Effect of ranolazine on glycaemic control in patients with type 2 diabetes treated with either glimepiride or metformin.

AIM: To report the results of two phase III trials assessing the efficacy of ranolazine for glycaemic control in patients with type 2 diabetes on metformin or glimepiride background therapy. METHODS: In two double-blind trials we randomized 431 and 442 patients with type 2 diabetes to ranolazine 1000 mg twice daily versus placebo added to either glimepiride (glimepiride add-on study) or metformin background therapy (metformin add-on study). Patients receiving ranolazine added to metformin had their metformin dose halved (with the addition of a metformin-matched placebo) relative to the placebo group to correct for a metformin-ranolazine pharmacokinetic interaction. The primary endpoint of the trials was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS: When added to glimepiride, ranolazine caused a 0.51% least squares mean [95% confidence interval (CI) 0.71, 0.32] decrease from baseline in HbA1c at 24 weeks relative to placebo and roughly doubled the proportion of patients achieving an HbA1c of <7% (27.1 vs 14.1%; p = 0.001). When added to metformin background therapy, there was no significant difference in the 24-week HbA1c change from baseline [placebo-corrected LS mean difference -0.11% (95% CI -0.31, 0.1)]. CONCLUSIONS: Compared with placebo, addition of ranolazine in patients with type 2 diabetes treated with glimepiride, but not metformin, significantly reduced HbA1c over 24 weeks. The decreased dose of metformin used in the metformin add-on study complicates the interpretation of this trial. Whether an effective regimen of ranolazine added to metformin for glycaemic control can be identified remains unclear.

Subcutaneous injection of hyaluronidase with recombinant human insulin compared with insulin lispro in type 1 diabetes.

AIMS: Prandial treatment with human regular insulin for diabetes may result in early postprandial hyperglycaemia and late hypoglycaemia due to its slow onset and long duration of action. This study compared injections of recombinant human insulin (rHI) formulated with recombinant human hyaluronidase [rHuPH20] (INSULIN-PH20) to insulin lispro for prandial treatment in subjects with type 1 diabetes (T1D). METHODS: After a 1-month run-in period using twice-daily insulin glargine (or usual basal insulin therapy for pump users) with prandial lispro, 46 subjects with T1D (42 ± 13 years; body mass index: 26 ± 4 kg/m(2); A1c: 6.8 ± 0.5%) were assigned to INSULIN-PH20 or lispro in a random sequence for two consecutive, 12-week periods as the prandial insulin in an intensive treatment regimen. RESULTS: The mean glycaemic excursion for INSULIN-PH20 (0.96 ± 2.00 mmol/l) was comparable (p = 0.322) to lispro (0.80 ± 1.95 mmol/l). The 8-point self-monitored blood glucose profiles were also comparable in the two groups. Good glycaemic control (A1c) was maintained for both treatments at 12 weeks (INSULIN-PH20: 7.0 ± 0.5%; lispro: 6.9 ± 0.6%). Overall rates of hypoglycaemia (≤ 3.9 mmol/l) were 24 events per patient per 4 weeks for INSULIN-PH20 and 22 events for lispro. There were no significant differences in adverse events or immunogenicity between treatments and both treatments were well tolerated. CONCLUSIONS: Unlike commercially available formulations of regular human insulin, a formulation of rHI with rHuPH20 was comparable to lispro for postprandial glucose excursions in a basal-bolus treatment regimen for T1D patients. Glycaemic control, safety and tolerability profiles were comparable for both treatments.

Options for prandial glucose management in type 2 diabetes patients using basal insulin: addition of a short-acting GLP-1 analogue versus progression to basal-bolus therapy.

Integrating patient-centered diabetes care and algorithmic medicine poses particular challenges when optimized basal insulin fails to maintain glycaemic control in patients with type 2 diabetes. Multiple entwined physiological, psychosocial and systems barriers to insulin adherence are not easily studied and are not adequately considered in most treatment algorithms. Moreover, the limited number of alternatives to add-on prandial insulin therapy has hindered shared decision-making, a central feature of patient-centered care. This article considers how the addition of a glucagon-like peptide 1 (GLP-1) analogue to basal insulin may provide new opportunities at this stage of treatment, especially for patients concerned about weight gain and risk of hypoglycaemia. A flexible framework for patient-clinician discussions is presented to encourage development of decision-support tools applicable to both specialty and primary care practice.

Primary and secondary prevention of Type 1 diabetes.

Since type 1 diabetes is an immunologically mediated disease, immune intervention should alter the natural history of the disease. This article reviews prevention studies undertaken either prior to any evidence of autoimmunity (primary prevention) or after the development of islet autoantibodies (secondary prevention). Most immune intervention studies have been conducted in recent-onset type 1 diabetes (tertiary prevention), and these are not reviewed herein. The goal of primary and secondary intervention is to arrest the immune process and thus prevent or delay clinical disease. Primary prevention studies have been conducted in infants with high genetic risk. Interventions tested include several dietary manipulations, including infant formulas free of either cow's milk or of bovine insulin, infant formula supplemented with the omega-3-fatty acid docosahexaenoic acid, delayed introduction of gluten-containing foods, and vitamin D supplementation. Secondary prevention studies have been conducted in both children and adults with diabetes autoantibodies. Interventions tested include nicotinamide, insulin injections, oral insulin, nasal insulin, glutamic acid decarboxylase, and cyclosporine. Underway are secondary prevention studies with teplizumab and with abatacept.

Innate and adaptive immune gene expression profiles as biomarkers in human type 1 diabetes.

The mRNA levels of a set of immune-related genes were analysed with peripheral blood samples from at-risk, new-onset and long-term type 1 diabetes (T1D) patients, in comparison to those from healthy controls. The selected set includes T lymphocyte genes [CD3G and cytotoxic T lymphocyte-associated antigen 4 (CTLA4)], B lymphocyte genes (CD19 and CD20) and myeloid cell-related genes [CD11b, Toll-like receptor (TLR)-9, arginase (ARG1)]. Also included is a subset of the S100 family members that has been documented recently as regulatory elements of innate immunity. Samples from patients with long-term T1D had a reduced level of mRNA for most of selected innate and adaptive immune genes. No such reduction was detected in samples collected from at-risk or new-onset T1D patients. Analyses of regulatory gene expression ratios revealed a dynamic disproportion of CTLA4 versus CD3G expression in samples from at-risk, new-onset and long-term T1D patients. These changes could serve as immunological biomarkers for the status of the immune system during T1D progression and therapeutic interventions.

Immune intervention for type 1 diabetes mellitus.

The major form of type 1 diabetes (T1D) is characterised by immune-mediated pancreatic islet ß-cell destruction, and has also been called type 1A diabetes to distinguish it from idiopathic forms of islet ß-cell loss. Since the first demonstration of islet cell antibodies in 1974, the concept has been that this form of diabetes is autoimmune in nature. The commonly accepted concept is that antibodies (representing the humoral arm of the immune system) do not mediate the ß-cell destruction but rather serve as markers of that destruction, while the cellular arm of the immune system, specifically T-lymphocytes, mediate the ß-cell destruction. Yet, the T-lymphocytes do not act alone. They receive help in initiating the response from antigen-presenting cells such as dendritic cells and macrophages, and appear to receive help also from B-lymphocytes. In addition, the initial immune response engenders secondary and tertiary responses - involving the whole immunological army - which collectively result in impairment of ß-cell function, progressive destruction of ß-cells, and consequent development of type 1A diabetes. The process is insidious and may evolve over many years, with the overt expression of clinical symptoms becoming apparent only when most ß-cells have been destroyed. Yet, the process clearly evolves at different speeds - much more rapidly in young children, much more slowly in older individuals. And, although it has been thought that ultimately there is complete ß-cell destruction, several studies have now demonstrated some degree of persistent ß-cell function or existence (at autopsy) in long-standing T1D. A major focus of investigation in T1D is the preservation of ß-cell function (and, it is hoped, of ß-cells themselves), in the expectation that continuing endogenous insulin secretion will contribute towards better glycaemic control, reduce episodes of severe hypoglycaemia, and slow the development of complications such as retinopathy and nephropathy. Thus, there have been many studies designed to interdict the T1D disease process, mostly by altering the immune system, both during the stage of evolution of the disease and at the time of disease onset. This chapter of the Yearbook of Advanced Technology and Treatments in Diabetes reviews the key papers that have appeared in this field between July 2009 and June 2010. Articles selected were confined to studies in human beings. All immune intervention studies reported in this time frame were included. In addition, the author selected other relevant articles dealing with mechanisms, markers, triggers, and pathology of human type 1 diabetes.

Practical steps to improving the management of type 1 diabetes: recommendations from the Global Partnership for Effective Diabetes Management.

The Diabetes Control and Complications Trial (DCCT) led to considerable improvements in the management of type 1 diabetes, with the wider adoption of intensive insulin therapy to reduce the risk of complications. However, a large gap between evidence and practice remains, as recently shown by the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, in which 30-year rates of microvascular complications in the 'real world' EDC patients were twice that of DCCT patients who received intensive insulin therapy. This gap may be attributed to the many challenges that patients and practitioners face in the day-to-day management of the disease. These barriers include reaching glycaemic goals, overcoming the reality and fear of hypoglycaemia, and appropriate insulin therapy and dose adjustment. As practitioners, the question remains: how do we help patients with type 1 diabetes manage glycaemia while overcoming barriers? In this article, the Global Partnership for Effective Diabetes Management provides practical recommendations to help improve the care of patients with type 1 diabetes.

Immunomodulation for type 1 diabetes mellitus.

Type 1 diabetes (T1D) is characterised by immune-mediated pancreatic islet beta-cell destruction. The initial immune response engenders secondary and tertiary responses which collectively result in impairment of beta-cell function, progressive destruction of beta-cells and consequent development of T1D. The process is insidious and may evolve over many years, with the overt expression of clinical symptoms becoming apparent only when most beta-cells have been destroyed. Over the last quarter century much investigation has been directed at interdicting the T1D disease process, both during the stage of evolution of the disease and at the time of disease onset. This chapter of the Yearbook of Advanced Technology and Treatments in Diabetes reviews the key articles that have appeared in this field between January 2008 and June 2009.

Prediction and prevention of type 1 diabetes: progress, problems, and prospects.

Type 1 diabetes mellitus (T1D) arises from selective immunologically mediated destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans with consequent insulin deficiency. This occurs in genetically susceptible individuals and is a cellular-mediated process, presumably a specific reaction to one or more beta-cell proteins (autoantigens), although probably initiated by some environmental factor(s). There is consequent progressive impairment of beta-cell function and decline in beta-cell mass. A secondary humoral immune response is characterized by the appearance of autoantibodies that serve as markers of the immune damage to beta-cells. This insidious T1D disease process evolves over a period of years. The decline in beta-cell function and mass is evidenced metabolically by loss of first-phase insulin response to an intravenous glucose challenge, and later by the appearance of impairment in glycemic regulation, manifested as dysglycemia--usually as impaired glucose tolerance, but occasionally as impaired fasting glucose. Ultimately, the clinical syndrome of T1D becomes evident when the majority of beta-cells have been destroyed and frank hyperglycemia supervenes. Given this sequence of events, for which it is possible to envision intervention to interdict the process, it is not surprising that much research effort has been expended to identify individuals at risk of the disease.

Microvascular complications. Retinopathy and nephropathy.

Diabetic retinopathy and diabetic nephropathy extract an enormous toll on patients with diabetes and an enormous burden on the health care system. With aggressive control of glycemia and blood pressure, coupled with aggressive use of laser photocoagulation and treatment of microalbuminuria, these problems can largely be eliminated. In the future, specific interventions may emerge that will allow interdiction of the pathophysiologic processes that lead to initiation and progression of these microvascular complications. The challenge for the primary care physician and diabetologist is to attain excellent glycemic control and aggressive control of blood pressure, while assuring that every patient has appropriate dilated fundus examinations at least annually, preferably by an ophthalmologist or retinal specialist, and regular screening for microalbuminuria. With such medical management, appropriate intervention can occur to reduce the risk of blindness and renal failure and to lessen the burden from diabetic retinopathy and nephropathy.

Modeling preclinical cardiovascular risk for use in epidemiologic studies: Miami community health study.

To develop a method for assessing preclinical cardiovascular disease risk, models of resting cardiovascular regulation and of insulin metabolic syndrome were derived from information collected from 1991 to 1996 in a culturally heterogeneous sample of 319 healthy men and women (aged 25-44 years) from Miami-Dade County, Florida. The model of resting cardiovascular regulation used 8 noninvasive measures of autonomic and cardiovascular function. Three factors were derived: 1) parasympathetic, 2) inotropy, and 3) systemic vascular resistance. The model of insulin metabolic syndrome used 12 measures assessing body mass, insulin, glucose, and lipid metabolism. Four factors were derived: 1) body mass and fat distribution, 2) glucose level and regulation, 3) insulin level and regulation, and 4) plasma lipid levels. Analyses of the association of the two models revealed that subjects with lower cardiac contractility had greater body mass, higher fasting and postload insulin and glucose levels, and lower insulin sensitivity. Subjects with greater vascular resistance had greater body mass, higher total cholesterol and triglyceride levels, and lower high density lipoprotein cholesterol levels. These findings indicate that preclinical cardiovascular disease risk may involve pathophysiologic processes in which cardiac inotropic and vasodilatory functions are linked to specific aspects of insulin metabolic syndrome.

Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study.

BACKGROUND: Effective glycaemic control in type 1 diabetes mellitus usually requires two or more insulin injections daily. Inhaled intrapulmonary delivery of insulin offers a potential new way to deliver meal-related insulin, eliminating the need for preprandial injections. METHODS: 73 patients with type 1 diabetes mellitus were studied in an open-label, proof-of-concept, parallel-group randomised trial. Patients in the experimental group received preprandial inhaled insulin plus a bedtime subcutaneous ultralente insulin injection. Patients in the control group received their usual insulin regimen of two to three injections per day. Participants monitored their blood glucose four times daily, and adjusted insulin doses weekly to achieve preprandial glucose targets of 5.6-8.9 mmol/L. The primary outcome measure was change in glycosylated haemoglobin (HbA1c) after 12 weeks. Secondary outcomes were fasting and postprandial glucose response to a mixed meal; hypoglycaemia frequency and severity; pulmonary function; and patients' satisfaction. FINDINGS: Changes in HbA1c were indistinguishable between groups (difference 0.2% [95% CI -0.2 to 0.5]). Changes in fasting and postprandial glucose concentrations, and occurrence and severity of hypoglycaemia were also similar between groups. Inhaled insulin was well tolerated and had no effect on pulmonary function (ie, spirometry, lung volumes, diffusion capacity, and oxygen saturation). INTERPRETATION: This proof-of-concept study shows that preprandial insulin can be given by inhalation in individuals with insulin-deficient type 1 diabetes as a less invasive alternative to conventional preprandial insulin injections.

Inhaled human insulin treatment in patients with type 2 diabetes mellitus.

BACKGROUND: Despite demonstrated benefits, intensive insulin therapy has not gained widespread clinical acceptance for several reasons: Multiple daily injections are inconvenient, adherence is a concern, and the time-activity profile may not mimic normal insulin secretion. As such, alternate means of administering insulin are being evaluated. OBJECTIVE: To assess the efficacy and safety of pulmonary delivery of insulin in type 2 diabetic patients who require insulin. DESIGN: Randomized, open-label, 3-month study consisting of a screening visit, a 4-week baseline lead-in phase, and a 12-week treatment phase. SETTING: General clinical research center and outpatient research clinics. PATIENTS: 26 patients (16 men, 10 women) with type 2 diabetes (average age, 51.1 years; average duration of diabetes, 11.2 years). INTERVENTION: Patients received inhaled insulin before each meal plus a bedtime injection of ultralente insulin, performed home glucose monitoring, and had weekly adjustment of insulin dose; target level for preprandial plasma glucose was 5.55 to 8.88 mmol/L (100 to 160 mg/dL). MEASUREMENTS: Glycemic control (hemoglobin A(1c) level) obtained at baseline and monthly for 3 months. Pulmonary function tests were done at baseline and at the end of the study. RESULTS: Inhaled insulin treatment for 3 months significantly improved glycemic control compared with baseline: Mean hemoglobin A(1c) levels decreased by 0.0071 +/- 0.0072 (0.71% +/- 0.72%). Patients experienced an average of 0.83 mild to moderate hypoglycemic event per month; no severe events were recorded. Patients showed no significant weight gain or change in pulmonary function compared with baseline. CONCLUSIONS: Pulmonary delivery of insulin in type 2 diabetic patients who require insulin improved glycemic control, was well tolerated, and demonstrated no adverse pulmonary effects. Larger-scale studies are ongoing to provide long-term efficacy and safety data.

Validation of the insulin sensitivity index (ISI(0,120)): comparison with other measures.

The purpose of this study was to explore possible calculations using oral glucose tolerance test (OGTT) values in order to develop a simple measure of insulin sensitivity. We devised a formula for an insulin sensitivity index, ISI(0,120), that uses the fasting (0 min) and 120 min post-oral glucose (OGTT) insulin and glucose concentrations. It appears to be generalizable across a spectrum of glucose tolerance and obesity. Most importantly, our data show that ISI(0,120) correlates well, when applied prospectively in comparative studies, with the insulin sensitivity index obtained from the euglycemic hyperinsulinemic clamp (r = 0.63, P < 0.001). This correlation was demonstrably superior to other indices of insulin sensitivity such as the HOMA formula presented by Matthews, and performed comparably to the computerized HOMA index. Measurement of insulin sensitivity has traditionally been possible only in research settings because of the invasiveness and expense of the methods used. Clinical investigators have therefore sought more practical methods to obtain an index of insulin sensitivity. Such an index should approximate insulin sensitivity as measured by the euglycemic hyperinsulinemic clamp (M). We present ISI(0,120), a simple yet sensitive measure of insulin sensitivity which is adaptable for use in clinical settings as well as large epidemiologic studies.

Is fasting leptin associated with insulin resistance among nondiabetic individuals? The Miami Community Health Study.

OBJECTIVE: Whether serum leptin levels are associated with insulin resistance independent of the effects of hyperinsulinemia and adiposity is an important unanswered question. We examined the relationship between the rate of insulin-mediated glucose uptake and serum leptin concentrations among nondiabetic men and women. RESEARCH DESIGN AND METHODS: A cross-sectional analysis was performed among 49 young to middle-aged men and women who participated in the Miami Community Health Study. All participants had measures of insulin resistance (euglycemic-hyperinsulinemic clamp), postchallenge insulin levels, fasting serum leptin levels, and several measures of adiposity. RESULTS: The rate of insulin-mediated glucose uptake (M in milligrams per kilogram per minute) was significantly associated with leptin concentrations in both men (r = -0.83; P < 0.001) and women (r = -0.59; P < 0.001). M was also inversely related to percent body fat and to the 2-h insulin area under the curve (AUC). After covariate adjustment for sex, percent body fat, and AUC, leptin remained a significant correlate of M (P = 0.04). CONCLUSIONS: Cross-sectionally, leptin was significantly associated with insulin resistance in this nondiabetic sample of men and women. There may be a different physiological mechanism to explain the leptin/insulin resistance association apart from the insulin/adiposity link. Confirmatory evidence awaits the results of clinical trials.

History of gestational diabetes, insulin resistance and coronary risk.

The purpose of this study was to examine characteristics associated with the insulin metabolic syndrome, including insulin resistance, abnormal glucose tolerance, dyslipidemia, obesity, and elevated blood pressure, among women who have experienced gestational diabetes. 39 nondiabetic, young (20-42 years), postpartum (3-18 months) white women were recruited from obstetrical clinics. Twenty-one women had a history of gestational diabetes; 18 had uncomplicated pregnancies. Multivariate analyses revealed a significant difference between groups in insulin resistance (M, measured by euglycemic clamp) and insulin levels (from an oral glucose tolerance test), with insulin resistance showing a statistically stronger difference than insulin levels. Groups also differed significantly when compared on a set of variables associated with insulin metabolic syndrome: glucose tolerance, triglycerides, blood pressure, and body-mass index. Using insulin resistance as a covariate eliminated these group differences, suggesting that insulin resistance is the key factor underlying insulin metabolic syndrome. The higher risk of later developing type 2 diabetes and hypertension in women who have a history of gestational diabetes is explicable by their poorer profile on variables associated with insulin metabolic syndrome, and appears to be attributable to insulin resistance. Thus, insulin resistance appears to distinguish young women at risk for cardiovascular disease.