Sum Lam

Sitagliptin: a novel drug for the treatment of type 2 diabetes.

Type 2 diabetes mellitus is a common chronic disease that causes significant morbidity and mortality worldwide. The primary goal of treatment is to target glycemic control by maintaining the glycosylated hemoglobin level near 6–7% without predisposing patients to hypoglycemia. Diabetes results from a combination of increased hepatic glucose production, decreased insulin secretion from beta cells, and insulin resistance in the peripheral tissues. Currently available antidiabetic agents work by different mechanisms to lower blood glucose levels. Unfortunately, each of them has its tolerability and safety concerns that limit its use and dose titration. Sitagliptin is the first antidiabetic agent from the class of dipeptidyl peptidase-4 enzyme inhibitors.31 It increases the amount of circulating incretins, which stimulate insulin secretion and inhibit glucose production. Sitagliptin was approved by the US Food and Drug Administration (FDA) for use with diet and exercise to improve glycemic control in adult patients with type 2 diabetes. It can be used alone or in combination with metformin or a thiazolidinedione (pioglitazone or rosiglitazone) when treatment with either drug alone provides inadequate glucose control. The usual adult dose is 100 mg once daily. A dose of 25–50 mg once daily is recommended for patients with moderate-to-severe renal impairment. In randomized, placebo-controlled trials that lasted for up to 6 months, sitagliptin lowered glycosylated hemoglobin levels by 0.5–0.8%. In a 52-week clinical trial, sitagliptin was shown to be noninferior to glipizide as an add-on agent in patients inadequately controlled on metformin alone. Sitagliptin was well tolerated with the most common side effects being gastrointestinal complaints (up to 16%), including abdominal pain, nausea and diarrhea; hypoglycemia and body weight gain occurred at similar rates compared with placebo. Overall, sitagliptin provides a treatment option for patients with type 2 diabetes as a monotherapy, or as an adjunct to metformin or a thiazolidinedione when patients achieve inadequate glycemic control while on either of the agents. It is also an alternative therapy for those patients who have contraindications or intolerability to other antidiabetic agents.

Varenicline: a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist approved for smoking cessation.

Tobacco smoking remains a significant health problem in the United States. It has been associated with staggering morbidity and mortality, specifically due to malignancies and cardiovascular disease. Smoking cessation can be difficult and frequently requires pharmacologic interventions in addition to nonpharmacologic measures. Previously available agents are nicotine replacement products and bupropion, which increased quit rates by about 2-fold compared with placebo. Varenicline is the first drug in a new class known as the selective α4β2 nicotinic receptor partial agonists. In several randomized, double-blind, 52-week clinical trials involving healthy chronic smokers, varenicline demonstrated superiority to placebo and bupropion in terms of efficacy measures. Additionally, it improved tobacco withdrawal symptoms and reinforcing effects of smoking in relapsed patients. Patients should start therapy in combination with tobacco cessation counseling 1 week before quit date and continue the regimen for 12 weeks. The dose of varenicline should be titrated to minimize nausea. The recommended dosage is 0.5 mg once daily (QD) on days 1–3; titrate to 0.5 mg twice daily (BID) on days 4–7; and 1 mg BID starting on day 8. An additional 12-week maintenance therapy may be considered for those who achieve abstinence. The most common side effects are nausea (30%), insomnia (18%), headache (15%), abnormal dreams (13%), constipation (8%), and abdominal pain (7%). Overall, varenicline is a breakthrough in the management of tobacco addiction and has demonstrated good efficacy in motivated quitters. It also provides an option for smokers who cannot tolerate other pharmacologic interventions.

Emerging Therapies for the Treatment of Helicobacter pylori Infections

Objective: To describe emerging therapies, such as levofloxacin, moxifloxacin, rifabutin, rifaximin, tinidazole, doxycycline, minocycline, lactoferrin, and plaunotol for the eradication of Helicobacter pylori infection. Data Sources: Relevant information was identified through a search of MEDLINE (1966–July 2008), PubMed (1955–July 2008), American Search Premier (1975–July 2008). International Pharmaceutical Abstracts (1960–2008), Science Citation Index Expanded (1996–2008), Cochrane Databases (publications archived until July 2008), and various tertiary sources using the terms Helicobacter pylori, fluoroquinolones, levofloxacin, moxifloxacin, rifabutin, rifaximin, lactoferrin, plaunotol, tinidazole, doxycycline, minocycline, faropenem, new treatments, refractory, and salvage alone or in combination. Study Selection and Data Extraction: Relevant information was identified and selected based on clinical relevance and value of information. In vitro and in vivo data were included if available. Data Synthesis: Data exist supporting the use of levofloxacin or rifabutin as salvage therapies for H. pylori infection. Levofloxacin triple therapy has been recommended in the current treatment guideline, but more data are needed, especially from studies conducted in the US. A rifabutin-based regimen is better tolerated than conventional quadruple therapy, but its use is limited due to cost, hematologic adverse effects, drug interactions, and predicted development of resistance. Tinidazole appears to be an option, particularly as sequential therapy when combined with other agents; however, its use is limited by the high prevalence ot nitroimidazole-resistant H. pylori strains in the US. Moxifloxacin data are limited. Data supporting the use of rifaximin, doxycycline, and minocycline are lacking or do not show benefit of these drugs over standard treatments. Conclusions: H. pylori infection remains one of the most significant infections worldwide, and treatment failure rate with the current standard therapy continues to rise. Other treatment options should be explored to meet the emerging challenge.

Aliskiren: an oral renin inhibitor for the treatment of hypertension.

Hypertension is a common chronic disease that leads to significant cardiovascular morbidity and mortality worldwide. Blood pressure control is critical in reducing the end-organ complications, such as stroke, myocardial infarction, heart failure, or kidney disease. Currently available antihypertensive agents work by different mechanisms to reduce blood pressure. Aliskiren, a novel direct renin inhibitor, lowers blood pressure by decreasing renin activity, and angiotensin I and II levels. At the approved dosage (150–300 mg once daily), it reduces systolic blood pressure by 12–16 mm Hg and diastolic blood pressure by 2–12 mm Hg. In studies its efficacy was comparable to losartan 100 mg, irbesartan 150 mg, and valsartan 80–320 mg. When used adjunctively with ramipril, an angiotensin-converting enzyme (ACE) inhibitor, valsartan, an angiotensin II receptor blocker (ARB), or hydrochlorothiazide, a diuretic, it provides additional blood pressure reduction compared with placebo or monotherapy. Aliskiren is well tolerated, with the most common side effects being gastrointestinal symptoms, fatigue, weakness, and headache. In short-term clinical trials, aliskiren caused fewer disturbances in potassium levels when compared with hydrochlorothiazide, ACE inhibitors and ARBs. Long-term data on morbidity and mortality outcomes are not currently available, thus it is unknown whether aliskiren would join ACE inhibitors and ARBs as the preferred hypertensive agents for end organ protection. At this time, aliskiren should be considered as an alternative agent for mild-to-moderate hypertension, or as an adjunctive therapy when preferred agents fail to maintain optimal blood pressure control. It is also an option for those patients who have contraindications or intolerability to other antihypertensive agents, including dry cough induced by ACE inhibitors.

Exenatide: a novel incretin mimetic agent for treating type 2 diabetes mellitus.

Maintaining glycemic control is the primary goal for preventing macrovascular and microvascular complications associated with type 2 diabetes. Currently available antidiabetic drugs work in different ways to lower blood glucose levels; unfortunately, each of them has its tolerability and safety concerns. Exenatide is the first drug in a new class known as the incretin mimetic agents. It improves glucose control by mimicking the effects of glucagon-like peptide-1, a natural mammalian incretin hormone secreted during food intake. Exenatide was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in conjunction with metformin and/or sulfonylurea. The recommended dosage is 5 &mgr;g to 10 &mgr;g twice daily subcutaneously before breakfast and dinner. In randomized, placebo-controlled, 30-week clinical studies, exenatide improved glycemic control and promoted weight loss of up to 2.8 kg. The most common adverse effects were nausea (44%), vomiting (13%), diarrhea (13%), and hypoglycemia (5–36%). Hypoglycemia occurred in a dose-dependent fashion. Patients should be closely monitored for hypoglycemia, especially when exenatide is added to sulfonylurea therapy. Overall, exenatide provides a treatment option for patients with type 2 diabetes who fail to obtain glycemic control while on a maximum dose of metformin and/or sulfonylurea therapy. It is also an alternative therapy for those patients who cannot tolerate other antidiabetic drugs.

Disease Modifying Agents for Multiple Sclerosis

Objective: To summarize major clinical trials which evaluate the efficacy and safety data of approved disease modifying agents for the treatment of various types of multiple sclerosis. Data Sources: A MEDLINE (1966 to August 2008) search of clinical trials using the terms multiple sclerosis, interferon, glatiramer, mitoxantrone and natalizumab was performed. A manual bibliographic search was also conducted. English-language articles identified from the searches were evaluated. New agents under investigation in phase 3 clinical trials were identified using www.clinicaltrials.gov. Study Selection & Data Extraction: Relevant information was identified and selected based on clinical relevance and evidence-based strength. Prescribing information leaflets were used to provide usual dosage, contraindications, precautions, monitoring parameters and other relevant drug-specific information. Data Synthesis: Interferon beta products are more efficacious for the treatment of relapsing-remitting multiple sclerosis. Interferon beta 1-b also delayed the time to diagnosis of definite multiple sclerosis and reduced brain lesion burden in patients with clinical isolated syndrome. Glatiramer and natalizumab have both established efficacy in relapsing forms of multiple sclerosis; whereas mitoxantrone is more commonly used in patients with advanced disease. There are limited data the comparative efficacy among different disease modifying agents. New agents currently under investigation have showed promising results and may offer more treatment options in the future. Conclusions: MS is a complex and devastating disease with challenging treatment considerations and approaches. Interferon beta products continue to be the mainstay of therapy in many patients, however, other treatments are proving to be at least as effective in the management of various types of MS. Newer compounds are being developed and studied with much anticipation and promise for the clinical management of the disease.

Azilsartan: a newly approved angiotensin II receptor blocker.

Hypertension is a common chronic disease that leads to significant cardiovascular morbidity and mortality. Blood pressure control is essential to prevent end-organ complications, such as stroke, myocardial infarction, heart failure, or kidney disease. Azilsartan is the eighth angiotensin II receptor blocker approved for the management of hypertension, alone or in combination with other agents. At the approved dosage, it reduces systolic blood pressure by 12 to 15 mm Hg and diastolic blood pressure by 7 to 8 mm Hg. A higher dose of azilsartan (80 mg) was superior to valsartan 320 mg or olmesartan 40 mg in lowering systolic blood pressure in short-term studies. Additional blood pressure reduction is expected when azilsartan is used adjunctively with a diuretic. However, the effects of azilsartan on cardiovascular morbidity or mortality are still lacking. Azilsartan is well tolerated; the most common side effects are headache and diarrhea. No cases of hyperkalemia have been reported in 6-week clinical trials. Worsening of renal function and hypotension should be monitored, particularly in those with baseline risk factors. It is unknown whether azilsartan would join angiotensin-converting enzyme inhibitors and other angiotensin receptor blockers as the preferred hypertensive agents for end-organ protection. At this time, azilsartan should be considered as an alternative agent for mild-to-moderate hypertension, or as an adjunctive therapy when preferred agents fail to maintain optimal blood pressure control. It is also an option for those patients who have contraindications or cannot tolerate other antihypertensive agents, including dry cough induced by angiotensin-converting enzyme inhibitors.

Rivaroxaban: an oral direct factor Xa inhibitor for the prevention of thromboembolism.

Rivaroxaban is a novel oral direct factor Xa inhibitor. It is currently awaiting approval from the US Food and Drug Administration as a prophylaxis for venous thromboembolism in total knee and hip replacements. Based on phase II and III trials, rivaroxaban has been shown to be as efficacious, if not more, as traditional antithrombotic therapy with similar safety profiles. The Regulation of Coagulation in Major Orthopedic Surgery Reducing the Risk of Deep Vein Thrombosis and Pulmonary Embolism (RECORD) phase III trials have shown rivaroxaban 10 mg once daily to be superior to the low molecular weight heparin, enoxaparin, when used for prophylaxis of venous thromboembolism in orthopedic surgeries. Rivaroxaban has been shown to have tolerable adverse effects and a low potential for drug-drug or drug-food interactions. It has the major advantages of once daily oral dosing and no required laboratory monitoring, giving it the potential to replace current antithrombotics in the market today.

Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for type 2 diabetes.

Type 2 diabetes mellitus is a common chronic disease that causes significant morbidity and mortality worldwide. The primary goal of treatment is to target glycemic control by maintaining the glycosylated hemoglobin (HbA1c) level near 6% to 7% without predisposing patients to hypoglycemia. Currently available antidiabetic agents work by different mechanisms to lower blood glucose levels. Unfortunately, each of them has its tolerability and safety concerns that limit use and dose titration. Dipeptidyl peptidase-4 enzyme inhibitors are novel drugs that prolong the action of incretins, and lead to increased insulin secretion and reduced hepatic glucose production. Saxagliptin is another dipeptidyl peptidase-4 (after sitagliptin) that is approved for the management of type 2 diabetes. It can be used alone or in combination with metformin, sulfonylurea, or thiazolidinedione (pioglitazone or rosiglitazone) when treatment with one drug alone provides inadequate glucose control. The usual adult dose is 2.5 to 5 mg once daily regardless of meals. A daily dose of 2.5 mg is recommended for patients with moderate to severe renal impairment or those who are taking potent CYP 3A4 inhibitors. In randomized clinical trials, saxagliptin alone lowered HbA1c levels by about 0.5%; with better efficacy seen when combined with other agents. It is well tolerated with the most common side effects being upper respiratory tract infection, headache, and urinary tract infection. In summary, saxagliptin is an option as an adjunct to lifestyle modifications and other antidiabetic agents to target glycemic control. It is also an alternative therapy for patients who have contraindications or intolerability to other antidiabetic agents.

Interferon-β1b for the treatment of multiple sclerosis

Background: Multiple sclerosis is a debilitating autoimmune disorder that causes disability in young adults. Objective: To review the efficacy and safety of IFN-β1b in the management of relapsing-remitting and secondary progressive multiple scleroses and clinical isolated syndrome. Methods: A MEDLINE (1966 – May 2007) search of clinical trials using the terms ‘multiple sclerosis’ and ‘interferon’ was performed. Manual bibliographic search was conducted. English-language articles were evaluated. Results: IFN-β1b is more efficacious than placebo and at least as efficacious as IFN-β1a or glatiramer for the management of relapsing-remitting multiple sclerosis. IFN-β1b also delayed the time to diagnosis of definite multiple sclerosis and reduced brain lesion burden in patients with clinical isolated syndrome. More long-term, large scale clinical data are warranted to ascertain its relative efficacy compared to other treatments. Conclusion: IFN-β1b is an effective treatment for multiple sclerosis. Common side effects are lymphopenia, injection site reactions, asthenia, flu-like symptoms and headache.