Elizabeth M. Lamos

A review of the efficacy and safety of oral antidiabetic drugs

Introduction: Additional oral antidiabetic agents to metformin, sulfonylureas (SU) and thiazolidinediones (TZD) are approved for the treatment of type 2 diabetes. Areas covered: The efficacy and safety of metformin, SUs, TZDs, dipeptidyl peptidase-IV (DPP-4) inhibitors, meglitinide analogs, α-glucosidase inhibitors (AGIs), bile-acid sequestrants (BAS) and bromocriptine will be reviewed. Expert opinion: Several new oral agents have been approved for type 2 diabetes management in recent years. It is important to understand the efficacy and safety of these medications in addition to the older agents to best maximize oral drug therapy for diabetes. Of the recently introduced oral hypoglycemic/antihyperglycemic agents, the DPP-4 inhibitors are moderately efficacious compared with mainstay treatment with metformin with a low side-effect profile and have good efficacy in combination with other oral agents and insulin. They are a recommended alternative when metformin use is limited by gastrointestinal (GI) side effects or when SU treatment results in significant hypoglycemia or weight gain. Meglitinide analogs are limited by their frequent dosing, expense and hypoglycemia (repaglinide > nateglinide), while AGIs are also limited by their dosing schedule and GI side-effect profile. BAS and bromocriptine have the lowest efficacy with regard to HbA1c reduction, also are plagued by GI adverse reactions, but have a low risk of hypoglycemia.

Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus.

Introduction: Canagliflozin is an orally administered sodium glucose cotransporter 2 inhibitor proposed for the treatment of type 2 diabetes. Canagliflozin improves glycemic control in an insulin-independent fashion through inhibition of glucose reuptake in the kidney. Areas covered: This article reviews the available data on the pharmacodynamics, the pharmacokinetics and metabolism, and the efficacy and safety of canagliflozin. Relevant articles were identified via PubMed using the search term canagliflozin with no date restriction. The authors also discuss the abstracts from canagliflozin studies presented at large diabetes conferences. Expert opinion: Canagliflozin offers a relatively modest reduction in HbA1c, FPG, and PPG. It has a low incidence of hypoglycemia and a reduction in body weight. Dose adjustment may be recommended in the elderly, those on loop diuretics, and those with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 if there are concerns or symptoms of volume-related side effects. Issues remain with observed increases in low-density lipoprotein cholesterol (LDL-C) and the odds of heart attack and stroke. Canagliflozin offers a novel mechanism of action, a modest glycemic control, and a favorable side-effect profile. It was approved by the US Food and Drug Administration in April 2013 and is undergoing evaluation by the European Medicines Agency.

Empagliflozin, a sodium glucose co-transporter 2 inhibitor, in the treatment of type 1 diabetes

Introduction: Available anti-hyperglycemic therapy in type 1 diabetes (T1DM) is currently restricted to insulin, pramlintide, and pancreas or islet cell transplantation. The imperfect replication of normal insulin secretion and glucose control has been a driver for development of other anti-hyperglycemic agents for this population. Empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is currently under investigation as an add-on therapy to insulin in T1DM. Areas covered: Within the drug evaluation, the authors describe the mechanism of action of SGLT2 inhibitors and preliminary results from studies investigating treatment in rodent models and in individuals with T1DM. Expert opinion: Studies on adjunct therapeutic effects of empagliflozin in individuals with T1DM are limited, but initial reports show favorable effects on reducing HbA1c, body weight, total daily insulin dose and hypoglycemic events. Intriguingly, this drug may confer a degree of renal protection by reducing glomerular hyperfiltration that can arise in the diabetic state. Currently, the primary concern seems to be the presence of ketone levels indicating an under-insulinized state. Long-term effects can only be inferred from studies in type 2 diabetes mellitus at this time. Empagliflozin represents a novel non-insulin-mediated therapy that warrants further investigation.

An insight into the recent diabetes trials: what is the best approach to prevent macrovascular and microvascular complications?

Type 2 diabetes mellitus (T2DM) accounts for 90%-95% of all diabetes cases. The overarching goal in caring for patients with T2DM is to prevent microvascular and macrovascular complications with glycemic control. Several studies such as UKPDS, DCCT, and EDIC have been performed to evaluate the effects of glucose control on tissue complications in patients with diabetes. In recent diabetes trials including ACCORD, ADVANCE, VADT, BARI 2D, and ORIGIN, intensive glucose control did not prevent macrovascular complications in older patients with long-standing diabetes with either cardiovascular disease or risk factors for cardiovascular disease. In fact, intensive therapy was associated with increased mortality in the ACCORD trial. Although no clear macrovascular benefit was seen in these trials, analyses of earlier studies in younger patients with type 1 and type 2 diabetes have suggested a significant benefit of intensive glycemic control in patients with a shorter duration of diabetes and less vasculopathy. In the UKPDS, the incidence of microvascular disease, particularly retinopathy, was reduced significantly with intensive glucose control, but in the more recent trials (ACCORD, ADVANCE, VADT, ORIGIN) the benefit was relatively modest and limited to reduced proteinuria. Perhaps the most important message from the above trials is to optimize control of cardiovascular risk factors. Although the goal HbA1c to prevent microvascular and macrovascular complications, per the American Diabetes Association, is less than 7%, hypoglycemia should be avoided as it can increase the risk for severe cardiovascular events.

The Effect of Contact Precautions on Frequency of Hospital Adverse Events.

OBJECTIVE To determine whether use of contact precautions on hospital ward patients is associated with patient adverse events DESIGN Individually matched prospective cohort study SETTING The University of Maryland Medical Center, a tertiary care hospital in Baltimore, Maryland METHODS A total of 296 medical or surgical inpatients admitted to non-intensive care unit hospital wards were enrolled at admission from January to November 2010. Patients on contact precautions were individually matched by hospital unit after an initial 3-day length of stay to patients not on contact precautions. Adverse events were detected by physician chart review and categorized as noninfectious, preventable and severe noninfectious, and infectious adverse events during the patients stay using the standardized Institute for Healthcare Improvements Global Trigger Tool. RESULTS The cohort of 148 patients on contact precautions at admission was matched with a cohort of 148 patients not on contact precautions. Of the total 296 subjects, 104 (35.1%) experienced at least 1 adverse event during their hospital stay. Contact precautions were associated with fewer noninfectious adverse events (rate ratio [RtR], 0.70; 95% confidence interval [CI], 0.51-0.95; P=.02) and although not statistically significant, with fewer severe adverse events (RtR, 0.69; 95% CI, 0.46-1.03; P=.07). Preventable adverse events did not significantly differ between patients on contact precautions and patients not on contact precautions (RtR, 0.85; 95% CI, 0.59-1.24; P=.41). CONCLUSIONS Hospital ward patients on contact precautions were less likely to experience noninfectious adverse events during their hospital stay than patients not on contact precautions.

Concentrated insulins: the new basal insulins

Introduction Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered This review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration.

The cardiovascular effects of insulin

Introduction: Cardiovascular disease remains one of the leading causes of morbidity and mortality in diabetes mellitus. A causal link between insulin, atherosclerosis and cardiovascular risk has been investigated at the basic science level and studied in large clinical trials. Areas covered: The cardiovascular actions of insulin and its role at the level of the endothelium will be reviewed. Cardiovascular outcomes in several large diabetes trials where insulin management was prominent will be summarized. Expert opinion: The vascular actions of insulin are complex and mediated primarily via nitric oxide and endothelin-1. It appears that insulin resistance, rather than hyperinsulinemia itself, increases cardiovascular risk. In fact, hyperinsulinemia in the setting of normal beta cell function protects obese and insulin-resistant individuals from type 2 diabetes. Large clinical trials have supported that insulin management is not associated with increased adverse outcomes. A multifactorial approach targeting modifiable risk factors, including smoking cessation, blood pressure and lipid management, reduces cardiovascular risk. Therapy goals should be individualized and hypoglycemia, especially in individuals receiving insulin management, should be strictly avoided.

Combination of glibenclamide–metformin HCl for the treatment of type 2 diabetes mellitus

Introduction: Combination of glibenclamide (glyburide in the U.S.) and metformin hydrochloride simultaneously addresses two different but complimentary mechanisms to improve glycemic control in type 2 diabetes. Areas covered: The pharmacokinetics, efficacy, and side effect profile of the oral combination of glibenclamide–metformin are reviewed. Expert opinion: Those patients, uncontrolled with single oral agent sulfonylurea or metformin alone, benefit from combination glibenclamide–metformin. There is improvement in fasting plasma glucose, HbA1C, and post-prandial glucose control, and patients are more likely to achieve a HbA1C < 7%. Initiation should be started at the lowest doses and titrated to get the desired effect. Combination therapy allows for reduced pill burden while treating a multifactorial disease by two different mechanisms. Practitioners should be cognizant of risks of hypoglycemia and the theoretical potential for lactic acidosis in the elderly and those with renal impairment. We caution the use of glibenclamide–metformin in patients at risk for cardiovascular disease. Therapy should be individualized, but overall, combination of glibenclamide–metformin should be considered in patients, without renal or cardiovascular impairment, who are not controlled on monotherapy alone. Alternatively, practitioners may want to weigh the efficacy and safety of available dipeptidyl-peptidase-4 inhibitor–metformin combinations to those of glibenclamide–metformin when considering combination therapy.

GLP-1 receptor agonists in the treatment of polycystic ovary syndrome

ABSTRACT Introduction: Polycystic ovarian syndrome (PCOS) affects many women of child-bearing age and is characterized by hyperandrogenism, ovulatory and metabolic dysfunction. A primary treatment goal is weight reduction. The weight loss effects of glucagon-like peptide-1 receptor agonists (GLP-1RA), previously demonstrated in diabetic and obese non-diabetic patients, offer a unique opportunity to expand the medical options available to PCOS patients. Areas covered: Available clinical trials of glucagon-like peptide-1 receptor agonist therapy in PCOS were reviewed. Literature was searched from PubMed using appropriate search terms up to November 2016. Expert commentary: The available studies of GLP-1 RA therapy in the treatment of excess body weight in women with PCOS demonstrate that exenatide and liraglutide are effective in weight reduction either as monotherapy or in combination with metformin. A few studies showed that androgens may be modestly decreased and menstrual frequency may be increased. Eating behavior may be improved with liraglutide therapy. Glucose parameters are generally improved. GLP-1RAs were well-tolerated, with nausea being the most significant adverse side effect. Barriers to utilization may be the short duration studies, lack of familiarity of the medication, the route of administration (injection) and the variable outcomes on ovulation and hyperandrogenism.

Diabetes type 2 management: what are the differences between DPP-4 inhibitors and how do you choose?

Type 2 diabetes mellitus (T2DM) is characterized by progressive beta cell dysfunction and insulin resistance. Pharmacotherapy to treat dysregulated glucose metabolism focuses on augmenting the insulin response to hyperglycemia, improving insulin sensitivity or altering glucose disposal through the gut or urine. Dipeptidyl-peptidase-4 (DPP-4) inhibitors or ‘gliptins’ block the inactivation of glucagon-like peptide-1 (GLP-1), which stimulates glucose-dependent insulin secretion and inhibits glucagon secretion. Additionally, gastric emptying is slowed, satiety is improved, and food intake is reduced [1]. These effects are more prominent with use of GLP-1 receptor agonists. There are five DPP-4 inhibitors, including alogliptin, linagliptin, saxagliptin, and sitagliptin in the United States and Europe and vildagliptin which is only available in Europe (Table 1). This class of anti-hyperglycemic therapy is orally administered once per day with the exception of vildagliptin which is dosed twice per day. DPP-4 inhibitors can be taken without regard to food. DPP-4 inhibitors are not recommended for use as initial monotherapy for T2DM treatment [3]. They are most commonly prescribed in combination with lifestyle modification and metformin, sulfonylureas, thiazolidinediones, and/or basal insulin, but select patients intolerant to metformin have been successfully treated with DPP-4 inhibitor monotherapy. There are a number of combination products available, including gliptin–metformin and gliptin–sodium glucose transporter-2 inhibitor products. There is a paucity of direct head-to-head studies of DPP-4 inhibitors. Most comparisons are indirect. Evaluation of singular beneficial effects have been published, such as effects on cholesterol, and attributed to one particular drug within the class; however, it is reasonable to consider that these effects may be applicable across the class of medications.