John R. White

Metformin: A New Oral Biguanide

The biguanide metformin is an oral anti-hyperglycemic agent used in the treatment of patients with non-insulin-dependent diabetes mellitus (NIDDM). Metformin is an important addition to the drug therapy options available for those patients because it reduces blood glucose levels predominantly by decreasing hepatic glucose production and release and also by increasing peripheral tissue sensitivity to insulin; it does not stimulate insulin secretion from the beta cells in the pancreas. Metformin also has a potentially beneficial effect by reducing serum lipid levels. Its glycemic control is similar to that of the sulfonylureas and is effective as monotherapy or in combination with sulfonylureas or insulin. Unlike sulfonylureas and insulin, it does not cause a gain in body weight, and when used as monotherapy, it does not cause hypoglycemia. The most common side effects associated with metformin are mild, transient, gastrointestinal symptoms, which are usually self-limiting. These side effects can be minimized by initiating metformin therapy at a low dose and gradually titrating upward, and by taking metformin with meals. Lactic acidosis caused by metformin is rare, and the risk of this complication may be diminished by the observance of prescribing precautions and contraindications that avoid accumulation of metformin or lactate in the body. In patients who are not getting the desired effect with sulfonylureas, it is useful to combine sulfonylureas with metformin therapy. Metformin should be considered a first-line agent, particularly in obese and/or hyperlipidemic NIDDM patients.

Efficacy and safety of incretin-based therapies: Clinical trial data

OBJECTIVEnProvide a comprehensive overview of efficacy and safety data on incretin-based agents in the treatment of type 2 diabetes.nnnDATA SOURCESnA PubMed search was conducted for the years 2000-2009, using as keywords the names of glucagon-like peptide-1 (GLP-1) receptor agonists (exenatide and liraglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, alogliptin, and saxagliptin). World Diabetes Congress abstracts from 2008 to 2009 were also searched for clinical studies of these agents.nnnSTUDY SELECTIONnThe author included randomized controlled trials of incretin therapies that were published in English and enrolled > or =100 participants.nnnDATA EXTRACTIONnData on the effects of incretins on glycemic control, weight, beta-cell function, blood pressure, lipid levels, safety, and tolerability were extracted and summarized.nnnDATA SYNTHESISnA total of 27 randomized controlled studies of incretin therapy were identified and included in the review. GLP-1 receptor agonists and DPP-4 inhibitors were evaluated at different points in the diabetes treatment spectrum, i.e., added to diet and exercise alone (monotherapy) or added to oral antihyperglycemic regimens (combination therapy).nnnCONCLUSIONnIn addition to decreasing glycemia in type 2 diabetes, incretin therapies may improve other important parameters, including beta-cell function, blood pressure, and lipid levels, with a low risk for hypoglycemia. A comparison of the study data differentiates the clinical profiles of the GLP-1 receptor agonists, which are associated with weight loss, and DPP-4 inhibitors, which are weight neutral, as well as the individual agents within each class.

Insulin Glargine: A New Basal Insulin

OBJECTIVE: To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of insulin glargine. DATA SOURCES: Primary and review articles regarding insulin glargine were identified by MEDLINE search (1966–July 2001); abstracts were identified through Institute for Scientific Information Web of Science (1995–July 2001) and the American Diabetes Association. Additional information was obtained from the insulin glargine product information. STUDY SELECTION AND DATA EXTRACTION: All of the articles and meeting abstracts identified from the data sources were evaluated, and all information deemed relevant was included in this review. Priority was placed on data from the primary medical literature. DATA SYNTHESIS: Insulin glargine is a long-acting, recombinant human insulin analog that is given once daily as a basal source of insulin in patients with type 1 or type 2 diabetes mellitus. Modification of the basic insulin structure has produced a new insulin that is soluble at an acidic pH, but precipitates in the subcutaneous tissue and is slowly released from a depot. Insulin glargine has a slower onset of action than NPH insulin and a longer duration of action with no peak activity. Once-daily administration of insulin glargine has comparable efficacy to that of NPH insulin administered once or twice daily in basal-bolus regimens when used in combination with intermittent doses of regular insulin or insulin lispro in patients with type 1 and type 2 diabetes, and in conjunction with oral antidiabetic agents in patients with type 2 diabetes. Overall, insulin glargine has an incidence of hypoglycemia comparable to or less than that of NPH insulin, with a reduced incidence of nocturnal hypoglycemia compared with NPH insulin seen in some studies. CONCLUSIONS: Insulin glargine is a long-acting insulin analog capable of providing 24-hour basal insulin coverage when administered once daily at bedtime. Its activity profile, which lacks a pronounced peak, more closely resembles that of endogenous basal insulin than that of other intermediate- or long-acting insulins and appears more likely to be associated with a reduced incidence of hypoglycemia, particularly nocturnal hypoglycemia. Insulin glargine physiologically provides basal insulin but, for most patients, the addition of a rapid-acting insulin, like insulin lispro, before or with meals will need to be included in the treatment regimen to achieve optimal management of blood glucose concentrations.

Insulin Aspart: A New Rapid-Acting Insulin Analog

OBJECTIVE: To examine the pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, and drug interactions of insulin aspart, and summarize the clinical trials of efficacy and safety in patients with type 1 or type 2 diabetes mellitus. DATA SOURCES: A MEDLINE database search (1985–May 2000) was performed to identify all applicable published articles and abstracts; in some cases, Novo Nordisk unpublished information was also obtained. Review articles on insulin analogs were also identified, as well as review chapters in medical textbooks. STUDY SELECTION: The majority of the studies identified were in abstract form. These studies reported information on the pharmacokinetics of insulin aspart in healthy volunteers and in those with diabetes, as well as the therapeutic utility, safety, and clinical efficacy in patients with diabetes. A limited number of randomized studies were reported as articles in the medical literature. DATA EXTRACTION: All published clinical studies were reviewed. DATA SYNTHESIS: Insulin aspart, the second Food and Drug Administration—approved rapid-acting insulin analog, is produced by recombinant technology that replaces the proline at position 28 on the B chain of insulin with negatively charged aspartic acid. Insulin aspart exists as hexamers that rapidly dissociate into monomers and dimers on subcutaneous injection. When administered immediately prior to a meal, insulin aspart is at least as effective as regular human insulin in control of postprandial blood glucose concentrations. Insulin aspart achieves higher peak insulin concentrations in less time and with a shorter duration of action than regular human insulin. CONCLUSIONS: Insulin aspart is a convenient premeal insulin for use by patients requiring mealtime insulin. Furthermore, due to favorable pharmacokinetics, insulin aspart controls postprandial blood glucose concentrations at least as well as regular human insulin and contributes to improved quality of life.

Insulin Therapy in Type 2 Diabetes

OBJECTIVEnTo review the increasingly common use of insulin therapy in patients with type 2 diabetes and the practical aspects of initiating insulin therapy in these patients.nnnDATA SOURCESnRecent scientific and clinical literature identified through MEDLINE searches for the years 1995-2001 using the terms oral agents, type 2 diabetes, insulin therapy, glycemic control and diabetic complications, glucose toxicity, insulin lispro, insulin aspart, and insulin glargine. STUDY SECTION: Reports of key large (1,000 patients or more) and significant smaller, randomized, controlled clinical trials were reviewed. For studies comparing insulin analogs, the authors reviewed a sampling of the identified trials for their characteristics and clinical importance.nnnDATA SYNTHESISnTight blood glucose control can help reduce the risk of diabetes complications. Evidence suggests that early insulin therapy can help correct the underlying pathogenetic abnormalities in type 2 diabetes and improve long-term glycemic control. For these reasons, some diabetes experts advocate the initiation of insulin therapy earlier in the course of type 2 diabetes than has been common in the past. Insulin regimens should be designed to mimic the bodys natural physiologic secretion of insulin, including the basal amounts released continuously by the pancreas and the insulin surges produced in response to glucose loads. Using new insulin analogs is a useful approach to achieving this ideal. Insulin glargine provides a nearly constant, peakless release of insulin when injected subcutaneously once daily. Two new rapid-acting insulin analogs, insulin lispro (Humalog--Lilly) and insulin aspart (NovoLog--Novo Nordisk), enhance patients flexibility in terms of meals by permitting injection immediately before meals, rather than 30 minutes before meals, as with regular insulin.nnnCONCLUSIONnPatients should be reassured that early initiation of insulin therapy is a positive event that should improve their long-term health and does not represent a decline in the course of their disease.

Nateglinide Therapy for Type 2 Diabetes Mellitus

OBJECTIVE: To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of nateglinide. DATA SOURCES: Primary and review articles regarding nateglinide were identified by MEDLINE search (from 1966 to January 2001); abstracts were identified through the Institute for Scientific Information Web of Science (from 1995 to January 2001) and the American Diabetes Association; additional information was obtained from the nateglinide product information. STUDY SELECTION/DATA EXTRACTION: All articles and meeting abstracts identified from the data sources were evaluated and all information deemed relevant was included in this review. Much of the information was from abstracts or the product labeling, since few clinical studies have been published in the medical literature. DATA SYNTHESIS: Nateglinide is a novel nonsulfonylurea oral antidiabetic agent that stimulates insulin secretion from the pancreas. It has a rapid onset and short duration of action, allowing administration before a meal to reduce postprandial hyperglycemia. Improvement in glycemic control with nateglinide monotherapy has been demonstrated in patients not previously treated with antidiabetic medications. Greater improvement in glycemic control was observed when nateglinide was administered in combination with metformin. CONCLUSIONS: Nateglinide is similar to repaglinide, but has a quicker onset of action, quicker reversal, and does not usually require dosage titration. Based on the pharmacodynamics of nateglinide and repaglinide, nateglinide produces a more rapid postprandial increase in insulin secretion, and its duration of response is shorter than that of repaglinide. The risk of postabsorptive hypoglycemia should be lower than with either sulfonylureas or repaglinide.

Pharmacokinetic analysis and comparison of caffeine administered rapidly or slowly in coffee chilled or hot versus chilled energy drink in healthy young adults

Abstract Context: There is a paucity of data describing the impact of type of beverage (coffee versus energy drink), different rates of consumption and different temperature of beverages on the pharmacokinetic disposition of caffeine. Additionally, there is concern that inordinately high levels of caffeine may result from the rapid consumption of cold energy drinks. Objective: The objective of this study was to compare the pharmacokinetics of caffeine under various drink temperature, rate of consumption and vehicle (coffee versus energy drink) conditions. Materials: Five caffeine (doseu2009=u2009160u2009mg) conditions were evaluated in an open-label, group-randomized, crossover fashion. After the administration of each caffeine dose, 10 serial plasma samples were harvested. Caffeine concentration was measured via liquid chromatography–mass spectrometry (LC–MS), and those concentrations were assessed by non-compartmental pharmacokinetic analysis. The calculated mean pharmacokinetic parameters were analyzed statistically by one-way repeated measures analysis of variance (RM ANOVA). If differences were found, each group was compared to the other by all pair-wise multiple comparison. Results: Twenty-four healthy subjects ranging in age from 18 to 30 completed the study. The mean caffeine concentration time profiles were similar with overlapping SDs at all measured time points. The ANOVA revealed significant differences in mean Cmax and Vdu2009ss/F, but no pair-wise comparisons reached statistical significance. No other differences in pharmacokinetic parameters were found. Discussion: The results of this study are consistent with previous caffeine pharmacokinetic studies and suggest that while rate of consumption, temperature of beverage and vehicle (coffee versus energy drink) may be associated with slightly different pharmacokinetic parameters, the overall impact of these variables is small. Conclusion: This study suggests that caffeine absorption and exposure from coffee and energy drink is similar irrespective of beverage temperature or rate of consumption.

New Insulin Glargine 300 U/mL for the Treatment of Type 1 and Type 2 Diabetes Mellitus:

Objective: To describe the studies evaluating the efficacy and safety of new insulin glargine 300 U/mL (Gla-300) as a basal insulin in the treatment of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Data Sources: A literature search of MEDLINE was conducted (January 2008-June 2015) using the terms U300, Gla-300, and insulin glargine 300 units/mL and supplemented with congress abstracts published in 2014 and 2015. Study Selection and Data Extraction: All English language studies assessing the efficacy and/or safety of Gla-300 were evaluated. Data Synthesis: The efficacy and safety of once-daily Gla-300 has been compared with insulin glargine 100 U/mL (Gla-100) in the EDITION trials, 6 phase-3, multinational, open-label studies in T1DM and T2DM. Across these studies, Gla-300 consistently demonstrated glycemic control comparable to Gla-100; a mean (standard error) change in glycated hemoglobin A1c of −1.02% (0.03) with both Gla-100 (n = 1235) and Gla-300 (n = 1239) was seen in a patient-level meta-analysis. Gla-300 was associated with comparable or reduced nocturnal hypoglycemia compared with Gla-100; the relative risk for nocturnal hypoglycemia with Gla-300 versus Gla-100 was 0.75 (95% CI = 0.68 to 0.83) in a patient-level meta-analysis. There is also some evidence for less weight gain with Gla-300 compared with Gla-100, despite a higher insulin dose. Gla-300 was well tolerated, with the number of adverse events being comparable to that with Gla-100. Conclusions: These results suggest that Gla-300 may have a place as an alternative, long-acting basal insulin for patients with T1DM or T2DM, with the possibility for improved tolerability.

DANGEROUS AND COMMON DRUG INTERACTIONS IN PATIENTS WITH DIABETES MELLITUS

As more medications are made available to the prescriber, the likelihood of drug interactions will increase. The number of drug interactions encountered by the provider treating the patient with diabetes has increased over the past few years because the number of medications used in the management of hyperglycemia has dramatically increased during that time. These interactions are complex but can be predicted.

Empagliflozin, an SGLT2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus A Review of the Evidence

Objective: To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). Data Sources: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. Study Selection and Data Extraction: All publications reporting clinical trials of empagliflozin were eligible for inclusion. Data Synthesis: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. Conclusion: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.