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.

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.

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.

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 A(1c) (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.

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.

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 detemir's 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.