Failure Of Monotherapy Research Articles

Initial anticonvulsant monotherapy in routine care of children and adolescents: levetiracetam fails more frequently than valproate and oxcarbazepine due to a lack of effectiveness

Since anticonvulsants such as valproate or oxcarbazepine have quite a disadvantageous profile of possible adverse drug events (ADEs), safer alternatives are being sought. The newer anticonvulsant levetiracetam is often considered advantageous. We performed a chart review of children and adolescents aged from 0.5 to 16.9years, who had been started on an initial monotherapy with levetiracetam, valproate, or oxcarbazepine between 2007 and 2011, in order to analyze the therapy's failure rate during the first year. We differentiated failure of monotherapy due to a lack of effectiveness and due to ADEs. No psychometric tests were performed. Lack of effectiveness and inacceptable ADEs were assumed according to the judgment of physicians and families. Anticonvulsive monotherapy failed in 29/61 (48%) levetiracetam patients and in 18/49 (37%) valproate patients (for focal and generalized epilepsies; n.s.). This was caused by a lack of effectiveness in 25/61 (41%) levetiracetam patients and in 11/49 (22%) valproate patients (p ≤ 0.05). A modification of therapy due to ADEs was performed in 4/61 (7%) levetiracetam patients and in 7/49 (14%) valproate patients (n.s.). An anticonvulsive monotherapy failed in 21/42 (50%) patients treated with levetiracetam and in 10/34 (29%) patients treated with oxcarbazepine (for focal epilepsies; n.s.). Changes of monotherapy were caused by a lack of effectiveness in 17/42 (40%) of levetiracetam patients and in 6/34 (18%) of oxcarbazepine patients (p ≤ 0.05). ADEs leading to changes in therapy were reported for 4/42 (10%) of levetiracetam and 4/34 (12%) of oxcarbazepine patients (n.s.). An initial monotherapy of levetiracetam failed more frequently due to a lack of effectiveness than a monotherapy with valproate or oxcarbazepine. We found no significant difference in therapy failure due to ADEs.

AB0343 A high serum level of haptoglobin is associated with the response of 12 weeks methotrexate therapy in recent-onset rheumatoid arthritis patients

BackgroundAmong the several available DMARDs, Methotrexate (MTX) is currently the most widely used drug in clinical practice. About 30-40% of the patients could experience an adequate response to MTX alone;...

GLP-1 receptor agonists or DPP-4 inhibitors: How to guide the clinician?

Pharmacological treatment of type 2 diabetes has been enriched during recent years, with the launch of incretin therapies targeting glucagon-like peptide-1 (GLP-1). Such medications comprise either GLP-1 receptor agonists, with short (one or two daily injections: exenatide, liraglutide, lixisenatide) or long duration (one injection once weekly: extended-released exenatide, albiglutide, dulaglutide, taspoglutide); or oral compounds inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that inactives GLP-1, also called gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin). Although both pharmacological approaches target GLP-1, important differences exist concerning the mode of administration (subcutaneous injection versus oral ingestion), the efficacy (better with GLP-1 agonists), the effects on body weight and systolic blood pressure (diminution with agonists versus neutrality with gliptins), the tolerance profile (nausea and possibly vomiting with agonists) and the cost (higher with GLP-1 receptor agonists). Both agents may exert favourable cardiovascular effects. Gliptins may represent a valuable alternative to a sulfonylurea or a glitazone after failure of monotherapy with metformin while GLP-1 receptor agonists may be considered as a good alternative to insulin (especially in obese patients) after failure of a dual oral therapy. However, this scheme is probably too restrictive and modalities of using incretins are numerous, in almost all stages of type 2 diabetes. Physicians may guide the pharmacological choice based on clinical characteristics, therapeutic goals and patient's preference.

Efficacy and safety of lanreotide in combination with pegvisomant in clinical practice in patients with active acromegaly with monotherapy failure

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Efficacy and safety of lanreotide in combination with cabergoline in clinical practice in patients with active acromegaly with monotherapy failure

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A patient-centred approach to treatment with incretin-based agents in patients with type 2 diabetes

The 2012 position statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends a haemoglobin A1c level of <7% for most patients with type 2 diabetes (T2D). Initial therapy consists of lifestyle changes plus metformin, with an emphasis on a patient-centred approach to management. Addition of incretin-based therapy is recommended as an add-on after metformin failure, and later on in combination with basal insulin. Basal insulin is recommended from the onset in patients with A1c ≥10%. The possibility of incorporating incretin-based therapy in the patient-centred approach will be investigated both in the literature and clinical experience. Incretin-based therapy targets multiple dysfunctional organ systems in T2D and provides sustained glycaemic control, with extraglycaemic benefits and low risk of hypoglycaemia. To initiate an incretin-based therapy that best fits an individual patient's needs, the patient's A1c level, preference and comorbid conditions should be considered along with any drug safety and adherence-related issues. There is good evidence to support the patient-centred approach to T2D management. This approach allows patient treatment goals and personal preferences to be matched with the clinical profile(s) of one or more agents to formulate a treatment plan that can best achieve the goals. Incretin-based therapies are an important class of agents to consider after metformin monotherapy failure and later in combination with basal insulin. By matching patient needs with the clinical profiles of the various treatment options, pharmacists can actively engage in the practice of patient-centred care and management.

SOP Conservative (Medical and Mechanical) Treatment of Erectile Dysfunction

Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation.

Metformin Based Dual-Combination Therapies in Drug Naïve Type 2 Diabetic Patients

Metformin Based Dual-Combination Therapies in Drug Naïve Type 2 Diabetic Patients

Efficacy and tolerability between an olmesartan/amlodipine fixed-dose combination and an amlodipine double dose in mild to moderate hypertension

Fixed-dose combinations (FDCs) are one of the options for improving blood pressure (BP) goal attainment. We enrolled 141 patients and evaluated the efficacy and safety between a fixed dose of olmesartan/amlodipine (OA) and a double dose of amlodipine (DA) for treating mild to moderate hypertension after amlodipine monotherapy failure. After at least 2 weeks of monotherapy failure, the patients were randomized to receive either OA or DA for 8 weeks. We compared the systolic blood pressure (SBP)-lowering efficacy of the OA and DA using both an office BP and an ambulatory blood pressure monitoring (ABPM) device. The intent-to-treat analysis found that the early (2nd week) and final visit (8th week) SBP reductions were significantly greater in those patients receiving OA (n = 70) than DA (n = 71) (17.57 ± 15.49 vs. 10.46 ± 13.36 and 24.89 ± 14.09 vs. 17.03 ± 13.27 mmHg, p = 0.002 and 0.001, respectively). Among those using ABPM, the patients with 8-week OA had a greater SBP-lowering effect in comparison with those on DA (14.08 ± 10.74 vs. 6.32 ± 10.21, p = 0.018). Both treatment strategies were well tolerated. This study showed that an OA FDC is more effective than DA in reducing SBP for mild to moderate hypertension after the failure of amlodipine monotherapy.

The short-term efficacy of entecavir in lamivudine-resistant chronic hepatitis B: influence of sequential adefovir-refractoriness.

Sequential antiviral therapy for chronic hepatitis B may lead to the selection of multidrug-resistant mutation. This study was carried out to assess the efficacy of entecavir in patients that have experienced adefovir monotherapy failure after the development of lamivudine resistance. Fifty-three patients with confirmed genotypic lamivudine-resistant chronic hepatitis B were treated with entecavir. Thirty patients were switched to entecavir directly (LAM-ETV group), whereas the remaining 23 were adefovir-refractory patients who were switched to entecavir (LAM-ADV-ETV group). These 23 patients included 9 patients with inadequate response (ADV-I subgroup) and 14 that exhibited adefovir resistance (ADV-R subgroup). Significantly greater reductions in HBV DNA levels were observed after 24, 48 and 72 weeks of entecavir therapy in the LAM-ETV group than in the LAM-ADV-ETV group, respectively. However, between these two groups at 48 and 72 weeks, no significant differences were observed in cumulative proportions of virological response or breakthrough, respectively. Furthermore, efficacy of entecavir was not significantly different in the ADV-I and ADV-R subgroups. Four patients in the LAM-ETV group and six patients in the LAM-ADV-ETV group developed genotypic resistance to entecavir. Entecavir therapy is less effective in adefovir-refractory patients with prior lamivudine resistance than in lamivudine-resistant patients.

What Next after Metformin? A Retrospective Evaluation of the Outcome of Second-Line, Glucose-Lowering Therapies in People with Type 2 Diabetes

After failure of metformin monotherapy, many second-line, glucose-lowering therapies are available to treat people with type 2 diabetes. The objective of the study was to compare clinical outcomes using common alternative regimens. This was a retrospective cohort study using data from the U.K.-based General Practice Research Database. These were primary care patients with type 2 diabetes who had metformin monotherapy as their first treatment and who then initiated on relevant second-line, glucose-lowering regimens during the study period 2000-2010. A total of 27,457 patients were prescribed a second-line therapy, of whom 26,278 (95.7%) were prescribed a regimen with 1,000 or more observations. All-cause mortality, major adverse cardiovascular events (MACE), cancer, and a combined end point of any of these were measured. Secondary end points were change in glycosylated hemoglobin between baseline and 12 months. Time to clinical end points was compared using Cox proportional hazards models. Sulfonylurea monotherapy had significantly higher hazard ratios (HRs) for all-cause mortality (HR 1.459, 1.207-1.763); MACE (HR 1.578, 1.187-2.099); stroke (HR 1.444, 1.050-1.987); and the combined end point (HR 1.381, 1.194-1.597). Metformin plus pioglitazone had significantly lower adjusted HRs for all-cause mortality (HR 0.707, 0.515-0.970) and the combined end point (HR 0.747, 0.612-0.911). Mean glycosylated hemoglobin improved between baseline and 12 months for all regimens other than sulfonylurea monotherapy. The combination of metformin plus pioglitazone appears to provide superior clinical outcomes compared with the most commonly used regimen, metformin plus sulfonylurea. Sulfonylurea monotherapy resulted in worse outcome.

Treatment-Refractory Actinic Keratoses Successfully Treated Using Simultaneous Combination Topical 5-Fluorouracil Cream and Imiquimod Cream: A Case–Control Study

Most actinic keratoses (AKs) respond to standard treatments, but a subset persist and require further intervention. We report a series of 10 patients with AKs that failed to respond to conventional treatment with cryotherapy and topical monotherapy but responded completely to simultaneous therapy with topical 5-fluorouracil (5-FU) and imiquimod creams. To report the success of this combination therapy in refractory AKs and to determine whether any clinical or histologic features predict for treatment resistance. Case-control study with two control groups matched to each patient according to lesion location and sex. Mean lesion diameter (p < .001), lesion diameter greater than 1 cm (p < .001), and the presence of pain (p = .01) were statistically associated with failure of cryotherapy and topical monotherapy. None of the histologic features evaluated were found to be statistically significant, although thicker epidermis was nearly so (p = .054). In patients who have failed standard therapy for AKs, combination treatment using topical 5-FU and imiquimod cream may be an effective alternative therapeutic strategy. Larger lesion diameter, specifically greater than 1 cm, and the presence of pain predict conventional treatment resistance.

Combination Treatment of Essential Thrombocythemia with Hydroxyurea and Anagrelide

Abstract 5177 BACKGROUND: Hydroxyurea and anagrelide are therapeutic options for essential thrombocythemia (ET) with distinct mechanism of actions and side effect profiles. However, therapeutic goals may not be achieveable due to drug intolerance or disease resistance. Here we report our successful clinical experience with combination treatment with hydroxyurea and anagrelide. METHODS: Medical records of six patients who were on the combination treatment for the ET were retrospectively reviewed. All had history of unsuccessful monotherapy with either hydroxyurea or anagrelide. RESULTS: All patients were female with median age of 59.5 years. All were positive for the V617_ jak2 mutation. Two had prior major thromboses (portal vein; ischemic stroke), and one had Raynaud's disease. Reasons for failure of hydroxyurea monotherapy were leukopenia and/or inadequate platelet reduction, while reasons for anagrelide failure were palpitations and orthostasis. Rather than discontinue the primary drug, doses were lowered to a tolerable level and the second agent was added. These patients have been treated with the combination of hydroxyurea and anagrelide for a mean duration of 4.89+ years. Combination regimen achieved 64% reduction of platelet counts (mean best platelet counts during treatment 328×109/L), while maintaining adequate leukocyte counts (range 3.64–7.88 × 109/L). Relatively low daily doses of hydroxyurea (mean 684mg/day) and anagrelide (1.7mg/day) were required. Adverse events noted during the combination therapy were one case with rectal bleeding and two cases of myelofibrosis. One patient returned to monotherapy due to persistent headache to low-dose anagrelide. No arterial or venous thromboses bleeding events have occurred. CONCLUSION: This is the longest follow-up experience of hydroxyurea and anagrelide combination therapy in ET that has been resistant to monotherapy or where high monotherapy doses could not be tolerated. The low-dose combination regimen was able to achieve clinical and laboratory response in all patients with a low incidence of medication side effects. This strategy is made more attractive by data that hydroxyurea may be more effective in prevent arterial events while anagrelide was found more effective in preventing venous clots, but conclusions on superior efficacy of the combination would require formal study. We recommend that rather than substitute for an agent that has had partial success or is causing dose-related side-effects, the dose can be adjusted and a second agent added. Disclosures: No relevant conflicts of interest to declare.

Reconstructing the pyramid as a therapeutic approach to rheumatoid arthritis

Several recent clinical studies have clearly established that rheumatoid arthritis (RA) is a disease identifiable since its early phases, a disease that can be adequately and efficaciously treated provided the therapeutic program can be started early on. To reach the aim of controlling effectively the disease and of leading the patients to live a normal life, several points must be fulfilled. The first is an early diagnosis obtained through a careful clinical examination along with an appropriate laboratory immunological work-up, followed by an adequate monotherapy within the first 4 months from symptoms onset. The second is the therapeutic re-assessment that needs to be done every three months, to start a possible combination therapy (COMBO), in order to rescue monotherapy failures. The third is the initiation of biological response modifiers (BRMs) within 6 months from monotherapy onset, within 3 months from COMBO in the most resistant cases. Having at hand several molecules with BRMs characteristics, we believe that the future appears much more favourable in most cases even in those with the severe disease.

Novel strategy to restore the activity of taxanes: A multicenter phase II study of combination therapy with taxanes and toremifene at 120 mg for advanced/recurrent breast cancer—Kinki Multidisciplinary Breast Oncology Group (KMBOG0612).

e13611 Background: A preclinical study reported that toremifene (TOR) increased the level of an anticancer agent such as doxorubicin and paclitaxel in the breast cancer cell which has acquired resistance to them by the expression of P-glycoprotein. Methods: The subjects were postmenopausal females with advanced/recurrent breast cancer who showed PD after PR or SD to mono therapy with taxanes (paclitaxel or docetaxel) was confirmed. In a phase II prospective study, 120 mg of TOR was administered orally every day after the treatment failure of taxane mono therapy, while continuing the respective taxane regimen. As a primary end point, we assessed the response rate (RR) including clinical benefits. Secondary end points were the time to progression (TTP) and adverse reactions. Results: Twenty-seven patients were registered between November 1, 2006 and October 31, 2010, and 25 patients were analyzed at this time. The median age was 57 years (range: 36-79) and the median ECOG PS was zero (range: 0-1). The RR, clinical benefit (CB) rate, and median TTP were 8.7%, 21.7%, and 12.1 weeks (range: 3.1-69.6), respectively. Moreover, with adding TOR to taxanes, treatment duration could be extended more than 100% in 5 patients (i.e., paclitaxel+TOR 323 days / paclitaxel 288 days = 112%). Adverse reactions to this combination regimen were observed in 8 patients. In 2 cases, grade 2 numbness was noted. However, the other patients showed grade 1 adverse reactions; this therapy was tolerable. Conclusions: Combination therapy with taxanes and TOR at 120 mg was tolerable and useful. The results suggest that TOR may restore the activity of taxanes in taxane refractory advanced/recurrent breast cancer patients.

Abstract 719: Erlotinib-resistant non-small cell lung cancer cells exhibit enhanced cell motility via activation of TGFβ/Smad signaling pathway

Abstract Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have been shown to be effective in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the majority of responders ultimately develop acquired resistance to EGFR-TKIs mainly due to the EGFR T790M mutation or the MET gene amplification which accounts for about 50 % and 20 % of the cases with acquired resistance, respectively. It is urgently needed to further investigate other mechanisms of acquired resistance than those reported previously and on top of that, little has been elucidated about the biological behavior of EGFR-TKI-resistant tumors. Materials and Methods: Erlotinib-resistant PC-9/ER cells were generated after continuous exposure of PC-9 NSCLC cells which harbor the EGFR-activating mutation (exon 19 deletion) to increasing concentrations of erlotinib. Growth-inhibitory effect of inhibitors was evaluated by MTT assay. EGFR mutations and MET amplification were examined by PNA-LNA clamping method and fluorescent in situ hybridization, respectively. Immunoblot analysis was performed to investigate the modulation of molecules relevant to EGFR signaling pathways. Wound closure assay and transwell assay were performed to evaluate the cell migration. Expression level of receptor ligands was detected by ELISA. Transcriptional regulatory activity of Smad was measured by luciferase assay. Results: PC-9/ER cells were 100-150-fold more resistant to erlotinib than parental PC-9 cells. Neither the EGFR T790M mutation nor the MET gene amplification was detected in the resistant cells suggesting novel mechanisms responsible for acquired resistance to erlotinib. PC-9/ER cells showed cross-resistance to gefitinib and were insensitive to irreversible EGFR-TKI and MET inhibitor as well. Most notably, cell motility of PC-9/ER cells was significantly enhanced than that of PC-9 cells. Phosphorylation of Smad2 turned out to be markedly induced and the subsequent transcriptional activity was elevated in PC-9/ER cells and TGFβ2 overexpression was suggested to be responsible for its activation. TGFβ receptor I inhibitor LY364947 attenuated the cell motility of PC-9/ER cells, while it had no effect in PC-9 parental cells. Combined treatment of erlotinib and LY364947 effectively suppressed the motility of PC-9/ER cells though they either alone or in combination showed little growth-inhibitory effect, suggesting that cell motility and cell growth are driven by different signaling pathways in PC-9/ER cells. Conclusion: Activated TGFβ/Smad pathway is suggested to confer enhanced cell motility in PC-9/ER cells while it is unlikely to drive cell growth. Blockade of TGFβ signaling pathway with continuative EGFR-TKIs treatment seems to be beneficial in preventing metastasis after the failure of EGFR-TKIs monotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 719. doi:10.1158/1538-7445.AM2011-719

Inappropriate claim of ‘failure of ritonavir-boosted lopinavir monotherapy in HIV’ in the Monotherapy Switzerland/Thailand (MOST) trial

Inappropriate claim of ‘failure of ritonavir-boosted lopinavir monotherapy in HIV’ in the Monotherapy Switzerland/Thailand (MOST) trial

Letter: Predictive Clinical Parameters for the Therapeutic Efficacy of Sitagliptin in Korean Type 2 Diabetes Mellitus (Diabetes Metab J 2011;35:159-65)

Type 2 diabetes mellitus (T2DM) is a complex progressive metabolic derangement associated with comorbidities such as obesity, dyslipidemia, and hypertension. Although a wide range of pharmacotherapies is available for T2DM, determining management strategies for T2DM that balance effectiveness, safety, and tolerability remains complex and challenging. The prevalence of T2DM has increased rapidly in Asia, including South Korea, over the past several decades [1]. The pathophysiologic mechanisms underlying T2DM in Asia are thought to be different from those in Western countries. In particular, pancreatic β-cell dysfunction may be important for the development of T2DM in certain Asian populations [2,3]. Progressive β-cell failure, weight gain and hypoglycemia are the main side effects of sulfonylurea, one of the most commonly used antidiabetic agents. Long-term use of sulfonylurea can lead to the failure of monotherapy and ultimate dependence on insulin injections. Glucagon like peptide (GLP)-1 stimulates pancreatic β-cell differentiation and proliferation, and inhibits apoptosis [4]. Dipeptidyl peptide-4 (DPP-4) inhibitors enhance levels of active incretin hormones, gut-derived peptides that are released into the circulation after eating [5]. Sitagliptin is an oral, once-daily, potential, highly selective DPP-4 inhibitor. Numerous clinical studies of sitagliptin have been reported since the US Food and Drug Administration approved sitagliptin for monotherapy or combination therapy with metformin or thiazolidinedione in 2006 [5-9]. According to a systemic review and meta-analysis, DPP-4 inhibitors lowered HbA1C by 0.74% (95% confidence interval [CI], 0.62% to 0.85%) compared with placebo [10]. Most studies indicate that sitagliptin treatment leads to significant improvements in β-cell function. Given the important role that β-cell dysfunction plays in the progression of hyperglycemia, especially in Asian patients, sitagliptin treatment may be of particular therapeutic relevance for T2DM in Asian contexts. However, clinical studies of sitagliptin therapies in Asian or Korean diabetic patients are rare. A 2009 study found that 18 week sitagliptin monotherapy was associated with significantly improved glycemic control (mean HbA1c reduction, -1.0%) and was well tolerated by T2DM patients from China, India, and Korea [11]. According to this study, the reduction of HbA1C relative to placebo was greater in Korean and Indian patients than in Chinese patients. The mean (95% CI) reductions in HbA1C with sitagliptin treatment were -1.4% (-1.9% to -0.8%) in Korean patients, -1.4% (-1.7% to -1.0%) in Indian patients, and -0.7% (-0.9% to -0.5%) in Chinese patients. Furthermore, Korean patients showed the greatest reductions of fasting glucose and 2-hour postprandial glucose levels. However, the reasons for these differences were not elucidated, although the authors suggested regional differences in environment, genetics, or adherence to study co-interventions such as diet and exercise. Due to the current insufficiency of Asian or Korean data regarding sitagliptin efficacy in patients with T2DM, the study by Kim et al. [12] is particularly relevant. In that study, younger, thinner diabetic patients were observed to have better therapeutic results than older, heavier patients, suggesting that BMI and age should be considered before the selection of sitagliptin or other DPP-4 inhibitors for use in diabetic therapies. Treatment response was defined as >10% HbA1c reduction or >20% fasting glucose reduction, and by this definition, the frequency of response in their sample was 81%. As many previous clinical studies defined successful glucose-lowering effects according to the number of patients with HbA1c <7%, additional studies are necessary to assess the therapeutic effects of sitagliptin and to identify clinical characteristics of patients that predict sitagliptin response.

Initial Combination Therapy for Type 2 Diabetes Mellitus: Is It Ready for Prime Time?

The increased prevalence of type 2 diabetes mellitus is primarily being driven by the increasing global rates of overweight/obesity. Given the magnitude of this epidemic, we can expect these metabolic abnormalities to play an increasing role in the development of cardiovascular disease. In a pathophysiologic sense, type 2 diabetes is a multiorgan, multifactorial condition, characterized by β-cell dysfunction, insulin resistance in peripheral tissues and the liver, defective incretin activity, and elevated levels of free fatty acids and proinflammatory mediators. Despite the considerable burden of disease associated with type 2 diabetes, most patients are not at, or are unable to achieve, recommended glycemic control guideline targets. In part, this is because of the relentlessly progressive nature of the disease, but it may also be attributable to the current diabetes treatment paradigm, which is characterized by ineffective lifestyle interventions, followed by monotherapy and frequent early treatment failure with prolonged periods of elevated glucose as a consequence of clinical inertia. Thus, it is most appropriate to rethink the current treatment paradigm for type 2 diabetes in the context of a more aggressive initial therapy; specifically with early initiation of combination therapy. Our current understanding of the complex pathophysiology of the disease and the progressive deterioration in glycemic control over time supports the philosophy of earlier intervention with a more comprehensive initial therapy. Thus, while control of hyperglycemia remains the paramount goal, focusing on the underlying pathophysiology of type 2 diabetes is increasingly becoming the therapeutic strategy, with the aim of potentially providing disease modification. Although this is a logical approach, it remains to be demonstrated that early combination therapy will result in disease modification in a clinical setting. Not surprisingly, the incretin-based therapies have gained a great deal of attention in the context of being a component of initial combination therapy, given their potential beneficial effects on β-cell function with lowered risk of weight gain and hypoglycemia.

Add-on therapies to metformin for type 2 diabetes

Importance of the field: As of 2010, approximately 285 million people worldwide have diabetes; that number is estimated to increase to 439 million by 2030. The majority of these individuals (> 90%) have type 2 diabetes, a chronic and progressive disease.Areas covered in this review: Metformin monotherapy is a safe and effective option. However, its effects on glycemia are typically of limited durability. Progressive loss of β-cell function and failure of metformin monotherapy to control glucose adequately prompt the addition of other oral antidiabetic drugs, such as sulfonylureas and thiazolidinediones, which have their own limitations. Evidence suggests that incretin-based agents can successfully achieve glycemic control while potentially providing cardiovascular and β-cell-function benefits.What the reader will gain: Knowledge of the available clinical evidence on the incretin-based therapies and other pharmacotherapeutic options for patients with type 2 diabetes who fail first-line therapy with metformin, through an analysis of improved glycemic parameters and overall risk:benefit profiles.Take home message: Traditional oral antidiabetic agents, recommended as first- and second-line therapies in patients with type 2 diabetes inadequately controlled with diet/exercise or monotherapy, have limited durability of effect and are associated with an increased risk of adverse events. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors provide glycemic control and are promising additions to the pharmacotherapeutic armamentarium.