Jennifer D. Goldman-Levine

Insulin Detemir—A New Basal Insulin Analog

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, adverse effects, and role in therapy of insulin detemir. DATA SOURCES: Articles and meeting abstracts were identified through searches of MEDLINE (1996–June 2004), EMBASE (1980–June 2004), and International Pharmaceutical Abstracts (1970–June 2004) databases, and unpublished information was provided by the manufacturer. STUDY SELECTION AND DATA EXTRACTION: All available studies relating to insulin detemirs pharmacology were selected. Only human studies were used for pharmacokinetic, drug interaction, efficacy, and safety data. DATA SYNTHESIS: Insulin detemir is a basal insulin analog that has been shown to improve glycemic control in patients with type 1 and type 2 diabetes. CONCLUSIONS: Insulin detemir offers some benefits over NPH for use as basal insulin in patients with type 1 and type 2 diabetes.

Beyond Metformin: Initiating Combination Therapy in Patients with Type 2 Diabetes Mellitus

The majority of patients with type 2 diabetes mellitus will eventually require combination therapy involving two or more agents to achieve their glycemic target as their disease progresses. This review contrasts current treatment guidelines and recommendations by the American Diabetes Association and the European Association for the Study of Diabetes (referred to as ADA) and the American Association of Clinical Endocrinologists and American College of Endocrinology (referred to as AACE) for the initiation of combination therapy. Both treatment guidelines emphasize that treatment selection for patients with type 2 diabetes should be guided by the goal of lowering hemoglobin A1c (A1C) level and individualizing therapy to each patient based on clinical factors and comorbidities. In addition, combination therapy should include classes of drugs with complementary mechanisms of action that efficiently and effectively target the underlying type 2 diabetes pathophysiology. Both the ADA and AACE recommend metformin as a firstline oral agent; however, the ADA supports early use of sulfonylureas or insulin in patients who do not reach their target A1C goal, whereas the AACE recommends earlier and more frequent use of the newer incretin agents—glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors. Mechanisms of action, benefits, and risks of traditional and newer agents are discussed to better enable the pharmacist to recommend the best combinations of agents for individual patients.

Dramatic Worsening of Type 2 Diabetes Mellitus Due to Olanzapine After 3 Years of Therapy

Olanzapine, a serotonin‐dopamine‐receptor antagonist, is an atypical antipsychotic agent used to treat schizophrenia and other psychotic disorders. It is preferred over older antipsychotics because of its relatively low frequency of sedation, orthostatic hypotension, extrapyramidal symptoms, and anticholinergic side effects. A 45‐year‐old man with well‐controlled type 2 diabetes mellitus experienced an abrupt worsening of his diabetes after 3 years of olanzapine therapy. His hemoglobin A1c (HbA1c) level rose from a baseline of 5.9–6.2% to 12.5%. Discontinuation of olanzapine by means of a 3‐month taper resulted in a reduction in HbA1c to pretreatment levels. Although cases of olanzapine‐induced hyperglycemia have been documented in the literature, this complication has not been reported in a patient maintained on therapy for this duration. Clinicians should be aware of this possible complication in patients receiving long‐term olanzapine therapy.

Insulin Degludec: A Novel Basal Insulin Analogue

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, adverse effects, and potential role in therapy of insulin degludec. DATA SOURCES: Articles were identified using the MEDLINE database (January 1996-December 2012). Abstracts and posters were identified from respective congressional websites and published supplements of the American Diabetes Association, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists (January 2008-December 2012). Clinicaltrials.gov was used to identify any ongoing clinical trials or completed trials whose results had not been presented or published. STUDY SELECTION AND DATA EXTRACTION: All available studies were reviewed for inclusion; pharmacokinetic studies were limited to those reporting human data. DATA SYNTHESIS: Insulin degludec is a novel, ultra-long-acting basal insulin analogue that has a similar safety and efficacy profile when compared with insulin glargine in patients with type 1 or type 2 diabetes. Clinical trials have indicated that there is less hypoglycemia, particularly nocturnal hypoglycemia, associated with this agent. CONCLUSIONS: If insulin degludec is approved, it may offer an alternative basal insulin for patients needing more flexible dosing, having a history of nocturnal hypoglycemia, or those with severe insulin resistance needing a higher concentration of basal insulin.

Insulin Glargine and Cancer Risk: An Opinion Statement of the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy

Diabetes mellitus has reached epidemic proportions worldwide, eliciting extensive research on both the disease process and its treatment. Regardless of diabetes type, the progressive nature of the disease makes insulin the long‐term mainstay of diabetes management. Recently, the insulin analog glargine was reported in several epidemiologic studies to be associated with an increased risk of cancer. Inconsistent study results and media attention have caused much angst and concern to health care professionals and the general population. A clear understanding of the current evidence is needed to adequately develop a patient‐oriented risk:benefit assessment. Members of the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy evaluated available evidence to provide guidance and discussion on the risk of cancer with insulin glargine use. We believe the current link between insulin glargine and cancer is tenuous but merits further evaluation. An independent analysis of all available glargine clinical trial data should be performed, and a vigorous postmarketing safety study of glargine should be conducted. Until more substantial data are available, however, neither the choice of initial insulin therapy nor insulin maintenance regimens should be influenced by the current information linking insulin glargine to cancer.

Combination Therapy When Metformin Is Not an Option for Type 2 Diabetes

Objective: Consensus on combination options for patients with type 2 diabetes mellitus (T2DM) unable to use metformin is lacking. This review summarizes data describing–non-metformin based combination therapy. Data Sources: PubMed searches (January 1990 to August 2014) were conducted with terms for newer drug therapies alone and with the term combination; filters were applied for Clinical Trial, Meta Analysis, and English language. Study Selection and Data Extraction: Results were reviewed for multicenter, randomized controlled trials of non-metformin–based combination therapy conducted in the past 5 years and specific to the US or multinational populations. Data Synthesis: Although multiple injectable and oral agents have been studied in combination with metformin for management of T2DM, data are more limited for combinations without metformin. Combinations of incretins (injectable glucagon-like peptide-1 receptor agonists or oral dipeptidyl peptidase-4 [DPP-4] inhibitors) with a sulfonylurea, thiazolidinedione, or insulin are well studied and provide greater glucose-lowering efficacy than monotherapy. Incretins are associated with a low risk of hypoglycemia when used as monotherapy; the dosage of sulfonylurea or insulin should be reduced when used in combination. Newer studies are investigating the combined use of an oral sodium-glucose cotransporter 2 inhibitor and a DPP-4 inhibitor. In a recent study, reductions in glycated hemoglobin (A1C) of 1.1% to 1.2% and reduced weight with no additive risk of hypoglycemia were observed. Conclusions: Selecting the most appropriate combination therapy for patients with T2DM requires balancing clinical benefits with the risks, such as weight gain and hypoglycemia. Treatment approaches should be individualized for vulnerable patient populations for whom metformin is not appropriate.

Aripiprazole: An Antipsychotic with a Novel Mechanism of Action

Objective: To evaluate aripiprazole in the treatment of schizophrenia, including a comparison of available agents, pharmacology, pharmacokinetics, assessment of clinical trials, and adverse effects. Data Sources: A MEDLINE search (1962–March 2003) was conducted for primary and secondary sources. Search terms included OPC-14597, aripiprazole, typical antipsychotics, atypical antipsychotics, and schizophrenia. The Review and Evaluation of Clinical Data from NDA 21-436 was accessed from the FDA Web site. Study Selection: All articles retrieved were evaluated, and the most appropriate studies were selected. Relevant poster presentations were included. Data Synthesis: Aripiprazole is a potent partial agonist/antagonist at the dopamine D2 receptor, as well as a partial agonist at the serotonin 5-HT1A receptor and an antagonist at the 5-HT2A receptor. Clinical trials were assessed for information on dosing, side effects, and adverse drug reactions. Conclusions: Aripiprazole appears to be superior to placebo for the treatment of schizophrenia, with a favorable adverse effect profile.

Breaking Down Barriers A Second Attempt at Inhaled Insulin

Basal-bolus insulin is required for all patients with type 1 diabetes mellitus (T1DM), and the progressive nature of type 2 diabetes mellitus (T2DM) often leads to patients requiring basal insulin, bolus insulin, or both to meet glycemic targets. Until recently, exogenous insulin could only be delivered via injection using a syringe, an insulin pen, or an insulin pump. A new ultra-rapid acting insulin delivered via Technosphere Insulin Inhalation Powder (TI) (Afrezza, MannKind, Valencia, CA) was approved by the United States (US) Food and Drug Administration (FDA) on June 27, 2014. It will be manufactured by MannKind and marketed by Sanofi. TI provides patients and providers with a non-injectable option for bolus insulin needs. This is the second inhaled insulin to come to the US marketplace after a failed inhaled formulation of human insulin (Exubera, Pfizer, New York, NY). Some of the limitations of the earlier inhaler that BREAKING DOWN BARRIERS: A Second Attempt at Inhaled Insulin

Past, Present, and Future Research Avenues for Metformin A Literature Review

Objective: To review why metformin is considered first-line therapy for type 2 diabetes mellitus (T2DM) and review newer avenues of research currently being evaluated. Data Sources: The Cochrane Library and Medline (to January 2014) were searched for case–control and cohort studies, clinical trials, and systematic reviews and meta-analyses involving metformin for any indication. Study Selection and Data Extraction: The literature search found 5 major avenues of research for metformin: reduction in mortality, delayed-onset or prevention of T2DM in the presence of prediabetes, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS), and decreased cancer risk. When available, multi-center, double-blind, controlled clinical trials or meta-analyses thereof were selected for review. If these types of studies did not exist, other types of studies were chosen for review. Data Synthesis: Metformin significantly decreases all-cause and diabetes-related mortality in overweight and obese patients with T2DM. It may also decrease risk of progression to T2DM in patients with prediabetes. Metformin has been studied for the treatment of NAFLD though data are limited. Metformin alone or combined with clomiphene may increase pregnancy and ovulation rates but has not yet been shown to increase live-birth rates in patients with PCOS. Metformin may decrease risk of colorectal cancer but not all-cancer risk. Conclusions: Metformin’s clinical role in T2DM and prediabetes is well established. Other avenues of research being evaluated at this time are NAFLD, PCOS, and reduced risk of cancer; more data are needed before it has a clinical role in these indications.

Metformin and Vitamin B-12 (Cyancobalamin) Deficiency

Metformin (Glucophage) is first-line therapy for type 2 diabetes (T2D) that has improved the prognosis of many patients. Although its exact mechanism of action is unknown, metformin helps improve insulin sensitivity and is associated with decreased cardiovascular morbidity and mortality. Metformin is generally well tolerated but has a less recognized adverse effect of malabsorption of vitamin B-12. Vitamin B-12 is a water-soluble essential vitamin, which is vital for both normal red blood cell function, DNA synthesis, and neurological function. It has been estimated that 10% to 30% of patients with T2D on metformin will develop evidence of B-12 deficiency. This article will review the identification and incidence of metformin-induced vitamin B-12 deficiency and its treatment.