Weight-loss therapy in type 2 diabetes: effects of phentermine and topiramate extended release.

OBJECTIVE: Treatment algorithms for type 2 diabetes recommend weight loss for disease management. The safety and efficacy of treatment with phentermine (PHEN)/topiramate (TPM) extended release (ER) plus lifestyle modification for weight loss and glycemic benefits were assessed in two randomized, double-blind, placebo-controlled 56-week studies of obese/overweight adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: The OB-202/DM-230 Study was a 56-week phase 2 trial that randomized subjects to receive once-daily placebo or PHEN/TPM ER 15 mg/92 mg (15/92). The primary end point was change in HbA1c level. A post hoc analysis of a subpopulation with type 2 diabetes from a second study, CONQUER, is also presented. All subjects made lifestyle modifications, and comorbidities were managed to the standard of care. RESULTS: The study groups comprised 130 subjects with type 2 diabetes enrolled in the OB-202/DM-230 Study (mean baseline HbA1c 8.7% [72 mmol/mol]) and 388 subjects with type 2 diabetes in the CONQUER Study (mean baseline HbA1c 6.8% [51 mmol/mol]). At week 56 in the OB-202/DM-230, change in weight (from intent-to-treat sample with last observation carried forward [ITT-LOCF]) was -2.7% for placebo and -9.4% for PHEN/TPM ER 15/92 (P < 0.0001 vs. placebo). Change in HbA1c level (from ITT-LOCF) was -1.2% (-13.1 mmol/mol) for placebo and -1.6% (-17.5 mmol/mol) for PHEN/TPM ER 15/92 (P = 0.0381). In both the OB-202/DM-230 and CONQUER, greater numbers of patients randomized to receive PHEN/TPM ER treatment achieved HbA1c targets with reduced need for diabetic medications when compared with the placebo group. Common adverse events included paraesthesia, constipation, and insomnia. CONCLUSIONS: PHEN/TPM ER plus lifestyle modification can effectively promote weight loss and improve glycemic control as a treatment approach in obese/overweight patients with type 2 diabetes.

Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release.

OBJECTIVE To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m(2)) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P < 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors.

Individualized treatment of type 2 diabetes mellitus using noninsulin agents: clinical considerations for the primary care physician.

BACKGROUND: The outcomes associated with some therapies may be potentially influenced by specific patient characteristics. Individualized therapy is an effort to achieve optimal health outcomes for a patient by selecting drugs known to be beneficial in persons with specific attributes or disease characteristics. With a broad literature base spanning several different medication classes, there is increasing potential for individualization of therapy in the treatment of type 2 diabetes mellitus. PURPOSE: To review the literature for data that support associations between patient characteristics and outcomes resulting from treatment with antihyperglycemic medications. RESULTS AND CONCLUSIONS: Review of the medical literature suggests that 3 general considerations are important for individualized therapy: disease pathophysiology, modifiers of treatment response, and risks of nonadherence. Currently, there are limited data demonstrating that nongenetic patient characteristics modify treatment response, while a number of genetic polymorphisms are known to influence the pharmacology of certain antidiabetic agents. The available literature includes evaluation of key nongenetic factors, such as age, race, body mass index, patient sex, disease duration, and baseline glycated hemoglobin level. Of these, glycated hemoglobin level is the best-described laboratory value correlated with treatment response. Recent literature has brought to physicians' attention the more practical aspects of treatment that can influence outcomes, mainly those associated with medication adherence. These include out-of-pocket costs, tolerability/side effects, and the complexity of daily treatment regimens.

TheV-Go insulin delivery device used in clinical practice: patient perception and retrospective analysis of glycemic control.

OBJECTIVE: To describe patient perceptions regarding their experience and to report findings in a retrospective analysis of glycemic control in a cohort of patients who used the V-Go, a mechanical, 24-hour disposable, subcutaneous continuous insulin delivery device that delivers a preset basal infusion rate and on-demand insulin. METHODS: Patients used the V-Go and answered telephone surveys about their perception of device use. Corresponding clinical data were retrospectively collected before V-Go initiation, after 12 weeks of use, at the end of treatment, and 12 weeks after discontinuation. Analyses were performed with nonparametric statistical tests. RESULTS: Twenty-three patients participated. Mean values of the following characteristics were documented: patient age, 61 years; body mass index, 30 kg/m2; diabetes duration, 16 years; duration of insulin therapy, 7 years; average duration of V-Go use, 194 days; and mean total daily insulin dose, 50 U at baseline, 46 U while on V-Go, and 51 U after stopping V-Go treatment. Mean patient rating of the overall experience was 9.1 at 12 weeks on a scale from 1 to 10 (10 being most positive). Mean hemoglobin A1c value decreased from baseline (8.8% to 7.6%; [P = .005]) while using the V-Go, and it increased to 8.2% after treatment. Fasting plasma glucose trended from 205 mg/dL at baseline to 135 mg/dL while using V-Go and increased to 164 mg/dL after V-Go was stopped. Weight was essentially unchanged. No differences in hypoglycemic events were found; site reactions were minor. CONCLUSION: Glycemic control improved when patients were switched to the V-Go for insulin delivery, and it deteriorated when the V-Go was discontinued.

Insulin patch pumps: their development and future in closed-loop systems.

Steady progress is being made toward the development of a so-called "artificial pancreas," which may ultimately be a fully automated, closed-loop, glucose control system comprising a continuous glucose monitor, an insulin pump, and a controller. The controller will use individualized algorithms to direct delivery of insulin without user input. A major factor propelling artificial pancreas development is the substantial incidence of-and attendant patient, parental, and physician concerns about-hypoglycemia and extreme hyperglycemia associated with current means of insulin delivery for type 1 diabetes mellitus (T1DM). A successful fully automated artificial pancreas would likely reduce the frequency of and anxiety about hypoglycemia and marked hyperglycemia. Patch-pump systems ("patch pumps") are likely to be used increasingly in the control of T1DM and may be incorporated into the artificial pancreas systems of tomorrow. Patch pumps are free of tubing, small, lightweight, and unobtrusive. This article describes features of patch pumps that have been approved for U.S. marketing or are under development. Included in the review is an introduction to control algorithms driving insulin delivery, particularly the two major types: proportional integrative derivative and model predictive control. The use of advanced algorithms in the clinical development of closed-loop systems is reviewed along with projected next steps in artificial pancreas development.

A review of the response to oral antidiabetes agents in patients with type 2 diabetes.

In patients with type 2 diabetes, a progressive decline in glycemic control exacerbates the microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (cardiovascular disease, stroke, and peripheral arterial disease) complications associated with this disease. In a consensus statement, the American Diabetes Association and the European Association for the Study of Diabetes stated that the main goal of antidiabetes therapy is to achieve glycemic control, defined as a glycated hemoglobin of < 7%, although goals should be individualized to each patient, especially in patients at highest risk of cardiovascular disease events. However, because type 2 diabetes is a progressive disease, the response to oral antidiabetes (OAD) agents declines over time and the majority of patients are unable to maintain glycemic control, thus necessitating additional therapy. This requirement for additional antidiabetes therapies as the disease progresses suggests that more aggressive and earlier use of synergistic therapies may help achieve and prolong glycemic control. This review examines the efficacy of OAD therapies to address the unmet need for prompt and maintained glycemic control to the recommended goal in patients with type 2 diabetes, the factors that can affect the glycemic response to the various classes of OAD agents, and ways in which the management of hyperglycemia can be improved in patients with type 2 diabetes.

Assessment of long-term immunological and pulmonary safety of inhaled human insulin with up to 24 months of continuous therapy.

BACKGROUND: This study was performed to characterize the long-term safety and efficacy of inhaled human insulin (EXU; Exubera * (insulin human [rDNA origin]) Inhalation Powder). * Pfizer Inc, New York, NY, USA. SCOPE: Patients with type 1 or type 2 diabetes (N = 1290) who had successfully completed one of six controlled EXU open-label trials elected to receive open-label treatment with EXU for up to 3 years, after which they were randomized to discontinue EXU or to continue therapy for 6 months, then discontinue. Immunologic safety was assessed by insulin antibody (IAb) binding, and pulmonary safety was assessed by tests for forced expiratory volume in 1 second (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)). In addition, changes over time in IAbs were compared with changes in FEV(1), DL(CO), hypoglycemia, and efficacy. FINDINGS: Antibody binding increased in patients with either type 1 or type 2 diabetes after initiation of EXU and plateaued within 6-12 months (increases were higher in patients with type 1 diabetes than in patients with type 2 diabetes). Decreases in FEV(1) occurred primarily during the first 3-6 months of EXU therapy. Among adult patients in the All Subjects set, the mean (± SE) annualized rate of decline in FEV(1) was -0.053 ± 0.007 liters/year (95% CI, -0.065, -0.040) in adult patients with type 1 diabetes, and -0.076 ± 0.005 liters/year (95% CI, -0.085, -0.067) in patients with type 2 diabetes. Changes in DL(CO) occurred primarily during the first 3-6 months of EXU therapy. Among adult patients, in the All Subjects set, the mean (± SE) annual decline in DL(CO) was -0.738 ± 0.097 mL/min/mmHg/year (95% CI, -0.927, -0.548) and -0.688 ± 0.082 mL/min/mmHg/year (95% CI, -0.849, -0.527) in patients with type 1 and type 2 diabetes, respectively. Antibody binding did not correlate with changes in glycemic control, lung function, dose, or hypoglycemia. Following discontinuation of EXU, IAbs decreased to near baseline levels. CONCLUSION: These results are consistent with other trials showing long-term maintenance of safety and efficacy of EXU despite insulin antibody formation and small treatment group differences in pulmonary function. A limitation of the study was the lack of a comparator therapy.

Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes: results of a 6-month, randomized, comparative trial.

OBJECTIVE: The aim of this study was to determine whether premeal pulmonary delivery of rapid-acting, dry-powder insulin (Exubera) plus Ultralente could provide glycemic control comparable to a conventional insulin regimen in type 1 diabetes. RESEARCH DESIGN AND METHODS: Three hundred thirty-five subjects were randomly assigned to receive either premeal inhaled insulin plus bedtime Ultralente or two to three injections of regular and NPH insulin for 24 weeks. The primary end point was a change in HbA(1c). RESULTS: Mean decreases in HbA(1c) values were comparable for inhaled (8.1-7.9%) and conventional groups (8.1-7.7%) (adjusted treatment group difference 0.16% [95% CI -0.01 to 0.32]). There were greater reductions for inhaled versus conventional regimen in fasting and postprandial plasma glucose (adjusted mean change differences -25.17 and -30.28 mg/dl, respectively [95% CI -43.39 to -6.95 and -54.58 to -5.97, respectively]). Hypoglycemia (events/subject month) was lower for the inhaled (8.6) versus the conventional (9.0) group (risk ratio, 0.96 [95% CI 0.93-0.99]). In subjects receiving inhaled insulin, increased insulin antibody levels were observed, but there were no associated clinical or laboratory changes. Adverse events were comparable between groups. Mild to moderate cough was more frequent in the inhaled insulin group (27 vs. 5%) but decreased during the treatment. Pulmonary function tests were not different between the groups except for a greater decrease in carbon monoxide diffusing capacity in the inhaled insulin group. Treatment satisfaction was greater in the inhaled than in the conventional group. CONCLUSIONS: Inhaled insulin is effective, well tolerated, and well accepted in patients with type 1 diabetes and provides glycemic control comparable to that with a conventional insulin regimen.

Optimizing insulin regimens in type 1 diabetes. How to help patients get control of their life.

The advances in insulin therapy in the past 5 years, including the introduction of insulin analogues, have made blood glucose control in patients with type 1 diabetes much more attainable. Diabetic patients can now achieve a better quality of life, including spontaneity and flexibility in lifestyle, than was possible with earlier insulin products. Here, Dr Bohannon discusses the latest improvements in acute and basal insulin therapy and presents three algorithms she has developed to help patients individualize their insulin regimens in relation to their eating and exercise patterns.

Treating dual defects in diabetes: insulin resistance and insulin secretion.

The therapeutic goals in patients with type 2 diabetes mellitus and the mechanisms of insulin resistance and secretion are discussed. Sulfonylureas improve glycemic control, restore the acute insulin response, and help improve beta-cell function in the short term. Meglitinides and phenylalanine derivatives and alpha-glucosidase inhibitors may be useful for elderly patients and others with normal fasting blood glucose levels and postprandial hyperglycemia, but they are less effective in achieving goal HbA1c levels in patients with marked fasting hyperglycemia. Metformin and thiazolidinediones act on hepatic, muscle, and adipose tissue through different mechanisms to improve glycemic control, beta-cell function, and the lipid profile. Thiazolidinediones have a greater impact on free fatty acids than metformin. They may have an additive effect with sulfonylureas, metformin, or insulin in improving glycemic control and the lipid profile. Many patients require combination therapy with one or more insulin sensitizers and an insulin secretagogue to achieve therapeutic goals. Insulin therapy should be initiated in patients in whom an HbA1c level less than 7.0% cannot be maintained with other therapies. This is vital in preventing diabetes complications. Insulin sensitizers should be continued during insulin therapy to reduce insulin resistance and treat the insulin resistance syndrome. Therapeutic goals for patients with type 2 diabetes mellitus include improvement in glycemic control and prevention of diabetes complications. Elevated levels of fasting blood glucose should be addressed before postprandial levels to reduce HbA1c levels and glucotoxicity to the beta cell. Dyslipidemia, hypertension, and hypercoagulability should be treated to minimize the increased cardiovascular risk seen in people with diabetes, which is responsible for the majority of deaths.

Effective use of insulin.

Preview Day-to-day control of diabetes demands an ongoing balance of diet, exercise, and insulin dosage that can only be achieved with regular self blood glucose monitoring. Patients need to be familiar with factors that affect the action of insulin and to know that "less is sometimes more." In this article, Dr Bohannon explains the simple concepts that lead to the most effective use of insulin.