Assessing 10-Year Cardiovascular Disease Risk in Malaysians With Type 2 Diabetes Mellitus: Framingham Cardiovascular Versus United Kingdom Prospective Diabetes Study Equations.

In this study, we evaluated the performance of the Framingham cardiovascular disease (CVD) and the United Kingdom Prospective Diabetes Study (UKPDS) risk equations to predict the 10-year CVD risk among type 2 diabetes mellitus (T2DM) patients in Malaysia. T2DM patients (n = 660) were randomly selected, and their 10-year CVD risk was calculated using both the Framingham CVD and UKPDS risk equations. The performance of both equations was analyzed using discrimination and calibration analyses. The Framingham CVD, UKPDS coronary heart disease (CHD), UKPDS Fatal CHD, and UKPDS Stroke equations have moderate discrimination (area under the receiver operating characteristic [aROC] curve = 0.594-0.709). The UKPDS Fatal Stroke demonstrated a good discrimination (aROC curve = 0.841). The Framingham CVD, UKPDS Stroke, and UKPDS Fatal Stroke equations showed good calibration (P = .129 to .710), while the UKPDS CHD and UKPDS Fatal CHD are poorly calibrated (P = .035; P = .036). The UKPDS is a better prediction equation of the 10-year CVD risk among T2DM patients compared with the Framingham CVD equation.

Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology.

The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30-40% of patients) and associated with a higher risk of HF hospitalization, all-cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first-line choice. Sulphonylureas and insulin have been the traditional second- and third-line therapies although their safety in HF is equivocal. Neither glucagon-like preptide-1 (GLP-1) receptor agonists, nor dipeptidyl peptidase-4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium-glucose co-transporter-2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM.

Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The effect of the α-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced. METHODS: The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in blocks by site, by a centralised computer system to receive oral acarbose (50 mg three times a day) or matched placebo, which was added to standardised cardiovascular secondary prevention therapy. All study staff and patients were masked to treatment group allocation. The primary outcome was a five-point composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure, analysed in the intention-to-treat population (all participants randomly assigned to treatment who provided written informed consent). The secondary outcomes were a three-point composite outcome (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, development of diabetes, and development of impaired renal function. The safety population comprised all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513. FINDINGS: Between March 20, 2009, and Oct 23, 2015, 6522 patients were randomly assigned and included in the intention-to-treat population, 3272 assigned to acarbose and 3250 to placebo. Patients were followed up for a median of 5·0 years (IQR 3·4-6·0) in both groups. The primary five-point composite outcome occurred in 470 (14%; 3·33 per 100 person-years) of 3272 acarbose group participants and in 479 (15%; 3·41 per 100 person-years) of 3250 placebo group participants (hazard ratio 0·98; 95% CI 0·86-1·11, p=0·73). No significant differences were seen between treatment groups for the secondary three-point composite outcome, death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function. Diabetes developed less frequently in the acarbose group (436 [13%] of 3272; 3·17 per 100 person-years) compared with the placebo group (513 [16%] of 3250; 3·84 per 100 person-years; rate ratio 0·82, 95% CI 0·71-0·94, p=0·005). Gastrointestinal disorders were the most common adverse event associated with drug discontinuation or dose changes (215 [7%] of 3263 patients in the acarbose group vs 150 [5%] of 3241 in the placebo group [p=0·0007]; safety population). Numbers of non-cardiovascular deaths (71 [2%] of 3272 vs 56 [2%] of 3250, p=0·19) and cancer deaths (ten [<1%] of 3272 vs 12 [<1%] of 3250, p=0·08) did not differ between groups. INTERPRETATION: In Chinese patients with coronary heart disease and impaired glucose tolerance, acarbose did not reduce the risk of major adverse cardiovascular events, but did reduce the incidence of diabetes. FUNDING: Bayer AG.

Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i): Their Role in Cardiometabolic Risk Management.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel category of oral antidiabetic drugs that inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels. This unique mechanism of SGLT2i action is insulin independent, thus improving glycemic control without promoting hypoglycemia in the absence of exogenously administered insulin. METHODS: The present narrative review addresses the putative associations between SGLT2i and several cardiovascular (CV) and microvascular risk factors, as well as their effects on cardiac and renal function. RESULTS: SGLT2i improve several CV risk factors, including fasting and postprandial plasma glucose levels, lipids, blood pressure, body weight, serum uric acid and arterial stiffness. These drugs may also favorably modulate cardiac and renal function via their effects on inflammation, oxidative stress, diuresis, fluid and sodium retention, myocardial function, vascular resistance and 'fuel' metabolism. In the EMPA-REG OUTCOME study, the first published large CV outcome SGLT2i trial, empagliflozin significantly reduced the primary composite outcome (i.e. CV death, nonfatal myocardial infarction or stroke) and all-cause death as well as hospitalization for heart failure. In addition, empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in patients at high CV risk. CONCLUSION: Multiple metabolic benefits may account for the positive clinical outcomes in the EMPA-REG OUTCOME study. Ongoing CV outcome trials involving other SGLT2i will help establish whether the reported CV and microvascular risk benefits are compound-specific or drug class effects.

Modeling the oral glucose tolerance test in normal and impaired glucose tolerant states: a population approach.

OBJECTIVE: The conventional approach to analyzing data from oral glucose tolerance testing (OGTT) requires model identification in each individual separately (standard two stage, STS), ignoring knowledge about the population as a whole. In practice, however, the OGTT is sparsely sampled and individual estimates are often not resolvable from available data. This weakness is often encountered in large scale trials or epidemiological studies, leading to either multiple imputations or simply much less data available for analysis. METHODS: We have applied a population approach, nonlinear mixed effects modeling, to plasma glucose, insulin and C-peptide data obtained from a 120 minute OGTT undertaken by 106 subjects with varying glucose tolerance. This method provides estimates of population means, variances and covariances of model parameters and empirical Bayes estimates of individual parameter values, as well as measures of intra-individual (within-subject) and inter-individual (between-subject) variability. The recently developed oral glucose minimal model was used to evaluate insulin sensitivity, and a combined model approach was used to assess ß-cell secretion. RESULTS: Applying these models allowed for the reconstruction of insulin secretion and glucose absorption profiles and gave population indexes of insulin sensitivity (SI = 6.51 ± 1.20 × 10-4 min-1·µU-1·ml), fractional hepatic extraction of insulin (F = 0.522 ± 0.291) and fractional insulin clearance (kI = 0.258 ± 0.151 min-1). Whereas the traditional approach to parameter estimation failed to recover estimates in more than one third of the population, the population approach provided individual estimates in all subjects. Examination of the empirical Bayes estimates showed that individual parameter estimates were able to differentiate well between individuals at glucose tolerant states ranging from euglycemia to overt type 2 diabetes. CONCLUSIONS: Our findings suggest that population analysis is a powerful tool for obtaining accurate assessments of indexes of insulin sensitivity and ß-cell function from the OGTT, especially in epidemiological studies with large numbers of sparsely sampled subjects.

Insulin dose adjustments with add-on glucagon-like peptide-1 receptor (GLP-1R) agonists in clinical practice.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining ground as therapeutic modalities in combination with insulin in patients with type 2 diabetes mellitus. Exploiting the multiple benefits of incretin-based therapies in certain patient populations, especially in those who would benefit most from potential weight loss or prevention of body weight gain, has provided a valuable add-on option in diabetes management. However, caution needs to be exercised when initiating such a double injectable therapy, as evidence indicates that, in most instances, the insulin dose needs to be re-adjusted. The majority of published studies suggest reduction of insulin dose, especially related to the 'bolus' component; however, some have also recommended that insulin dose should actually be increased, but we found no credible evidence to support the latter. An important determinant of the titration process is the insulin formulation already in use at baseline. As more potent and long-acting GLP-1RAs are introduced, optimal insulin dose scaling is a major challenge, especially in a primary setting. We provide an overview of the current knowledge in this rapidly changing field. Based on currently reported evidence, a reduction of basal insulin by 10% and a decrease of prandial insulin by 30 - 40% is recommended on addition of GLP-1RAs.

Rationale for and design of the Acarbose Cardiovascular Evaluation (ACE) trial.

Patients with cardiovascular disease and impaired glucose tolerance are at increased risk of cardiovascular events and type 2 diabetes mellitus (T2DM). Lifestyle modification or pharmacological intervention can delay progression to T2DM, but there is no clear evidence that they reduce cardiovascular risk in this population. Acarbose, an α-glucosidase inhibitor that lowers postprandial blood glucose, has been shown to reduce T2DM risk by 25%, and possibly cardiovascular risk in impaired glucose tolerance subjects without cardiovascular disease.

On the potential of acarbose to reduce cardiovascular disease.

In the emerging landscape of cardiovascular (CV) outcome trials evaluating the effects of blood glucose lowering drugs in individuals with type 2 diabetes, it is becoming increasingly apparent that since the promising signals coming from the United Kingdom Prospective Diabetes Study (UKPDS) no unequivocal benefits have been established for any single therapy thus far. There is an unmet need for introducing an effective pharmacological agent which could target both correlates of glycaemic regulation and CV risk factors, to ameliorate the enormous burden of fatal and non-fatal CV events in diabetic patients. Acarbose, like other alpha-glucosidase inhibitors (AGIs), has been proven to be an effective antidiabetic treatment for decades, but the overall significant impact of this class of drugs on modulating CV risk has only recently been appreciated. Accumulating evidence has shown that apart from its multiple effects on primarily postprandial glucose dysmetabolism, a key component of mechanisms linked to increased incidence of CV events, acarbose therapy also associates with a favorable impact on an array of surrogate markers of CV disease. Data stemming from in vitro testing of human cell lines as well as from preliminary trials in diabetic populations, like the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial, have highlighted - though not undisputed - the potential beneficial effects of the drug on CV morbidity. Large scale trials, like the ongoing Acarbose Cardiovascular Evaluation (ACE) trial, aim at conclusively establishing such a positive effect in patients with coronary heart disease and impaired glucose tolerance. In view of its usually acceptable level of side effects that are, if they occur, mostly limited to transient gastrointestinal symptoms, acarbose could well be a strong future player in CV disease secondary prevention. Current discouraging results from many trials of antidiabetic medications to significantly lower CV event rates in diabetic patients, should only draw further attention on alternative glucose lowering agents, among which acarbose is indeed promising.

Patient-reported outcomes among patients using exenatide twice daily or insulin in clinical practice in six European countries: the CHOICE prospective observational study.

BACKGROUND: Improvements in the clinical condition of patients with type 2 diabetes are often accompanied by improvements in health-related quality of life and other patient-reported outcomes (PROs), but data assessing injectable treatment initiation from the patient's perspective in routine clinical practice are lacking. We examined PROs in patients initiating injectable treatment in the CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy) study. METHODS: CHOICE was a 24-month, prospective observational study conducted in six European countries. Patients initiated exenatide twice daily (BID) or insulin based on a physician's clinical judgement. Clinical and PRO data were collected at baseline (injectable therapy initiation) and after approximately 3, 6, 12, 18 and 24 months. The two treatment cohorts had different baseline characteristics; therefore, no statistical comparisons of endpoints between main cohorts were conducted. RESULTS: There were 2388 patients eligible for analysis (exenatide BID cohort, n = 1114; insulin cohort, n = 1274). Mean positive changes in Impact of Weight on Quality of Life-Lite (IWQOL-Lite) total score and EuroQoL5-Dimension (EQ-5D) index and visual analogue scale (VAS) scores were observed in both cohorts with most changes observed during the first 6 months after injectable therapy initiation. Patients who experienced weight loss (≥ 1 kg) at 24 months appeared to have higher mean improvements in IWQOL-Lite total score than did patients with weight gain or no weight change. Patients who met the composite clinical endpoint of glycated haemoglobin (HbA1c) <7.0%, no weight gain (≤ 1 kg) and no hypoglycaemia generally experienced higher mean improvements in EQ-5D index and VAS scores (compared with patients who did not meet this endpoint) and Diabetes Health Profile-18 scores (versus the main cohorts). High levels of missing data were observed for all PRO measures in both cohorts compared with those for clinical outcomes. CONCLUSIONS: These data from a clinical practice study support those from clinical trials, suggesting that PROs are not adversely affected, and may be improved, by injectable therapy initiation. PRO data may aid appropriate treatment selection for individual patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00635492.

Nutritional clinical studies in dermatology.

BACKGROUND & AIMS: Nutrition has long been associated with skin health, beauty, integrity and aging through multiple pathways and cofactors implicated in skin biology. The onset and clinical course of various common skin diseases, especially acne, psoriasis, atopic dermatitis, and hair loss, have been suggested to be critically affected by nutrition patterns and habits. The relationship between acne and diet, predominantly the role of high glycemic load diets and dairy consumption have recently gained increased interest. Abnormal nutritional conditions such as obesity or malnutrition often manifest themselves by specific cutaneous features and altered skin function. Skin photoprotection, rendered by various nutrients, is well documented and appropriate nutritional supplementation has been shown to exert beneficial effects upon impaired skin integrity, restore its appearance and promote skin health. It is our intention to provide a comprehensive review of the most recent information on the role of nutrition for common skin diseases and regulation of skin biology. METHODS: Nutritional clinical studies in dermatology have been reviewed using the MedLine literature source and the terms "diet" or "nutrition" and "skin". RESULTS & CONCLUSIONS: The data on the relationship between nutrition and skin are until now controversial and much more work is needed to be done to clarify possible etiological correlations.

Using Exenatide Twice Daily or Insulin in Clinical Practice: Results from CHOICE.

INTRODUCTION: CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy; NCT00635492) assessed, as its primary objective, the time to a 'significant treatment change' (defined within this paper) after patients with type 2 diabetes mellitus initiated their first injectable, glucose-lowering therapy [exenatide twice daily (BID) or insulin] in clinical practice in six European countries and evaluated outcomes during the study. METHODS: CHOICE was a 24-month, prospective, noninterventional observational study. Patients were invited to participate in CHOICE only after their treating physician had made the clinical decision to initiate first injectable therapy with either exenatide BID or insulin. Clinical data were collected at initiation of first injectable therapy and after approximately 3, 6, 12, 18, and 24 months. RESULTS: A total of 2,515 patients were recruited; 1,114 patients in the exenatide BID cohort and 1,274 patients in the insulin cohort were eligible for the 24-month analysis. During the study, 42.2% and 36.0% of patients from each cohort, respectively, had a significant treatment change. By 24 months, improved mean glycated hemoglobin (p < 0.001 for both cohorts) and reduced severity of several cardiovascular risk factors were observed in both cohorts; additionally, mean weight was reduced in the exenatide BID cohort (p < 0.001) and increased in the insulin cohort (p < 0.001). Hypoglycemia was reported by 18.4% of the exenatide BID cohort and 36.8% of the insulin cohort; 25.9% of the exenatide BID cohort and 10.0% of the insulin cohort had met the secondary endpoint of glycated hemoglobin <7.0%, no weight gain, and no hypoglycemia. CONCLUSION: CHOICE provided data on exenatide BID and insulin usage patterns and 24-month outcomes in clinical practice. On average, improved glycemic control and reduced severity of cardiovascular risk factors were observed in both cohorts, and those in the exenatide BID cohort also had mean weight loss.

Resource use and costs of exenatide bid or insulin in clinical practice: the European CHOICE study.

PURPOSE: CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy) assessed patterns of exenatide bid and initial insulin therapy usage in clinical practice in six European countries and evaluated outcomes during the study. METHODS: CHOICE was a 24-month, prospective, noninterventional observational study. Clinical and resource use data were collected at initiation of first injectable therapy (exenatide bid or insulin) and at regular intervals for 24 months. Costs were evaluated from the national health care system perspective at 2009 prices. RESULTS: A total of 2515 patients were recruited. At the 24-month analysis, significant treatment change had occurred during the study in 42.2% of 1114 eligible patients in the exenatide bid cohort and 36.0% of 1274 eligible patients in the insulin cohort. Improvements in glycemic control were observed over the course of the study in both cohorts (P < 0.001 for both), but mean weight was reduced in the exenatide bid cohort (P < 0.001) and increased in the insulin cohort (P < 0.001) by 24 months. Across all countries, total per patient health care costs for the 24 months post baseline were €3997.9 in the exenatide bid cohort and €3265.5 in the insulin cohort (€1791.9 versus €2465.5 due to costs other than those of injectable therapy). When baseline direct cost and patients' and disease characteristics were controlled for, mean direct costs differed by country (P < 0.0001), irrespective of treatment initiated, and the mean cost difference between treatments varied by country (P < 0.0001). CONCLUSION: Much of the higher mean cost of exenatide bid, compared with insulin, therapy was compensated for by lower mean costs of other health service utilization. Costs associated with exenatide bid or insulin initiation varied across countries, highlighting the need to avoid generalization of resource use and cost implications of a particular therapy when estimated in specific country settings.

Treatment outcomes after initiation of exenatide twice daily or insulin in clinical practice: 12-month results from CHOICE in six European countries.

OBJECTIVE: The CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy (CHOICE) study assessed time to, and reasons for, significant treatment change after patients with type 2 diabetes (T2DM) initiated their first injectable glucose-lowering therapy (exenatide twice daily [BID] or insulin) in routine clinical practice, and these patients' clinical outcomes, in six European countries. This paper reports interim data from the first 12 months of the study. RESEARCH DESIGN AND METHODS: CHOICE (NCT00635492) is a prospective, noninterventional, observational study. Clinical data were collected at initiation of first injectable therapy and after approximately 3, 6, and 12 months. RESULTS: Of 2497 patients enrolled in CHOICE, 1096 in the exenatide BID and 1239 in the insulin cohorts had ≥1 post-baseline assessment and were included in this analysis. Overall, 32.2% of the exenatide BID cohort and 29.1% of the insulin cohort (Kaplan-Meier estimates) had significant treatment change during the first 12 months, most commonly discontinuing injectable therapy or adding new T2DM therapy, respectively. Glycemic control improved in both cohorts, but weight loss occurred only in the exenatide BID cohort (mean change -3.3 kg). Hypoglycemia occurred in 13.2% of the exenatide BID cohort and 28.6% of the insulin cohort (82.8% and 55.6% of these patients, respectively, received sulfonylureas). The post hoc endpoint of glycated hemoglobin < 7%, no weight gain, and no hypoglycemia was attained at 12 months by 24.3% and 10.3% of patients who had data at 12 months and who were receiving exenatide BID and insulin, respectively. CONCLUSION: About 30% of patients in CHOICE changed treatment in the first 12 months after initiation of first injectable therapy (exenatide BID or insulin). Overall, both cohorts achieved improved glycemic control, which was accompanied by a mean weight loss in the exenatide BID cohort.

Patients with Type 2 Diabetes Initiating Exenatide Twice Daily or Insulin in Clinical Practice: CHOICE Study.

INTRODUCTION: Changes to Treatment and Outcomes in Patients with Type 2 Diabetes Initiating Injectable Therapy (CHOICE) is a European prospective, observational cohort study assessing time to, and factors associated with, a significant change in therapy after type 2 diabetes patients initiate their first injectable glucose-lowering therapy, and these patients' clinical outcomes over 24 months. The authors report baseline data and factors associated with the injectable treatment regimen. METHODS: Demographic, clinical, and healthcare resource-use data were collected at initiation of injectable therapy and analyzed using univariate tests between cohorts and multivariate logistic regression analysis for treatment. RESULTS: Overall, 1,177 patients initiated exenatide twice daily (b.i.d.) and 1,315 initiated insulin. Most patients were recruited by secondary-care physicians. Univariate analyses revealed statistically significant differences between the characteristics of patients who initiated exenatide b.i.d. and patients who initiated insulin. On multivariate analysis, higher body mass index [BMI; 5 kg/m(2) higher: odds ratio (OR) 2.10, 95% confidence intervals (CI) 1.84-2.40], lower glycated hemoglobin (HbA(1c); 1% higher: OR 0.77, 95% CI 0.69-0.86), and lower age (5 years older: OR 0.82, 95% CI 0.76-0.88) were the variables most strongly associated with increased probability of receiving exenatide b.i.d. (P < 0.0001). Patients initiating exenatide b.i.d. had a mean BMI of 35.3 ± 6.5 kg/m(2), HbA(1c) of 8.4 ± 1.4%, and age of 58 ± 10 years, compared with 29.7 ± 5.4 kg/m(2), 9.2 ± 1.9%, and 64 ± 11 years, respectively, in patients initiating insulin (P < 0.0001). Other characteristics significantly associated with exenatide b.i.d. initiation were "disinhibited eating" (Diabetes Health Profile-18), lower random blood glucose, less blood glucose self-monitoring, lower low-density lipoprotein cholesterol, and receipt of diet/exercise advice. CONCLUSIONS: Patients who initiated exenatide b.i.d. were on average younger and more obese with lower HbA(1c) than those initiating insulin.

GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes.

OBJECTIVE: The incretin glucagon-like peptide 1 (GLP-1) exerts insulinotropic activity in type 2 diabetic patients, whereas glucose-dependent insulinotropic polypeptide (GIP) no longer does. We studied whether GIP can alter the insulinotropic or glucagonostatic activity of GLP-1 in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Twelve patients with type 2 diabetes (nine men and three women; 61 ± 10 years; BMI 30.0 ± 3.7 kg/m²; HbA(1c) 7.3 ± 1.5%) were studied. In randomized order, intravenous infusions of GLP-1(7-36)-amide (1.2 pmol · kg⁻¹ · min⁻¹), GIP (4 pmol · kg⁻¹ · min⁻¹), GLP-1 plus GIP, and placebo were administered over 360 min after an overnight fast (≥ 1 day wash-out period between experiments). Capillary blood glucose, plasma insulin, C-peptide, glucagon, GIP, GLP-1, and free fatty acids (FFA) were determined. RESULTS: Exogenous GLP-1 alone reduced glycemia from 10.3 to 5.1 ± 0.2 mmol/L. Insulin secretion was stimulated (insulin, C-peptide, P < 0.0001), and glucagon was suppressed (P = 0.009). With GIP alone, glucose was lowered slightly (P = 0.0021); insulin and C-peptide were stimulated to a lesser degree than with GLP-1 (P < 0.001). Adding GIP to GLP-1 did not further enhance the insulinotropic activity of GLP-1 (insulin, P = 0.90; C-peptide, P = 0.85). Rather, the suppression of glucagon elicited by GLP-1 was antagonized by the addition of GIP (P = 0.008). FFA were suppressed by GLP-1 (P < 0.0001) and hardly affected by GIP (P = 0.07). CONCLUSIONS: GIP is unable to further amplify the insulinotropic and glucose-lowering effects of GLP-1 in type 2 diabetes. Rather, the suppression of glucagon by GLP-1 is antagonized by GIP.

Long-term prognosis of acute kidney injury after first acute stroke.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) has been associated with increased mortality in a variety of clinical settings. We studied the incidence, predictors, and effect of AKI on long-term overall mortality and cardiovascular events after stroke. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective outcome study of 2155 patients who sustained an acute first-ever stroke and were followed for 10 yr. Patients were divided in two groups: (1) Those with an acute increase (over 48 h) in serum creatinine >or=0.3 mg/dl or a percentage increase of >or=50% and (2) those with a change <0.3 mg/dl, no change at all, or even a reduction. RESULTS: Twenty-seven percent of patients developed AKI after acute stroke. Stroke severity, baseline estimated GFR, heart failure, and stroke subtype predict the occurrence of AKI. The probability of 10-yr mortality for patients with AKI was 75.9 and 57.7 in the patients without AKI (log rank test 45.0; P = 0.001). When patients with AKI were subdivided into three groups according to AKI severity, the probability of 10-yr mortality increased: 73.7, 86.5, and 89.2 in stages 1, 2, and 3, respectively. In Cox proportional hazard analysis, AKI was an independent predictor of 10-yr mortality (P < 0.01) and for the occurrence of new composite cardiovascular events (P < 0.05) after adjustment for available confounding variables. CONCLUSIONS: AKI after stroke is a powerful and independent predictor of 10-yr mortality and new composite cardiovascular events.

Diurnal correlation of ambulatory blood pressure and interstitial glucose in patients with normal glucose tolerance.

OBJECTIVE: Among the physiological variables whose diurnal profile is governed by circadian rhythmicity, plasma glucose concentrations, and arterial blood pressure constitute key elements of the physiological regulation of energy homeostasis. Evidence on their diurnal association derived from frequent measurements of both variables is, however, lacking in humans. METHODS: We investigated the relationship between blood pressure levels recorded by an ambulatory device and interstitial glucose concentrations on an outpatient basis, in patients with normal glucose tolerance (N=20), either normotensive (group A; N=10), or newly diagnosed with essential hypertension (group B; N=10). RESULTS: In the population throughout the 24-h monitoring period, there was a significant positive correlation between interstitial glucose concentrations and systolic, diastolic, and mean 24-h blood pressure levels, which was retained in patients with hypertension compared with normotensive patients. In patients with newly diagnosed hypertension, interstitial glucose concentrations exhibit significant correlation to systolic blood pressure levels during the 24-h period, but no association with diastolic and mean blood pressure during the night, whereas the reverse is the case in patients with normal glucose tolerance and normal blood pressure. CONCLUSION: Diurnal variations of continuously monitored interstitial glucose concentrations significantly associate with blood pressure levels in both normotensive and hypertensive humans, indicating a common pathway of circadian autoregulation, probably stemming from both central mechanisms and peripheral inputs. Such a pathway might underlie similar pathophysiological aberration in disease states such as the metabolic syndrome.