R. Keith Campbell

Metformin hydrochloride in the treatment of type 2 diabetes mellitus: a clinical review with a focus on dual therapy.

BACKGROUND Type 2 diabetes mellitus typically involves abnormal beta-cell function that results in relative insulin deficiency, insulin resistance accompanied by decreased glucose transport into muscle and fat cells, and increased hepatic glucose output, all of which contribute to hyperglycemia. OBJECTIVE This review examines the pharmacology, pharmacokinetics, drug-interaction potential, adverse effects, and dosing guidelines for metformin hydrochloride, a biguanide agent for the treatment of type 2 diabetes. Clinical trial data are reviewed, including efficacy and tolerability information, with a focus on studies of dual metformin therapy (metformin plus another oral agent or insulin) published from 1998 to the present. Pharmacoeconomic considerations are also discussed. METHODS Primary research and review articles were identified through a search of MEDLINE (1966-May 2003) and International Pharmaceutical Abstracts (1970-May 2003) using the terms metformin and/or Glucophage. Web of Science (1995-May 2003) was used to search for additional abstracts. The package inserts for metformin and metformin combination products were consulted. All identified articles and abstracts were assessed for relevance, and all relevant information was included. Priority was given to the primary medical literature and clinical trial reports. RESULTS Metformin is the only currently available oral antidiabetic/hypoglycemic agent that acts predominantly by inhibiting hepatic glucose release. Because patients with type 2 diabetes often have excess hepatic glucose output, use of metformin is effective in lowering glycosylated hemoglobin (HbA1c) by 1 to 2 percentage points when used as monotherapy or in combination with other blood glucose-lowering agents or insulin. Other metabolic variables (eg, dyslipidemia, fibrinolysis) may be improved with the use of metformin. Body weight is often maintained or slightly reduced from baseline. Metformin is well tolerated and is associated with few clinically deleterious adverse events. The most important and potentially life-threatening adverse event associated with its use is lactic acidosis, which occurs very rarely. CONCLUSIONS Metformin has multiple benefits in patients with type 2 diabetes. It can effectively lower HbA1c values, positively affect lipid profiles, and improve vascular and hemodynamic indices. Adverse effects are generally tolerable and self-limiting. The availability of products combining metformin with a sulfonylurea or rosiglitazone has expanded the array of therapies for the management of type 2 diabetes.

Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus.

The kidney plays a major role in glucose homeostasis because of its role in gluconeogenesis and the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. Approximately 180 g of glucose is filtered daily in the glomeruli of a normal healthy adult. Typically, all of this glucose is reabsorbed with <1% being excreted in the urine. The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium-glucose co-transporters (SGLTs). SGLTs encompass a family of membrane proteins that are responsible for the transport of glucose, amino acids, vitamins, ions and osmolytes across the brush-border membrane of proximal renal tubules as well as the intestinal epithelium. SGLT2 is a high-capacity, low-affinity transporter expressed chiefly in the kidney. It accounts for approximately 90% of glucose reabsorption in the kidney and has thus become the focus of a great deal of interest in the field of diabetes mellitus.SGLT2 inhibitors block the reabsorption of filtered glucose leading to glucosuria. This mechanism of action holds potential promise for patients with type 2 diabetes mellitus (T2DM) in terms of improvements in glycaemic control. In addition, the glucosuria associated with SGLT2 inhibition is associated with caloric loss, thus providing a potential benefit of weight loss. Dapagliflozin is the SGLT2 inhibitor with the most clinical data available to date, with other SGLT2 inhibitors currently in the developmental pipeline. Dapagliflozin has demonstrated sustained, dose-dependent glucosuria over 24 hours with once-daily dosing in clinical trials. Although long-term safety data are lacking, studies to date have generally found dapagliflozin to be safe and well tolerated. Concerns related to SGLT2 inhibition include the fact that by their very nature they cause glucose elevation in the urine that can theoretically lead to urinary tract and genital infections, electrolyte imbalances and increased urinary frequency. Although studies to date have been promising in terms of these and other concerns, longer-term studies evaluating the usual safety and efficacy outcomes will need to be conducted. Similarly, head-to-head comparator trials are needed to determine the role of SGLT2 inhibitors in relation to the many other therapeutic options available for the treatment of T2DM. If significant reductions in haemoglobin Alc are associated with SGLT2 inhibitor therapy, and these agents are determined to be safe and well tolerated in the long term, they could become a major breakthrough in the T2DM treatment armamentarium.

Type 2 diabetes: where we are today: an overview of disease burden, current treatments, and treatment strategies.

OBJECTIVE To provide an overview of the disease burden and current strategies in the treatment of patients with type 2 diabetes. DATA SOURCES Medline search of all relevant clinical and review articles. STUDY SELECTION By the author. DATA EXTRACTION By the author. DATA SYNTHESIS The prevalence of diabetes in the United States has reached epidemic proportions with the total diagnosed and undiagnosed cases among people aged 20 years or older estimated at 12.9%, and it continues to rise at an alarming rate. This upsurge has been paralleled by an increase in rates of obesity. Type 2 diabetes accounts for up to 95% of diabetes cases and is often comorbid with hypertension and dyslipidemia. CONCLUSION Tight glycemic control is necessary for the management of type 2 diabetes, but progressive deterioration of beta-cell function can lead to a loss of glycemic control. Oral antidiabetes drugs and insulin are effective but do not always correct the associated metabolic and glucoregulatory dysfunctions, and hypoglycemia and weight gain are common adverse effects of these agents. A clear need exists for aggressive therapeutic options-particularly incretin-based agents-that can be combined with existing agents to preserve beta-cell function and halt the progression of type 2 diabetes.

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

Type 2 diabetes mellitus traditionally has been characterized by insulin resistance and β‐cell dysfunction, leading to hyperglycemia and eventual micro‐ and macrovascular complications. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a relatively new class of drugs available for the management of type 2 diabetes. In order to provide a comprehensive evaluation and comparison of the pharmacology, pharmacokinetics, efficacy, and safety of the DPP‐4 inhibitors—sitagliptin, vildagliptin, saxagliptin, and alogliptin—in the treatment of type 2 diabetes, we conducted a MEDLINE search (1966–July 2009) for pertinent English‐language articles. Abstracts of the annual meetings of the American Diabetes Association and European Association for the Study of Diabetes from 2005–2009 were also searched. As a drug class, the DPP‐4 inhibitors have become widely accepted in clinical practice because of their low risk of hypoglycemia, favorable adverse‐effect profile, and once‐daily dosing. They are weight neutral (do not cause weight gain or loss) and appear to decrease β‐cell apoptosis and increase β‐cell survival. Because clinical studies directly comparing agents from this class have not, to our knowledge, been conducted, making comparisons in terms of efficacy and safety will become difficult for clinicians as more agents become available. Based on information from preclinical, clinical, and postmarketing data, there does not appear to be a compelling advantage of one DPP‐4 inhibitor over another in terms of efficacy, safety, or ease of clinical use. Although theoretical advantages exist for agents with a higher specificity for DPP‐4 inhibition versus inhibition of other isoenzymes associated with toxicity comparative studies and/or increased clinical experience with this class of drug will determine the clinical advantages, if any, of one agent over another.

Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus.

BACKGROUND Glucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes. OBJECTIVES The aim of this article was to review incretin physiology and studies of incretin therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors that were developed to specifically address the blunted incretin response in patients with T2DM. METHODS Relevant English-language publications between 1995 and 2010 were identified through a search of the MEDLINE and EMBASE databases using the search terms incretin, type 2 diabetes mellitus, GLP-1, glucose-dependent insulinotropic polypeptide, and DPP-4. Review articles and preclinical and clinical trials that described relevant details of the epidemiology of diabetes and incretin physiology in health and in T2DM were selected for review and inclusion. Clinical trials were used to describe the clinical efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. An occasional systematic review article and/or meta-analysis summarizing numerous clinical trials of a particular agent was selected for summarizing key data. RESULTS Pharmacologic modulation of incretin pathophysiology by GLP-1 receptor agonists and DPP-4 inhibitors significantly improved glycemic control, benefited β-cell function, improved dyslipidemia, and lowered the risk of hypoglycemia compared with insulin and sulfonylureas. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produced weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The most common adverse events with GLP-1 receptor agonist therapy included nausea (28%-44%), vomiting (13%-17%), and diarrhea (11%-17%), which generally reduced in incidence and severity with continued therapy. The tolerability profile of the DPP-4 inhibitors was very good, with the incidence of adverse events similar to that of placebo. There was a suggestion of an increased incidence of nasopharyngitis versus placebo (5%-6% vs 3%-4%) with sitagliptin and urinary tract infection (6.8% vs 6.1% with placebo) and headache with saxagliptin (6.5% vs 5.9% with placebo). CONCLUSION The 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term β-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined.

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.

Magnesium and Diabetes: A Review

OBJECTIVE: To discuss the potential link between diabetes mellitus (DM) and Hypomagnesemia, the methods used to assess magnesium status, and the potential benefits of magnesium repletion in hypomagnesemic patients with DM. DATA SOURCES: A MEDLINE search (key terms: magnesium and diabetes) was conducted to identify pertinent literature. STUDY SELECTION: All major clinical trials and most published case reports were reviewed. SYNTHESIS: Several studies have demonstrated a higher than expected frequency of magnesium deficiency in patients with DM. Hypomagnesemia may play a role in the development of retinopathy, altered glucose disposition, hypertension, abnormal platelet function, and other problems frequently observed in patients with DM. The lack of a widely available, accurate screening methodology is one of the main problems in assessing total body magnesium status. One study has suggested that hypomagnesemia in patients with DM may be related to enhanced urinary loss of magnesium. Several studies evaluating hypomagnesemia and glucose disposal have suggested a direct correlation between magnesium concentration and glucose disposal, with an improvement in glucose disposal with magnesium supplementation. It has been suggested that there is a relationship between hypomagnesemia and diabetic retinopathy; however, the effect of magnesium supplementation on the development of diabetic retinopathy has not been evaluated. Researchers evaluating the effect of magnesium on platelet aggregation have suggested that magnesium supplementation may reduce the incidence of vascular disease in hypomagnesemic patients with DM. Several studies have demonstrated a correlation between hypomagnesemia and hypertension. CONCLUSIONS: Studies have suggested a link between hypomagnesemia and hyperglycemia, as well as an association between hypomagnesemia and the complications of DM. The American Diabetes Association has published a consensus statement suggesting that patients who have documented hypomagnesemia and DM receive magnesium supplementation.

Glimepiride: Role of a New Sulfonylurea in the Treatment of Type 2 Diabetes Mellitus

OBJECTIVE: To review the clinical pharmacology data regarding the sulfonylurea glimepiride, and to summarize the clinical trials of glimepiride efficacy and safety alone and in combination with insulin for the treatment of type 2 diabetes mellitus. DATA SOURCES: A MEDLINE database search (English language, January 1985–April 1997) was performed to identify relevant published articles, including reviews and abstracts; the manufacturer (Hoechst Marion Roussel, Kansas City, MO) provided unpublished data. STUDY SELECTION: Pharmacology information was taken from representative original research articles. Eight clinical studies were selected for analysis on the basis of large enrollment, appropriate study design, and publication of results. DATA EXTRACTION: All clinical trials, published and unpublished, were reviewed. DATA SYNTHESIS: Glimepiride is a sulfonylurea that is pharmacologically distinct from other sulfonylureas because of differences in receptor-binding properties and potentially selective effects on ATP-sensitive K+ channels. The pharmacokinetic and pharmacodynamic profile of glimepiride makes it suitable for once-daily dosing. The safety and efficacy of glimepiride have been confirmed in studies involving more than 5000 patients with type 2 diabetes. In one study, once-daily doses of 1–8 mg reduced fasting plasma glucose from baseline by 43–74 mg/dL more than did placebo (p < 0.001), and hemoglobin (Hb) A1C values decreased by 1.2–1.9% more than with placebo (p < 0.001). Two-thirds of patients achieved tight control (i.e., HbA1C ≤ 7.2%). Glimepiride was as effective as second-generation sulfonylureas. The most common adverse events were dizziness and headache, but no single adverse event occurred in more than 2% of patients. CONCLUSIONS: Glimepiride appears to be a useful option for patients with type 2 diabetes not controlled by diet and exercise and who want to achieve tight glucose control. Glimepiride can be used alone, in combination with other antihyperglycemic agents, or in patients with secondary sulfonylurea failure, as an adjunct to insulin therapy.

Phosphodiesterase 5 Inhibitors for Erectile Dysfunction

OBJECTIVE To review the pharmacologic and clinical trial data of the Food and Drug Administration–approved phosphodiesterase 5 (PDE5) inhibitors for the treatment of erectile dysfunction (ED). DATA SOURCES Primary research and review articles were identified through a search of ScienceDirect, PubMed/MEDLINE, and International Pharmaceutical Abstracts (1990–August 2004). The following search terms were used in the Medicine Dentistry and Pharmacology, Toxicology, and Pharmaceutical Sciences subcategories: phosphodiesterase 5 inhibitor, PDE5 inhibitor, erectile dysfunction, sildenafil, vardenafil, tadalafil, prostatectomy, and diabetes. Web of Science (1990–August 2004) was used to search for additional abstracts using the same search terms as above. The package inserts for sildenafil, vardenafil, and tadalafil were also consulted. STUDY SELECTION AND DATA EXTRACTION All identified research, review articles, and abstracts were assessed for relevance, and all relevant information was included. Priority was given to the primary medical literature and clinical trial reports. DATA SYNTHESIS ED is a common disorder in males with increased prevalence associated with age and presence of cardiovascular disease, prostatectomy, or diabetes mellitus. Sildenafil, vardenafil, and tadalafil are selective PDE5 inhibitors currently available for treatment of ED. Their pharmacology and pharmacokinetics vary slightly, but with potentially important clinical differences in duration of activity; all have similar clinical efficacy and adverse effect profiles in patients with ED of various causes. CONCLUSIONS Sildenafil, vardenafil, and tadalafil are safe and effective PDE5 inhibitors for the treatment of ED.

Miglitol: Assessment of its Role in the Treatment of Patients with Diabetes Mellitus

OBJECTIVE: To evaluate miglitol, a new oral α-glucosidase inhibitor, and discuss its pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy. DATA SOURCES: A MEDLINE English-language only database search using the keywords miglitol, glyset, and Bay m 1099 (1985 to December 1999), was completed to identify relevant articles including reviews, recent studies, and abstracts; American Diabetes Association 1999 Annual Meeting abstracts; Pharmacia & Upjohn data on file and product information. STUDY SELECTION: The clinical trials that were selected to be reviewed in detail were randomized, double-blind studies with at least 100 patients in the intention-to-treat group. DATA EXTRACTION: All articles and abstracts were reviewed along with the product labeling from Pharmacia & Upjohn. DATA SYNTHESIS: Miglitol is an α-glucosidase inhibitor that exerts its effect through the delayed absorption of complex carbohydrates in the small intestine, resulting in a decrease in postprandial glucose concentrations that are directly correlated with the dietary carbohydrate content. Both small, short-term trials and large, clinical trials show a decrease in postprandial glucose concentrations and a modest decrease in glycosylated hemoglobin of approximately 0.5–1.0% as a result of miglitols action. The adverse effects of miglitol are mild and transitory and include flatulence, diarrhea, and abdominal pain. The incidence of gastrointestinal problems may be reduced with a small initial dose, which is slowly titrated as tolerated. CONCLUSIONS: Miglitol is an effective and safe treatment option in patients with type 2 diabetes mellitus who are inadequately controlled with diet or oral sulfonylurea therapy. Miglitol is a good choice of therapy in Hispanic, African-American, and elderly patients, or any patients in whom hypoglycemia, weight gain, or lactic acidosis are risks. No published studies comparing miglitol with acarbose have been published, but there appears to be no major clinical or financial advantages to using one agent over the other.