy.Funding: Sanofi US, Inc.

Serious Hypoglycemia and Use of Warfarin in Combination With Sulfonylureas or Metformin.

Prior research suggests that warfarin, when given concomitantly with some sulfonylureas, may increase the risk of serious hypoglycemia. However, the clinical significance remains unclear. We examined rate ratios (RRs) for the association between serious hypoglycemia and concomitant use of warfarin with either sulfonylureas or metformin using a self-controlled case series design and US Medicaid claims (supplemented with Medicare claims) from 1999 to 2011. Across all risk windows combined, warfarin was associated with an elevated rate of serious hypoglycemia when given concomitantly with glimepiride (RR, 1.47; 95% confidence interval (CI), 1.07-2.02) and metformin (RR, 1.73; 95% CI, 1.38-2.16). Particularly in the late risk window (>120days since beginning concomitancy), most of the RRs for warfarin were elevated: glipizide (RR, 1.72; 95% CI, 1.29-2.29), glyburide (RR, 1.57; 95% CI, 1.15-2.15), metformin (RR, 2.26; 95% CI, 1.67-3.05), and glimepiride (RR, 1.56; 95% CI, 0.97-2.50). These results are consistent with a previously hypothesized hypoglycemic effect of warfarin in patients with type 2 diabetes through inhibition of the carboxylation of osteocalcin.

Biomedical Informatics Approaches to Identifying Drug-Drug Interactions: Application to Insulin Secretagogues.

Drug-drug interactions with insulin secretagogues are associated with increased risk of serious hypoglycemia in patients with type 2 diabetes. We aimed to systematically screen for drugs that interact with the five most commonly used secretagogues-glipizide, glyburide, glimepiride, repaglinide, and nateglinide-to cause serious hypoglycemia. We screened 400 drugs frequently coprescribed with the secretagogues as candidate interacting precipitants. We first predicted the drug-drug interaction potential based on the pharmacokinetics of each secretagogue-precipitant pair. We then performed pharmacoepidemiologic screening for each secretagogue of interest, and for metformin as a negative control, using an administrative claims database and the self-controlled case series design. The overall rate ratios (RRs) and those for four predefined risk periods were estimated using Poisson regression. The RRs were adjusted for multiple estimation using semi-Bayes method, and then adjusted for metformin results to distinguish native effects of the precipitant from a drug-drug interaction. We predicted 34 pharmacokinetic drug-drug interactions with the secretagogues, nine moderate and 25 weak. There were 140 and 61 secretagogue-precipitant pairs associated with increased rates of serious hypoglycemia before and after the metformin adjustment, respectively. The results from pharmacokinetic prediction correlated poorly with those from pharmacoepidemiologic screening. The self-controlled case series design has the potential to be widely applicable to screening for drug-drug interactions that lead to adverse outcomes identifiable in healthcare databases. Coupling pharmacokinetic prediction with pharmacoepidemiologic screening did not notably improve the ability to identify drug-drug interactions in this case.

Intensive Glucose Control in Diabetics with an Acute Myocardial Infarction Does not Improve Mortality and Increases Risk of Hypoglycemia-A Meta-Regression Analysis

Some early trials comparing intensive glucose control in type 2 diabetics with an acute myocardial infarction (MI) reported a decrease in mortality over a short period of follow up leading to a presumption of improved survival with intensive glucose control. Later data refuted this hypothesis. The 2009 ACC/AHA focused update on ST elevation MI gave a weak recommendation for the use of an insulin based regimen to achieve and maintain blood glucose less than 180 mg/dL. We decided to assess the validity of this recommendation.The authors searched the Pub- Med, Cochrane CENTRAL and EMBASE databases for randomized controlled trials from 1965 through 2011.Trials included were direct head-to-head comparisons of an intensive blood glucose control strategy using pharmacological means (insulin in most cases) with a less intensive regimen. The primary outcome assessed was the risk of all -cause mortality in the two groups at the end of follow up. Also assessed was the rate of hypoglycemia. The methodological quality of the studies was assessed. Event rates were compared using a forest plot of relative risk (RR; 95% confidence interval [CI]) using a random effects model (Mantel-Haenszel) assuming inter-study heterogeneity. Statistical analysis was done with Review Manager V5.1 and SYSTAT. Meta-regression was done with duration of therapy as covariate.Three studies (total N = 2113) met the inclusion exclusion criteria. Mortality was not different between the groups (RR 0.94, 95% CI of 0.66-1.34; p=0.73.). Rate of hypoglycemia was significantly higher in the intensive glucose control group (RR 13.40, 95% CI 3.69-48.61; p < 0.01), with a 12% absolute risk increase and a number needed to harm (NNH) of 9 (95% CI 6.8- 9.8)-even without achieving target glycemic control. Neither did intensive control improve CHF, arrhythmias and reinfarction rates. Meta regression revealed that mortality with intensive glycemic control was worse with increased duration of therapy (p=0.001, for trend).This systematic review suggests limited benefit of intensive glycemic control in type 2 diabetics with an MI, with a significant risk of serious hypoglycemia.

Intensive Glucose Control in Diabetics with an Acute Myocardial Infarction Does not Improve Mortality and Increases Risk of Hypoglycemia-A Meta-Regression Analysis

Some early trials comparing intensive glucose control in type 2 diabetics with an acute myocardial infarction (MI) reported a decrease in mortality over a short period of follow up leading to a presumption of improved survival with intensive glucose control. Later data refuted this hypothesis. The 2009 ACC/AHA focused update on ST elevation MI gave a weak recommendation for the use of an insulin based regimen to achieve and maintain blood glucose less than 180 mg/dL. We decided to assess the validity of this recommendation. The authors searched the Pub- Med, Cochrane CENTRAL and EMBASE databases for randomized controlled trials from 1965 through 2011.Trials included were direct head-to-head comparisons of an intensive blood glucose control strategy using pharmacological means (insulin in most cases) with a less intensive regimen. The primary outcome assessed was the risk of all -cause mortality in the two groups at the end of follow up. Also assessed was the rate of hypoglycemia. The methodological quality of the studies was assessed. Event rates were compared using a forest plot of relative risk (RR; 95% confidence interval [CI]) using a random effects model (Mantel-Haenszel) assuming inter-study heterogeneity. Statistical analysis was done with Review Manager V5.1 and SYSTAT. Meta-regression was done with duration of therapy as covariate. Three studies (total N = 2113) met the inclusion exclusion criteria. Mortality was not different between the groups (RR 0.94, 95% CI of 0.66-1.34; p=0.73.). Rate of hypoglycemia was significantly higher in the intensive glucose control group (RR 13.40, 95% CI 3.69-48.61; p < 0.01), with a 12% absolute risk increase and a number needed to harm (NNH) of 9 (95% CI 6.8- 9.8)-even without achieving target glycemic control. Neither did intensive control improve CHF, arrhythmias and reinfarction rates. Meta regression revealed that mortality with intensive glycemic control was worse with increased duration of therapy (p=0.001, for trend). This systematic review suggests limited benefit of intensive glycemic control in type 2 diabetics with an MI, with a significant risk of serious hypoglycemia.

Intensive Glucose Control in Diabetics with an Acute Myocardial Infarction Does not Improve Mortality and Increases Risk of Hypoglycemia-A Meta-Regression Analysis

Objectives: Some early trials comparing intensive glucose control in type 2 diabetics with an acute myocardial infarction (MI) reported a decrease in mortality over a short period of follow up leading to a presumption of improved survival with intensive glucose control. Later data refuted this hypothesis. The 2009 ACC/AHA focused update on ST elevation MI gave a weak recommendation for the use of an insulin based regimen to achieve and maintain blood glucose less than 180 mg/dL. We decided to assess the validity of this recommendation. Methods: The authors searched the Pub- Med, Cochrane CENTRAL and EMBASE databases for randomized controlled trials from 1965 through 2011.Trials included were direct head-to-head comparisons of an intensive blood glucose control strategy using pharmacological means (insulin in most cases) with a less intensive regimen. The primary outcome assessed was the risk of all -cause mortality in the two groups at the end of follow up. Also assessed was the rate of hypoglycemia. The methodological quality of the studies was assessed. Event rates were compared using a forest plot of relative risk (RR; 95% confidence interval [CI]) using a random effects model (Mantel-Haenszel) assuming inter-study heterogeneity. Statistical analysis was done with Review Manager V5.1 and SYSTAT. Meta-regression was done with duration of therapy as covariate. Results: Three studies (total N = 2113) met the inclusion ⁄ exclusion criteria. Mortality was not different between the groups (RR 0.94, 95% CI of 0.66-1.34; p=0.73.). Rate of hypoglycemia was significantly higher in the intensive glucose control group (RR 13.40, 95% CI 3.69-48.61; p<0.01), with a 12% absolute risk increase and a number needed to harm (NNH) of 9 (95% CI 6.8- 9.8)-even without achieving target glycemic control. Neither did intensive control improve CHF, arrhythmias and reinfarction rates. Meta regression revealed that mortality with intensive glycemic control was worse with increased duration of therapy (p=0.001, for trend). Conclusions: This systematic review suggests limited benefit of intensive glycemic control in type 2 diabetics with an MI, with a significant risk of serious hypoglycemia. Keywords: Myocardial infarction, intensive glycemic control, meta-analysis, regression, hypoglycemia, mortality

Counterpoint: Clinical Islet Transplantation: Not Ready for Prime Time

β-Cell replacement therapy's great promise is that it can safely and effectively restore insulin-independent euglycemia to individuals with diabetes. Although difficult and expensive, modern insulin-based treatment for type 1 diabetes has lead to remarkable improvements in disease prognosis (1–3). Based on recent population-based epidemiological studies, we have estimated that an individual diagnosed with type 1 diabetes today faces an excess mortality over the next 20 years of ∼2% or ∼0.1% per year (4). Even individuals with long-standing type 1 diabetes sufficiently problematic to be listed for a pancreas transplant have an annual mortality <2.0% per year (5). The perceived weaknesses associated with intensive insulin therapy are its cost estimated in 1996 to be 116,000 USD over a lifetime (6) and its inconvenience requiring meticulous attention to diet, exercise, frequent daily blood glucose measurements, and multiple daily injections. In addition, insulin therapy carries with it an increased risk of serious hypoglycemia (1). We attempt to address whether current β-cell replacement therapies overcome the shortcomings associated with medical management. Certainly, β-cell replacement therapy should not increase the subjects' risk above that associated with standard clinical care. For patients with type 1 diabetes and end-stage kidney disease, simultaneous pancreas-kidney (SPK) transplantation has appropriately achieved standard of care status. SPK recipients can reasonably expect improved and sustained insulin-independent metabolic control, and the surgery demonstrably improves survival rates compared with those medically treated (5). However, the options are much less clear for subjects with long-standing diabetes and preserved kidney function defined as a serum creatinine <2.0 mg/dl. (And with modern therapies, an ever-decreasing minority will develop renal failure.) For such patients, pancreas transplant alone (PTA) or pancreas-after-kidney (PAK) transplantation, despite reasonable insulin-independence rates, does not improve survival and may even increase mortality (5). The underlying cause of the apparent excess mortality post–pancreas transplantation …

Altered glycemia and brain—update and potential relevance to the aging brain

Hyperglycemia characterizes diabetes mellitus and is linked to its chronic and acute complications. Cognitive dysfunction in diabetes occurs especially in longstanding disease and with poor glycemic control. Recent data in humans suggests that hyperglycemia causes acute cognitive dysfunction. The underlying mechanisms are unknown but deserve further research as diabetes is becoming epidemic and will likely contribute increasingly to premature cognitive decline. The primary side effect of diabetes treatment is hypoglycemia, particularly resulting from insulin treatment. CNS adaptations to acute and chronic hypoglycemia underlie the inability of some people to promptly recognize and defend against the risk of serious hypoglycemia. Data from human and animal models may help explain how altered glycemia affects brain function both acutely and chronically. Improved mechanistic understanding of altered glycemia's effects could prevent the adverse impact of diabetes upon the CNS and give new insights into effects that may exist in normal aging.

State of the art: islet transplantation for the cure of type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) results from the immune destruction of insulin producing beta cells, located in the pancreatic islets of Langerhans [1]. Apart from the daily need for multiple insulin injections and blood glucose testing, individuals with T1DM are at greater risk for end organ complications, cardiovascular disease, and premature mortality. Although aggressive treatment aimed at keeping the blood sugar, blood pressure, and blood lipids within their normal ranges has been shown to markedly reduce diabetes complications [2], including a major impact on mortality [3], too few achieve these treatment goals, and aggressively treated patients have an increased risk of serious hypoglycemia [4]. The main reasons then to consider transplantation therapies (isolated islet or whole pancreas) are thus to overcome the lifelong need for daily insulin injections and frequent blood glucose testing, to promote maintenance of near normal blood glucose levels, and to avoid or even reverse the long-term diabetesassociated complications. In this review, we will critically look at current transplantation (pancreas or islet) therapies as they relate to these laudable goals. Transplanting beta cells by means of a whole pancreas transplant, for those with successful transplants, appears to improve quality of life while potentially ameliorating or preventing the complications associated with chronic hyperglycemia [5–12]. More specifically, the freedom from daily insulin injections and blood glucose monitoring is reported to improve the successfully transplanted recipient’s sense of well being, independence, and promote a perception of normality [5,7,10,13,14]. Over all however, when considering risks and toxicities associated with immunosuppressive medications, peri-operative complications, and uncertain graft survival, whether or not transplantation reduces end organ complications, or mortality, is not established [15]. Nearly all individuals given a pancreas transplant have battled with the disease for many years, and thus many already have suffered end organ complications and/or have cardiovascular disease. Thus, unlike patients enrolled in the Diabetes Control and Complication Trial (DCCT), it is harder to measure the effects transplantation may have on already established secondary complications. Studies of diabetic nephropathy provide perhaps the best evidence for a beneficial effect of transplantation. Several large studies have shown less progression or even an improvement in nephropathy in naive kidneys and renal grafts [16–18], and yet conflicting data exists as well. For instance, three different groups have studied whether individuals with T1DM and endstage kidney disease and treated with a kidney transplant alone, or with a simultaneous pancreas and kidney transplant fare differently [19–21]. One found that both patient and kidney allograft survival were improved by the pancreas allograft [20], one found a moderate effect that did not achieve statistical significance until several years after the transplant [21], and one found no independent effect of the pancreas allograft [19]. Evidence supporting a salutary effect of pancreas transplantation for neuropathy or retinopathy is even less compelling [22,23], perhaps secondary to the chronicity of those secondary complications, and/or those tissues’ limited capacity for repair. Further, even though pancreas transplantation results in one-year insulin independence rates approximating 80% and one-year patient survival rates approximating 95% [24], the procedure remains controversial for several other reasons. One, simultaneous pancreas kidney transplantation is associated with higher morbidity compared to kidney transplantation alone [24,25]. That is, pancreas transplantation is usually performed using an intra-abdominal approach frequently resulting in a prolonged ileus and thus a delayed return of bowel function, complicating

Incidence and Risk Factors for Serious Hypoglycemia in Older Persons Using Insulin or Sulfonylureas

Our knowledge about the risk of hypoglycemia associated with diabetes treatment is derived from studies that often exclude frail, elderly persons. To determine the incidence and risk factors for developing serious hypoglycemia among older persons using sulfonylureas or insulin. We conducted a population-based, retrospective cohort study of 19932 Tennessee Medicaid enrollees, aged 65 years or older, who used insulin or sulfonylureas from 1985 through 1989. The main end point was serious hypoglycemia defined as a hospitalization, emergency department admission, or death associated with hypoglycemic symptoms and a concomitant blood glucose determination of less than 2.8 mmol/L (< 50 mg/dL). We identified 586 persons with a first episode of serious hypoglycemia during 33,048 person-years of insulin or sulfonylurea use. The crude rates (per 100 person-years) of serious hypoglycemia were 1.23 (95% confidence interval [CI], 1.08-1.38) in users of sulfonylureas and 2.76 (95% CI, 2.47-3.06) among insulin users. Recent hospital discharge was the strongest predictor of subsequent hypoglycemia in older persons with diabetes. The adjusted relative risk of serious hypoglycemia occurring in days 1 through 30 after hospital discharge was 4.5 (95% CI, 3.5-5.7) compared with the risk associated with a hypoglycemic event occurring 366 or more days after hospital discharge. Other independent risk factors included advanced age (relative risk, 1.8; 95% CI, 1.4-2.3), black race (relative risk, 2.0; 95% CI, 1.7-2.4), and use of 5 or more concomitant medications (relative risk, 1.3; 95% CI, 1.1-1.5). In this population, the incidence of serious hypoglycemia is approximately 2 per 100 person-years, suggesting that many older adults can be safely treated with hypoglycemic drugs. Frail, elderly persons--the oldest-old, those using multiple medications, and those who are frequently hospitalized--are at a higher risk for drug-associated hypoglycemia. Such individuals may benefit from intensive education about the symptoms of hypoglycemia and close monitoring for adverse events related to diabetes treatment.

Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas

Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas