Search

Aim: To evaluate the long-term efficacy, safety and tolerability of dapagliflozin versus placebo added to usual care in patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD)., Methods: Data were pooled from two phase III studies (NCT01031680 and NCT01042977) in high-risk patients (N = 1887) with T2DM and CVD treated with dapagliflozin (10 mg/day) or placebo. Patients completing the double-blind treatment studies (24 weeks) entered one or two sequential double-blind, long-term (LT) extensions of 28 (LT1; n = 1649) and 52 (LT2; n = 568) weeks., Results: Baseline and CVD characteristics were similar in the two groups. Patients entering LT1 and LT2 on dapagliflozin maintained a greater mean reduction in glycated haemoglobin (HbA1c) versus placebo at 52 weeks [LT1, -0.58% (95% confidence interval -0.68, -0.49)] and 104 weeks [LT2, -0.35% (95% confidence interval -0.59, -0.12)]. Mean body weight and systolic blood pressure (SBP) reductions versus placebo were maintained in patients entering LT1 (52 weeks; -2.23 kg and -3.25 mmHg, respectively) and LT2 (104 weeks; -3.16 kg and -2.03 mmHg, respectively). Patients on dapagliflozin had a better three-item composite endpoint of clinical benefit (glycaemia, weight and SBP) compared with placebo at week 24 (LT1, 10.1% vs. 1.1%) and week 104 (LT2, 6.7% vs. 1.4%). Genital and urinary tract infections were more frequent with dapagliflozin than with placebo. Events of hypoglycaemia, renal impairment/failure and volume depletion were similar between groups., Conclusions: The long-term efficacy of dapagliflozin to maintain reductions in HbA1c, SBP and body weight over 2 years, together with its tolerability profile, make dapagliflozin an appropriate option in high-risk patients with T2DM and CVD., (© 2016 John Wiley & Sons Ltd.)

Aims: Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise., Methods: In this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 584) received canagliflozin 100 or 300 mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c < 7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study., Results: At week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300 mg compared with placebo (-0.77, -1.03 and 0.14%, respectively; p < 0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p < 0.001 for all), and increased HDL-C compared with placebo (p < 0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups., Conclusion: Canagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise., (© 2012 Blackwell Publishing Ltd.)

Objective: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes., Methods: After a 2 week placebo run-in period, eligible patients inadequately controlled on long-acting, intermediate-acting or premixed insulin (HbA1c > or = 7.5% and < or = 11%), were randomised 1:1 to the addition of once-daily sitagliptin 100 mg or matching placebo over a 24-week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24., Results: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m(2)), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long-acting and intermediate-acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2-h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol-specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group., Conclusion: In this 24-week study, the addition of sitagliptin to ongoing, stable-dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes.

Type 2 diabetes, the most common form of diabetes, is characterized by abnormalities in hepatic glucose production, insulin resistance, and a progressive decline in beta-cell function over time. To treat effectively the individual with type 2 diabetes, the provider must have a thorough understanding of the underlying pathophysiology to provide treatment that precisely addresses the metabolic abnormalities. Currently, the provider who cares for subjects with type 2 diabetes can choose an antidiabetic agent from no less than eight pharmacologic classes. These classes include agents that increase insulin secretion, improve insulin action, and delay absorption of carbohydrates. The newer treatments available, specifically incretin therapy, address a previously unmet need in diabetes by modulating glucose supply. The currently available agents can be combined and combination therapy markedly improves glycemic control. This allows the provider to design regimens to specifically address underlying abnormalities. A review of all currently available agents is provided.

Aims: This study evaluated the effects on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with mild-to-moderate, but suboptimally controlled type 2 diabetes., Methods: In this multicenter, double-blind, placebo-controlled study, 122 patients with type 2 diabetes inadequately controlled (A1c 7-8.5%) on metformin (> or =1000 mg/day for > or =3 months) were randomized to 16 weeks treatment with 2.5 mg/day glipizide GITS (n=61) or placebo (n=61), in addition to their current metformin dose. The primary efficacy variable was the change in A1c from baseline to endpoint. Changes in fasting plasma glucose (FPG), insulin concentrations, lipid profile and safety variables were also measured., Results: The addition of glipizide GITS to metformin gave significantly greater improvements in mean A1c and FPG from baseline to endpoint than placebo addition (p<0.0002). Significantly more patients in the glipizide GITS group than in the placebo group achieved the target A1c level of A1c<7.0% (p<0.0001) and an A1c<6.5% (p<0.0033). Fasting insulin concentrations were similar in both groups and unchanged by treatment. Addition of glipizide GITS to metformin did not produce any significant or clinically relevant weight gain or changes in BMI. Both treatment regimens were well tolerated., Conclusions: This study showed that the addition of 2.5 mg glipizide GITS to metformin significantly improved glucose control in patients with type 2 diabetes inadequately controlled by metformin monotherapy.

Antidiabetic agents that augment insulin secretion can cause hypoglycemia. With the current trend toward early and aggressive treatment of patients with type 2 diabetes, the hypoglycemic potential of insulinotropic agents is of concern. This study aimed to compare the propensity of the "glinide," nateglinide, and the sulfonylurea (SU), glyburide, to elicit hypoglycemia in type 2 diabetic patients with moderately elevated fasting plasma glucose (FPG). Hyperglycemic clamps (target plasma glucose = 11.1 mmol/L) were initiated, and 30 minutes later patients received a single oral dose of nateglinide (120 mg, n = 15) or glyburide (10 mg, n = 12) in a double-blind fashion. At the end of the 2-hour clamp when the glucose infusion was terminated, plasma glucose and insulin levels were measured for 4 additional hours. The minimum plasma glucose level achieved after terminating the glucose infusion (glucose nadir) was used as an index of hypoglycemic potential. The mean (+/-SEM) glucose nadir was significantly lower in patients given glyburide (3.3 +/- 0.2 mmol/L) versus nateglinide (4.4 +/- 0.3 mmol/L, P = .025). Confirmed hypoglycemia (plasma glucose < or = 2.8 mmol/L) occurred in 2 of 12 patients given glyburide and in none of those given nateglinide. Plasma insulin levels were significantly higher from 100 to 240 minutes after clamp termination in patients given glyburide versus nateglinide. Nateglinide has less hypoglycemic potential than glyburide, suggesting that nateglinide may be a more appropriate insulinotropic agent for patients with moderate fasting hyperglycemia, such as elderly patients and those with comorbid cardiac ischemia.

The prevalence of type 2 diabetes mellitus (DM) has become epidemic in Western society. The direct and indirect medical costs of caring for patients with type 2 DM and its complications are staggering and will continue to grow with the increasing incidence of the disease. Studies show that preventive treatment, such as lifestyle changes and potentially pharmacologic therapy, may reduce the risk for diabetes and its complications, potentially reducing the costs of the disease.

Subcutaneous insulin has been used to treat diabetes since the 1920s; however, despite a number of different formulations, intensive insulin therapy with multiple daily injections has not gained widespread clinical acceptance. Attempts to find effective, well-tolerated, nonenteral routes for delivering insulin began in the 1920s, and, over the years, have included ocular, buccal, rectal, vaginal, oral, nasal and uterine delivery systems. Until recently, many researchers believed that insulin delivered noninvasively was associated with too low a bioavailability to offer a realistic clinical approach. However, a growing body of evidence suggests that inhaled insulin is an effective, well-tolerated, noninvasive alternative to subcutaneous regular insulin. Critically, inhaled insulin shows a more physiological insulin profile than that seen with conventional insulin. Further studies are needed to confirm long-term efficacy and pulmonary safety, to compare the different approaches, and to characterize better their relative places in practice. As a result of the recognition of the importance of tighter control of glycaemia and the growing number of patients with type 2 diabetes who receive insulin, inhaled insulin could become an increasingly integral part of managing diabetes.

In healthy postmenopausal women, estrogen or hormone replacement therapy (ERT or HRT) can alleviate menopausal symptoms and prevent osteoporosis and may also protect against cardiovascular disease (CVD). In addition to improving lipid metabolism, there are reports that estrogen also improves parameters regulating carbohydrate metabolism, including insulin resistance, in healthy women. Therefore, it is likely that ERT or HRT would also benefit women with type 2 diabetes, not only in relieving menopausal symptoms but also in improving the metabolic abnormalities associated with diabetes and in preventing cardiovascular disease.

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.

Insulin resistance is defined as a clinical state in which a normal or elevated insulin level produces an attenuated biologic response. Specifically, the biologic response most studied is insulin-stimulated glucose disposal, yet the precise cellular mechanism responsible is not yet known. However, the presence of insulin resistance is observed many years before the onset of clinical hyperglycemia and the diagnosis of Type 2 diabetes. Insulin resistance at this stage appears to be significantly associated with a clustering of cardiovascular risk factors predisposing the individual to accelerated cardiovascular disease. An overview of insulin resistance and the associated clinical insulin resistant state will be discussed.

To further characterize spontaneous diabetes mellitus in cynomolgus macaques (Macaca fascicularis) as a model for human non-insulin-dependent diabetes mellitus (NIDDM), we evaluated the morphologic characteristics of the endocrine pancreas of 4 diabetic and 12 age-matched nondiabetic cynomolgus macaques. In addition, the cDNA-predicted amino acid sequence for islet amyloid polypeptide (IAPP) of this species was determined. Islet amyloid deposits exhibiting typical congophilia and green birefringence were found in 4/4 diabetic animals and in 8/12 nondiabetics. Islet amyloid deposits were significantly more extensive in the diabetic macaques (P = 0.001), in which they occupied a mean of 60% of the islet area. In contrast, in the nondiabetic group the maximum islet area occupied by amyloid was 24% (group mean = 6.8%), with four animals having no detectable islet amyloid. Amyloid deposits consistently showed immunoreactivity for IAPP but not for insulin. Comparisons between group means for diabetic versus nondiabetic macaques showed significantly greater islet area (P = 0.01, 85,390 versus 36,540 microns 2) and significantly greater islet area fraction (P = 0.02, 0.065 versus 0.032) for the diabetic group. The cDNA-predicted amino acid sequence for cynomolgus IAPP was identical to that previously reported for pig-tail macaques (M. nemestrina) and had 92%, 86%, and 84% amino acid sequence identity with human, domestic cat, and murine IAPPs, respectively. These findings support the use of cynomolgus macaques as an animal model of human NIDDM.

Clinical goals in patients with non-insulin-dependent (type II) diabetes are to control glucose levels and prevent microvascular complications (eye, kidney, and nerve damage) while improving risk factors associated with cardiovascular disease (obesity, smoking, hyperlipidemia, hypertension, and hyperinsulinemia or insulin resistance). A wide array of medications and approaches is available to treat type II diabetes. Still, establishing an effective treatment regimen can be difficult, because patients have varying degrees of insulin secretory defects and insulin resistance and different conditions that must be factored in. Therefore, an individualized plan centered on self-management is the key to successful therapy in type II diabetes.

Six 15- to 20-year-old obese cynomolgus monkeys were determined to have diabetes mellitus. These monkeys were hyperglycemic and hypertriglyceridemic, yet remained nonketotic for several years before requiring clinical intervention. A significant decrease in glucose disappearance and an increased area under the glucose disappearance curve were found in response to intravenous glucose tolerance testing. Basal hyperinsulinemia was found in three animals that, in response to glucose stimulation, had a blunted insulin response, resulting in an overall decrease in the area under the insulin curve. Two animals died during the study and had extensive amyloid infiltration of pancreatic islets. The combined findings of old age, obesity, hyperinsulinemia, improvement in response to caloric restriction, and islet amyloidosis are consistent with type 2 diabetes mellitus.

Both abnormal insulin levels and low insulin sensitivity have been implicated as risk factors for Type II diabetes mellitus and cardiovascular disease. While insulin level is relatively simple to assess, direct measurement of insulin sensitivity is much more invasive, costly, and time-consuming. The authors considered eight previously described measures or indices of indices of insulin sensitivity derived from the frequently sampled intravenous glucose tolerance test (FSIGT). Each one was evaluated by strength and consistency of association with insulin sensitivity computed from glucose clamp (SI(clamp)), across three glucose tolerance groups, including participants with normal glucose tolerance (n = 11), impaired glucose tolerance (n = 20), and non-insulin-dependent diabetes mellitus (n = 24). Minimal model analysis (MINMOD SI(22)), based on the 22-sample FSIGT, performed best based on statistical criteria of strong and consistent association with SI(clamp). An insulin sensitivity measure similar to that of Galvin et al. (Diabetic Medicine 1990;9:921-8), defined as glucose disappearance (10-50 minutes) divided by insulin area under the curve above baseline from 0-50 minutes, performed best based on statistical criteria and time-savings. Galvin insulin sensitivity is simple to calculate, requires only a 50-minute FSIGT, and is significantly (p < 0.001) and not inconsistently (p = 0.12 for inconsistent association) associated with SI(clamp) over a wide range of glucose tolerance.

alpha-Adrenergic blockers have shown favorable metabolic effects. We evaluated the glucose and insulin responses to a glucose load and lipid profiles in 36 diabetic hypertensive patients before and after 8 weeks of doxazosin administration. To evaluate insulin action at the cellular level, erythrocyte insulin binding and tyrosine kinase (TK) activity were measured in 12 of these patients. Systolic and diastolic blood pressures decreased significantly (P < .0001) after 8 weeks of doxazosin therapy. Doxazosin administration significantly reduced the integrated insulin response (area under the curve [AUC]-insulin: 6093 +/- 894 to 5260 +/- 807; P = .04) and the insulin/glucose index (I/G) at 90 and 120 min after a glucose load (at 90 min, 0.230 +/- 0.055 v 0.180 +/- 0.04, P < .05; at 120 min, 0.275 +/- 0.071 v 0.173 +/- 0.036, P < .05). HDL3 level increased from 31.1 +/- 1.5 mg% to 34 +/- 1.6 mg% (P < .05) after doxazosin. Erythrocyte insulin binding and tyrosine kinase activity were not significantly altered after doxazosin. No significant correlation was found between the insulin or glucose responses and the insulin receptor binding or tyrosine kinase activity before and after treatment.

Objective: To compare the efficacy and safety of controlled-release glipizide (glipizide-GITS [gastrointestinal therapeutic system]) and immediate-release glipizide in patients with non-insulin-dependent diabetes mellitus (NIDDM)., Research Design and Methods: In a multicenter, open-label, randomized, two-way crossover study, 132 patients with NIDDM received daily doses of 5, 20, or 40 mg of either glipizide-GITS or immediate-release glipizide for 8 weeks followed by 8 weeks of the alternate formulation. Plasma glucose, serum insulin, C-peptide, and plasma glipizide levels were measured at fasting and post-Sustacal challenge at the end of 1 and 8 weeks of each treatment phase. HbA1c was measured at the end of weeks 7 and 8 of each treatment phase., Results: Both formulations of glipizide yielded similar mean HbA1c values. However, mean fasting plasma glucose (FPG) levels were significantly lower with glipizide-GITS treatment than with immediate-release glipizide at the end of week 1 (11.0 vs. 11.6 mmol/l; P < 0.01) and at the end of the 8-week treatment phase (10.9 vs. 11.7 mmol/l; P < 0.001). Fasting insulin and C-peptide levels were lower after 5 mg glipizide-GITS vs. immediate-release glipizide. Glucose responses to Sustacal were similar after both formulations of glipizide; however, serum insulin (P < 0.01) and C-peptide responses (P < 0.05) were lower with glipizide-GITS than with immediate-release glipizide treatment at the end of the 8-week treatment phase. Mean plasma glipizide concentrations were stable by the end of week 1, and the concentrations increased proportionately with dose. Once-daily Glipizide-GITS provided effective mean glipizide concentrations (> 50 ng/ml) 24 h after dosing, even at the lowest (5 mg) dose level. Both formulations were well tolerated., Conclusions: Glipizide-GITS was significantly more effective than immediate-release glipizide in reducing FPG levels. Both formulations reduced postprandial plasma glucose levels equally; however, glipizide-GITS exerted its control in the presence of lower plasma glipizide concentrations in addition to significantly lower insulin and C-peptide levels. This suggests that glipizide-GITS improves insulin sensitivity.

We evaluated glycohemoglobin (GHb) and glycated plasma protein (GPP) by automated affinity HPLC for their ability to monitor both short-term and long-term antecedent glycemia in 70 diabetic subjects. We placed 30 subjects on an intervention protocol in which insulin and (or) dietary changes were made twice weekly to acutely decrease glycemia. We monitored 40 subjects at 6-week intervals; changes in the clinical regimen were made at that time only. Despite weekly changes in mean blood glucose in the subjects who received more intensive intervention. GHb concentrations correlated significantly with the weekly (r = 0.66, P < 0.001), 2-week (r = 0.70, P < 0.001), 3-week (r = 0.72, P < 0.001), and 6-week (r = 0.83, P < 0.001) mean glucose concentrations. GPP correlated significantly with measured glycated albumin determined by boronate affinity columns (r = 0.83, P < .001) and correlated best with the 1-week (r = 0.66, P < 0.001), 2-week (r = 0.64, P < .001) and 3-week (r = 0.60, P < 0.001) mean antecedent glucose concentration. Thus, GHb, traditionally considered a marker for only long-term diabetic control, correlated significantly with both short-term and long-term antecedent glycemia.