Treatment Of Type 2 Diabetes Mellitus Patients Research Articles

Influence of SLC22A1 rs622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients.

Metformin is an oral antidiabetic drug, commonly used for treating type 2 diabetes mellitus (T2DM) patients. It is transported into the hepatocytes by polyspecific organic cation transporter 1, which is encoded by the gene SLC22A1. It has been hypothesized that genetic variations of SLC22A1 gene will influence inter-individual variation in glucose lowering efficacy of metformin. Previous studies have demonstrated this in other populations with conflicting results, but it remains to be elucidated in Indian population. Henceforth, the objective of the study was to evaluate the impact of SLC22A1 rs622342 gene polymorphism on the clinical efficacy of metformin in South Indian T2DM patients. A total of 122 newly detected, treatment naive T2DM patients of either sex were included in this study. The patients were started on metformin monotherapy and followed up for 12 weeks. Genotype was determined using qRT-PCR. Before and after treatment with metformin, body mass index (BMI), serum lipid profile, glycated hemoglobin (HbA1c), fasting and postprandial glucose level, and blood pressure (BP) were measured. The study cohort mean age was 49.57 ± 9.88 years. Of the 122 T2DM patients, 93 were classified as responders and 29 as non-responders based on fall in HbA1c levels. Interestingly, carriers of one variant allele 'C' (AC) of rs622342 polymorphism were less among the responders than those who did not (44.8 vs. 22.6 %). The response was even lesser (13.8 vs. 4.3 %) in carriers of two copies of "C" allele (CC). On the contrary, patients with two copies of allele 'A' (AA) had 5.6 times greater chance of responding to metformin treatment. A similar trend was observed when the proportion was analyzed under different genetic models (OR 3.85, 95 % CI 1.61-9.19 for dominant; OR 3.56, 95 % CI 0.83-15.26 for recessive; OR 0.35, 95 % CI 0.14-0.86 for over-dominant; and OR 4.10, 95 % CI 1.78-9.43 for additive). Further, metformin showed significant beneficial effects on BMI, HbA1c, FPG, PPG, lipid parameters and BP. These data suggest that the allele and genotypes of SLC22A1 rs622342 gene polymorphism were associated with the therapeutic efficacy of metformin in South Indian patients with T2DM.

Fixed-Dose Combination Therapy in Type 2 Diabetes Mellitus

The management of type 2 diabetes mellitus (T2DM) often requires combinations of antihyperglycemic medications with complementary mechanisms of action. Inadequate adherence to combination therapy, possibly related to pill burden (greater number of pills and higher administration frequency) and poor tolerability, may lead to suboptimal clinical outcomes. One potential means of addressing these problems is the use of fixed-dose combinations (FDCs) that simplify the treatment regimen by reducing pill burden compared with the same combination delivered as separate pills. The present study evaluates the efficacy and tolerability of FDCs in the treatment of T2DM patients and provides an overview of dosing, costs, and adherence. A review of FDCs, with particular attention to those that contain metformin extended-release (XR) and allow once-daily dosing. Many FDCs contain metformin as one of the component drugs. However, the standard immediate-release (IR) formulation of metformin requires twice-daily dosing and may have tolerability problems related to adverse gastrointestinal (GI) effects. The XR formulations of metformin can be administered once daily and have been shown to reduce the occurrence of GI effects frequently observed with metformin IR; consequently, they may have significant advantages for inclusion in FDCs. The long-term cost-effectiveness of FDCs remains to be fully determined. For patients taking metformin, FDCs containing metformin XR offer equivalent efficacy with reduced dose frequency and, potentially, fewer GI events compared with standard IR formulation, as well as a reduced number of pills compared with separate-pill regimens. By reducing pill burden and improving tolerability, FDCs may improve adherence.

Low serum cartonectin/CTRP3 concentrations in newly diagnosed type 2 diabetes mellitus: in vivo regulation of cartonectin by glucose.

ObjectivesCartonectin is a novel adipokine of the C1q complement/TNF-related protein (CTRP) superfamily, with glucose lowering effects, anti-inflammatory and cardio-protective properties. We sought to investigate circulating cartonectin concentrations in subjects with type 2 diabetes mellitus (T2DM) as well as age and BMI matched control subjects. We also examined the effects of a 2 hour 75 g oral glucose tolerance test (OGTT) on serum cartonectin concentrations in T2DM subjects.DesignCross-sectional study [newly diagnosed (first discovery, not on any treatments) T2DM (n = 47) and control (n = 63) subjects]. Serum cartonectin was measured by ELISA.ResultsSerum cartonectin concentrations were significantly lower in patients with T2DM compared to controls (P<0.05). Furthermore, serum cartonectin was significantly negatively correlated with glucose and CRP, and significantly positively correlated with leptin, in all subjects (n = 110). When subjected to multiple regression analysis, none of these variables were predictive of serum cartonectin (P>0.05). There were no significant correlations in T2DM subjects (n = 47). In control subjects (n = 63), serum cartonectin was significantly negatively correlated with CRP, and significantly positively correlated with insulin, HOMA-IR and leptin. However, when subjected to multiple regression analysis, none of these variables were predictive of serum cartonectin (P>0.05). Finally, serum cartonectin concentrations were significantly lower in T2DM subjects after a 2 hour 75 g OGTT (P<0.01).ConclusionsCartonectin may serve as a novel biomarker for the prediction and early diagnosis of T2DM patients. Furthermore, cartonectin and/or pharmacological agents that increase circulating cartonectin levels can represent a new therapeutic field in the treatment of T2DM patients. Further research is needed to clarify these points.

Diabetes self-management education improves quality of care and clinical outcomes determined by a diabetes bundle measure.

PurposeThe purpose of this study was to determine the impact of diabetes self-management education (DSME) in improving processes and outcomes of diabetes care as measured by a five component diabetes bundle and HbA1c, in individuals with type 2 diabetes mellitus (T2DM).MethodsA retrospective analysis was performed for adult T2DM patients who received DSME training in 2011–2012 from an accredited American Diabetes Association center at Intermountain Healthcare (IH) and had an HbA1c measurement within the prior 3 months and 2–6 months after completing their first DSME visit. Control patients were selected from the same clinics as case-patients using random number generator to achieve a 1 to 4 ratio. Case and control patients were included if 1) pre-education HbA1c was between 6.0%–14.0%; 2) their main provider was a primary care physician; 3) they met the national Healthcare Effectiveness Data and Information Set criteria for inclusion in the IH diabetes registry. The IH diabetes bundle includes retinal eye exam, nephropathy screening or prescription of angiotensin converting enzyme or angiotensin receptor blocker; blood pressure <140/90 mmHg, LDL <100 mg/dL, HbA1c <8.0%.ResultsDSME patients had a significant difference in achievement of the five element IH diabetes bundle and in HbA1c % compared to those without DSME. After adjusting for possible confounders in a multivariate logistic regression model, DSME patients had a 1.5 fold difference in improvement in their diabetes bundle and almost a 3 fold decline in HbA1c compared to the control group.ConclusionStandardized DSME taught within an IH American Diabetes Association center is strongly associated with a substantial improvement in patients meeting all five elements of a diabetes bundle and a decline in HbA1c beyond usual care. Given the low operating cost of the DSME program, these results strongly support the value adding benefit of this program in treating T2DM patients.

Mild Electrical Stimulation with Heat Shock Reduces Visceral Adiposity and Improves Metabolic Abnormalities in Subjects with Metabolic Syndrome or Type 2 Diabetes: Randomized Crossover Trials

BackgroundThe induction of heat shock protein (HSP) 72 by mild electrical stimulation with heat shock (MES+HS), which improves visceral adiposity and insulin resistance in mice, may be beneficial in treating metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM). MethodsUsing open-label crossover trials, 40 subjects with MS or T2DM were randomly assigned using computer-generated random numbers to 12weeks of therapeutic MES+HS followed by 12weeks of no treatment, or vice versa. During the intervention period, physical and biochemical markers were measured. FindingsCompared to no treatment, MES+HS treatment was associated with a significant decrease in visceral adiposity (−7.54cm2 (−8.61%), 95% CI −8.55 to −6.53 (p=0.037) in MS, −19.73cm2 (−10.89%), 95% CI −20.97 to −18.49 (p=0.003) in T2DM). Fasting plasma glucose levels were decreased by 3.74mg/dL (−5.28%: 95% CI −4.37 to −3.09mg/dL, p=0.029) in MS and by 14.97mg/dL (10.40%: 95% CI −15.79 to 14.15mg/dL, p<0.001) in T2DM, and insulin levels were also reduced by 10.39% and 25.93%, respectively. HbA1c levels showed a trend toward reduction (−0.06%) in MS, and was significantly declined by −0.43% (95% CI −0.55 to −0.31%, p=0.009) in T2DM. HbA1c level of less than 7.0% was achieved in 52.5% of the MES+HS-treated T2DM patients in contrast to 15% of the non-treated period. Several insulin resistance indices, inflammatory cytokines or adipokines, including C-reactive protein, adiponectin, and tumor necrosis factor-α, were all improved in both groups. In isolated monocytes, HSP72 expression was increased and cytokine expression was reduced following MES+HS treatment. Glucose excursions on meal tolerance test were lower after using MES+HS in T2DM. InterpretationThis combination therapy has beneficial impacts on body composition, metabolic abnormalities, and inflammation in subjects with MS or T2DM. Activation of the heat shock response by MES+HS may provide a novel approach for the treatment of lifestyle-related diseases. FundingFunding for this research was provided by MEXT KAKENHI (Grants-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology, Japan).

Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis.

The red wine polyphenol, resveratrol, is highly effective in treating type 2 diabetes mellitus (T2DM) in animal models, but there is no consensus regarding its efficacy in humans. We conducted a systematic review, which included searches in nine scholarly databases and six clinical trial registries, and identified randomized controlled clinical trials whereby resveratrol was used as an adjunct to pharmaceutical interventions in T2DM. Meta-analysis on clinical parameters was performed for available data. Of 764 articles originally identified, data from six unique datasets, examining a total of 196 T2DM patients (104 resveratrol, 92 control/placebo) ultimately met inclusion criteria. Statistically significant (p < 0.05) positive effects, indicating that resveratrol supplementation was more effective than placebo/control, were identified for systolic blood pressure, hemoglobin A1c, and creatinine, but not for fasting glucose, homeostatic model assessment of insulin resistance, diastolic blood pressure, insulin, triglycerides, LDL, or HDL cholesterol. No major adverse events were reported and side effects of resveratrol were not different than placebo/control. Though limitations in sample size and treatment duration preclude definitive changes in clinical practice, significant improvements in multiple cardiometabolic biomarkers and an excellent safety profile support resveratrol as a leading candidate as an adjunct to pharmacological management of T2DM.

Long-acting Insulin Analogues and Diabetic Retinopathy: A Retrospective Cohort Study

PurposeLong-acting insulin analogues were developed to facilitate consistent glycemic control without excessive hypoglycemia. However, structural modifications of the insulin molecule can alter biological responses and binding characteristics with specific receptors. The aim of this study was to estimate the risk of sight-threatening diabetic retinopathy (STDR) associated with treatment using long-acting insulin analogues compared with intermediate-acting insulin in patients with type 2 diabetes mellitus (T2DM). MethodsA retrospective cohort consisting of patients with T2DM aged 20 years of age and older with newly initiated treatment with long-acting insulin analogues (glargine and detemir) and intermediate-acting human insulin was identified from the National Health Insurance database between January 2004 and December 2006 and was subdivided into different cohorts. The risk of the development of STDR was determined by Cox regression models and compared between different cohorts. FindingsOf the 46,739 eligible patients, initiators of insulin glargine, insulin detemir, and neutral protamine Hagedorn (NPH) insulin were identified for comparison using propensity-score matching methods. Long-acting insulin analogues were not associated with changed risk for STDR by intention-to-treat and time-varying use approaches between either matched or unmatched cohorts. ImplicationsThe strategies that aim at preventing diabetic retinopathy by treating T2DM patients with long-acting insulin analogues remain further prospective studies with longer follow-up period to validate our observations within an appropriate dosage range and to further evaluate the safety of long-acting insulin analogues on reducing the progression of diabetic retinopathy.

Role of serum vaspin in progression of type 2 diabetes: a 2-year cohort study.

Vaspin is a novel adipocytokine that has potential insulin-sensitizing effects. The aim of this study is to explore the role of vaspin in the progression of type 2 diabetes mellitus (T2DM) in humans through a longitudinal process. This was a 2-year follow-up study that included 132 patients with T2DM and 170 non-diabetic subjects. The serum vaspin and adiponectin levels were determined with ELISA. Anthropometric measurements, circulating glucose, hemoglobin A1c, insulin level, liver function, kidney function, and lipid profile were measured for each participant. The new onset of T2DM was counted in non-diabetic subjects and the glycemic control was analyzed in T2DM patients at follow-up. At enrollment, the serum vaspin and adiponectin levels were lower in T2DM patients compared with non-diabetic subjects. Significant positive correlation between serum vaspin and HDL-C levels (r = 0.23, P = 0.006) was observed in non-diabetic controls. The serum vaspin concentration was also significantly correlated with body mass index (BMI) (r = 0.19, P = 0.028), waist-hip ratio (WHR) (r = 0.17, P = 0.035) and homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.14, P = 0.029) in T2DM patients. In cohort analyses, it was found that lower serum vaspin [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.10–0.87, P = 0.015] and adiponectin (OR = 0.35, 95% CI: 0.20–0.72, P = 0.015) levels at baseline were risk factors for new onset of T2DM at follow-up. The percentage of insulin treatment in T2DM patients was higher in the sub-group with lower serum vaspin level than that in the sub-group with higher vaspin level at follow-up (55.3% vs. 44.7%, P = 0.020). Our study indicates that low serum concentration of vaspin is a risk factor for the progression of T2DM.

Liraglutide Versus Sitagliptin in a 24-week, Multicenter, Open-label, Randomized, Parallel-group Study in Japanese Type 2 Diabetes Mellitus Patients Responding Inadequately to a Sulfonylurea and/or One or Two Other Oral Antidiabetic Drugs (JDDM 33).

OBJECTIVELiraglutide (glucagon-like peptide-1 [GLP-1] receptor agonist) and sitagliptin (dipeptidyl peptidase-4 inhibitor) are approved in Japan for treating type 2 diabetes mellitus (T2DM). We compared the efficacy and safety of adding liraglutide or sitagliptin to a sulfonylurea in Japanese T2DM patients.METHODSPatients aged 18 to <80 years with hemoglobin A1c (HbA1c; National Glycohemoglobin Standardization Program [NGSP]) of 6.9–9.4%, body mass index ≤35 kg/m2, and treatment with a sulfonylurea and/or one or two non-sulfonylurea oral antidiabetic drugs for greater than or equal to eight weeks before enrollment were eligible. Patients were randomized in an open-label manner to either 0.9 mg/day liraglutide (n = 50) or 50–100 mg/day sitagliptin (n = 49) and were treated for 24 weeks. Non-sulfonylureas were discontinued before randomization. Patients using other oral antidiabetic drugs started sulfonylurea treatment. The primary endpoint was the change in HbA1c from baseline to Week 24.RESULTSHbA1c decreased in both groups, and the reduction was significantly greater throughout in the liraglutide group except for Week 24 (0.59 ± 0.80 vs. 0.24 ± 0.94%; P = 0.0525). Fasting plasma glucose (FPG) decreased significantly in the liraglutide group compared with the sitagliptin group (−21.15 ± 31.22 vs. +0.46 ± 39.39 mg/dL; P = 0.0014). Homeostasis model assessment of β cell function and C-peptide increased significantly in the liraglutide group but not in the sitagliptin group. Hypoglycemic symptoms and adverse events occurred in four and nine patients, respectively, in the liraglutide group, and in two and five patients, respectively, in the sitagliptin group.CONCLUSIONTreatment with liraglutide or sitagliptin together with a sulfonylurea improved HbA1c in Japanese T2DM patients in primary care. Both drugs were associated with low rates of adverse events and hypoglycemia. The improvement in β cell function probably contributed to the improvement in glycemic control in the liraglutide group.

On pens and needles: Treatment strategies for psychological insulin resistance in type 2 diabetes mellitus

Background: Psychological insulin resistance (PIR) refers to psychological opposition towards insulin therapy. Although not a formal psychological diagnosis, PIR is an under-recognized issue clinicians may encounter when treating patients with diabetes requiring insulin therapy. Methods: Review articles, clinical trials, and practice guidelines were located using online databases. A total of 39 abstracts were reviewed and 11 articles were included in the analysis. Results: Eleven articles were included. Proposed strategies used to mitigate the occurrence of PIR include: identifying the patient's personal obstacles via administration of PIR questionnaires, use of insulin pens as opposed to conventional syringe and needle, education on the risk of hypoglycemia and continuous emphasis of the importance of self-monitoring of blood glucose (SMBG) readings. Discussion: The management of type 2 diabetes mellitus (T2DM) in patients requiring insulin may present challenges such as PIR. Tailoring a patient's treatment plan to account for physiological, psychological, social and financial needs may thwart some of these challenges. Other factors to consider include the cost of the agent and/or devices required. Insulin-dependent patients with T2DM should be assessed for both physiological and psychological changes. Conclusion: Current treatment strategies for clinicians treating T2DM patients with PIR include administering the PIR or BIT questionnaire, initiating lower doses of insulin, switching from insulin vials to insulin pens, including assessment results in individualized treatment plans and using clinical outcomes to screen patients who are at risk for refusing the use of insulin. Further research evaluating clinical outcomes associated with treatment strategies is necessary.

Linagliptin added to sulphonylurea in uncontrolled type 2 diabetes patients with moderate-to-severe renal impairment

Glucose-lowering treatment options are limited for uncontrolled type 2 diabetes mellitus (T2DM) patients with advanced stages of renal impairment (RI). This retrospective analysis evaluated glycaemic efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin added to sulphonylurea. Three randomized phase 3 studies (n = 619) including T2DM subjects with moderate or severe RI [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²] were analysed; only sulphonylurea-treated subjects who received additional linagliptin (n = 58) or placebo (n = 33) were evaluated. Linagliptin provided meaningful placebo-adjusted HbA1c reductions of -0.68% (95% confidence interval: -1.19, -0.17), -1.08% (-2.02, -0.14) and -0.62% (-1.25, 0.01) after 24, 18 and 12 weeks, respectively. There was a similar incidence of overall adverse events (linagliptin: 79.3%, placebo: 75.8%) and hypoglycaemia (linagliptin: 37.9%, placebo: 39.4%). Severe hypoglycaemia was more common with placebo (linagliptin: 1.7%, placebo: 6.1%). These data suggest that linagliptin is a safe and effective glucose-lowering treatment in T2DM patients with moderate-to-severe RI for whom sulphonylurea treatment is no longer sufficient.

Comparative efficacy of exenatide versus insulin glargine on glycemic control in type 2 diabetes mellitus patients inadequately treated with metformin monotherapy

Comparative efficacy of exenatide versus insulin glargine primarily on glucemic control, and secondarily on body mass index (BMI), lipid profile and blood pressure, in type 2 diabetes mellitus (T2DM) patients suboptimally treated with metformin monotherapy. Forty-seven inadequately treated T2DM patients on metformin assigned to exenatide (n=18) or insulin glargine (n=29) for 26 weeks. Glycosylated hemoglobin (HbA1c), serum lipids, BMI, systolic and diastolic blood pressure, and adverse events, including episodes of hypoglycemia and gastrointestinal symptoms, were recorded. Either treatment had a similar favorable mean reduction in HbA1c. However, more patients in exenatide group achieved HbA1c ≤ 7% at the 26th week compared with insulin glargine group (p=0.036). Insulin glargine group had significantly more episodes of hypoglycemia compared with exenatide group (p=0.039). Gastrointestinal adverse events were non-significantly higher in the exenatide group. A significantly greater BMI reduction was observed in exenatide group, whereas ΒΜΙ was not altered in insulin glargine group. Total and LDL cholesterol (p=0.012), and triglycerides (p=0.016) significantly decreased, whereas HDL cholesterol increased (p=0.021) in the exenatide group, whereas only total cholesterol decreased in insulin glargine group. Changes in systolic and diastolic blood pressure were insignificant in both groups. Exenatide provided similar reduction in HbA1c, but fewer episodes of hypoglycemia, compared with insulin glargine. Exenatide had also a favorable effect on weight loss, although more gastrointestinal adverse events. Exenatide may provide a justified alternative in second line treatment of T2DM, but more trials are required to elucidate its long-term safety and cost-effectiveness.

Combination of peroxisome proliferator-activated receptor α/γ agonists may benefit type 2 diabetes patients with coronary artery disease through inhibition of inflammatory cytokine secretion

Patients with type 2 diabetes mellitus (T2DM) have a higher risk of cardiovascular disease (CVD). Peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of energy homeostasis. Therefore, we aimed to observe the effects of combined PPARα/γ agonists on T2DM patients with coronary artery disease (CAD). Patients were randomly divided into a rosiglitazone (RSG) group (n=20), a bezafibrate (BEZ) group (n=20), a combination of RSG and BEZ group (n=20) and a control group (n=20). Plasma C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) were measured by enzyme-linked immunosorbent assay before and 12 weeks after treatment. Fasting blood glucose (FBG), fasting insulin, insulin resistance index (IRI), hemoglobin A1c (HbA1c), lipid levels and body mass index were also investigated. At the end of the treatment, FBG, insulin, IRI, HbA1c and triglyceride levels decreased and the level of high-density lipoprotein cholesterol increased in the RSG, BEZ and combination groups. A decrease in low-density lipoprotein cholesterol was only observed in the combination group. Although the total cholesterol levels in all groups decreased, no significant difference was noted. The levels of CRP and MCP-1 were reduced in patients in the RSG, BEZ and combination groups. In addition, RSG, BEZ and the combination of RSG and BEZ also inhibited MCP-1 secretion. The combination of RSG and BEZ was more efficient than RSG or BEZ alone in downregulating cytokines. In conclusion, our results suggest that a combination of RSG and BEZ may be more efficient than RSG or BEZ alone in the treatment of T2DM patients with CAD.

Satisfaction with Treatment in Type 2 Diabetes Patients Requiring Insulin Treatment in Buenos Aires, Argentina

ObjectiveTo assess different dimensions of treatment satisfaction in patients with type 2 diabetes mellitus (T2DM) receiving insulin therapy. Study DesignCross-sectional study. We included 183 patients with T2DM followed by diabetes specialists in an ambulatory setting: 93 treated with neutral protamine Hagedorn insulin (NPH) and 90 with insulin glargine (IG). We used a Spanish version of the Diabetes Treatment Satisfaction Questionnaire (DTSQ) for Argentina. ResultsOverall treatment satisfaction was 30.04 (SD 5.40) for a maximum score of 36. The lowest score observed was for the satisfaction item “Flexibility of treatment” (4.7 out of 6, SD 1.27), and the highest score for the item “Recommending treatment to others” (5.39 out of 6, SD 1.23). In patients treated with IG, the overall treatment satisfaction score was 30.56 (SD 4.43); and 29.64 (SD 6.13) for those receiving NPH, not reaching a statistically significant difference. Perception of hypoglycemia was infrequent, with a mean score of 1.82 out of 6 (SD 1.62). For hyperglycemia, the mean score was 2.62 out of 6 (SD 1.54). In both cases, we found no difference between patients treated with IG and those treated with NPH insulin. ConclusionThis is the first study describing patient satisfaction with treatment in T2DM patients in Argentina. We have found levels of treatment satisfaction similar or greater to those described in developed countries. We expect that the results of this study may encourage physicians not to delay the initiation of insulin therapy in poorly controlled patients.

Current Issues in Glp-1 Receptor Agonist Therapy for Type 2 Diabetes

The clinical management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is guided not only by published treatment algorithms, but also by consideration of recent evidence and through consultation with colleagues and experts. Recent studies have dramatically increased the amount of information regarding the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Topics that may be of particular interest to clinicians who treat T2DM patients include relative glycemic control efficacy of GLP-1 RAs, use of GLP-1 RAs across T2DM progression and in combination with insulin, recent data regarding GLP-1 RA safety, nonglycemic actions of GLP-1 RAs, including weight effects, and impact of GLP-1 RAs on patient quality of life and treatment satisfaction. The following review includes expert consideration of these topics with emphasis on recent, relevant reports to illustrate current perspectives.

Long-term cost-utility analysis of exenatide once weekly versus insulin glargine for the treatment of type 2 diabetes patients in the US

Objective:The purpose of this study was to estimate the long-term cost-utility of treating type 2 diabetes mellitus (T2DM) patients with exenatide once weekly (EQW) compared with insulin glargine (IG) from a US payer perspective.Methods:A validated computer simulation model, the CORE Diabetes Model, was used to project lifetime clinical outcomes and direct medical costs. Direct medical costs included pharmacy costs and costs associated with the management of diabetes and its complications. The model was populated using patient characteristics (mean age: 57.9 years; mean diabetes duration: 7.9 years; mean HbA1c: 8.3%; mean body mass index [BMI]: 32.3 kg/m2) and clinical data from a phase 3 clinical trial that compared EQW with IG in T2DM patients on a background of metformin alone or a combination of metformin and a sulphonylurea (DURATION-3). All EQW patients were assumed to have stayed on treatment for 3 years before switching to IG. Health outcomes and costs were discounted at 3% per year. Complication costs were derived from published sources. A range of sensitivity analyses was performed.Results:Over a lifetime horizon, and compared with IG, EQW was associated with an incremental cost of $3914 (SD = 2923). EQW was projected to increase life expectancy by 0.135 (SD = 0.216) years and to improve quality-adjusted life expectancy by 0.246 (SD = 0.147) quality-adjusted life years (QALYs), generating an incremental cost-effectiveness ratio (ICER) of $15,936/QALY. Assuming a payer’s willingness to pay threshold of $50,000/QALY, EQW is therefore cost-effective compared to IG. One-way and probabilistic sensitivity analyses confirmed EQW’s cost-effective profile.Limitations:Short-term changes (26 weeks) in surrogate end-points (e.g., HbA1c, weight, complications) from one clinical trial were used to project long-term future effects on clinical outcomes.Conclusions:Treatment with EQW is projected to be cost-effective compared to treatment with IG.

Combination therapy with metformin plus vildagliptin in type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is pathophysiologically characterized by a combination of insulin resistance and beta-cell dysfunction. Consequently, a proper treatment of such a disease should target both of these defects. Dipeptidyl peptidase-4 (DPP-4) inhibitors are among the most recent additions to the therapeutic options for T2DM and are able to increase circulating levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus stimulating glucose-dependent insulin secretion.Areas covered: This paper provides an overview of the clinical results of combination therapy with metformin and the DPP-4 inhibitor vildagliptin in T2DM patients.Expert opinion: Vildagliptin–metformin single-tablet combination is indicated for the treatment of T2DM patients not achieving a sufficient glycemic control at their maximally tolerated dose of metformin. Results from clinical trials provide evidence of vildagliptin efficacy administered in addition to metformin, as either first- or second-line treatment. The vildagliptin–metformin association seems to have favorable effects on beta-cell function and is characterized by good safety and tolerability profiles when compared with other antidiabetic agents. Of note, data available suggest that administration of fixed-dose combination products, together with the low incidence of adverse gastrointestinal events, may improve compliance and adherence of patients to therapy, resulting in an improved metabolic control.

Modified Ling-Gui-Zhu-Gan decoction combined with short-term fasting improves therapeutic response in type 2 diabetic patients

ObjectiveTo evaluate the effects of a Traditional Chinese Medicine herbal decoction (modified Ling-Gui-Zhu-Gan decoction) combined with short-term fasting/very-low-calorie-diet (VLCD) on the therapeutic response in type 2 diabetes mellitus (T2DM) patients. Materials and methodsA randomized controlled pilot-study was conducted with 60 T2DM patients (age 52.1±13.4y, BMI 25.7±3.7kg/m2) with a lack of glycemic control. Patients were randomly allocated to the intervention group (n=30) or the control group (n=30). All patients received in-hospital treatment for one week followed by lifestyle recommendation. Patients in the intervention group participated in a 5-day modified fasting/VLCD combined with an intake of Ling-Gui-Zhu-Gan decoction. Patients in the control group received standard treatment only. Outcomes were assessed at baseline and at 3-months. ResultsFasting plasma-glucose, 2-h plasma-glucose after oral glucose tolerance-test, HbA1C, and the use of anti-diabetic medication decreased significantly in the intervention group compared to the control group after three months. Body weight also decreased significantly. ConclusionsA combined integrative treatment approach including fasting/VLCD and a Traditional Chinese Medicine decoction might be superior to standard treatment in T2DM patients. This therapeutic concept should be further evaluated.

Pharmacogenomics of Oral Antidiabetic Medications: Current Data and Pharmacoepigenomic Perspective

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent disease. Several classes of drugs are currently available to treat T2DM patients; however, clinical response to these drugs often exhibits significant variation among individuals. For the oral antidiabetic drug classes of sulfonylureas, nonsulfonylurea insulin secretagogs, biguanides and thiazolidinediones, pharmacogenomic evidence has accumulated demonstrating an association between specific gene polymorphisms and interindividual variability in their therapeutic and adverse reaction effects. These polymorphisms are in genes of molecules involved in metabolism, transport and therapeutic mechanisms of the aforementioned drugs. Overall, it appears that pharmacogenomics has the potential to improve the management of T2DM and help clinicians in the effective prescribing of oral antidiabetic medications. Although pharmacogenomics can explain some of the heterogeneity in dose requirements, response and incidence of adverse effects of drugs between individuals, it is now clearly understood that much of the diversity in drug effects cannot be solely explained by studying the genomic diversity. Epigenomics, the field that focuses on nongenomic modifications that influence gene expression, may expand the scope of pharmacogenomics towards optimization of drug therapy. Therefore, pharmacoepigenomics, the combined analysis of genetic variations and epigenetic modifications, holds promise for the realization of personalized medicine. Although pharmacoepigenomics has so far been evaluated mainly in cancer pharmacotherapy, studies on epigenomic modifications during T2DM development provide useful data on the potential of pharmacoepigenomics to elucidate the mechanisms underlying interindividual response to oral antidiabetic treatment. In summary, the present article focuses on available data from pharmacogenomic studies of oral antidiabetic drugs and also provides an overview of T2DM epigenomic research, which has the potential to boost the development of pharmacoepigenomics in antidiabetic treatment.

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

We appreciate the comments on our study Predictive clinical parameters for the therapeutic efficacy of sitagliptin in Korean type 2 diabetes mellitus, which was published in Diabetes & Metabolism Journal 2011;35:159-65. Sitagliptin is an oral hypoglycemic agent with characteristics that may make it particularly useful for treating type 2 diabetes mellitus (T2DM) [1]. The drug is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4) [2], which inactivates the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. By inhibiting the activity of DPP-4, sitagliptin stabilizes the active forms of these incretins, thereby supporting glucose homeostasis through mechanisms that are not in themselves likely to trigger hypoglycemia [3]. Previous randomized placebo-controlled clinical trials have shown that sitagliptin is an effective glucose lowering agent in patients with T2DM when used as monotherapy and when given in combination with other drugs such as metformin, sulfonylurea and thiazolidinediones [4-7]. In a meta-analysis of 18 randomized controlled trials, patients were more likely to reach the HbA1c goal of <7% when treated with sitagliptin compared with placebo (POR, 3.15; 95% confidence interval [CI], 2.47 to 3.72); sitagliptin was also associated with greater decline in HbA1c from baseline compared with placebo (WMD, -0.78%; 95% CI, -0.93 to -0.63) [8]. That study reported that sitagliptin treatment lead to improvements in glycemic control in patients with T2DM, including reductions in HbA1c 0.7 to 1.2%, and 17 to 63% of patients achieved HbA1c <7% at the end of the treatment. In our study, treatment with 100 mg sitagliptin with metformin or sulfonylurea for 24 weeks led to additional reductions of mean HbA1c to 1.23±1.15%. The likelihood of patients to reach the HbA1c goal of <7% with sitagliptin treatment was 47% at the end of 24 weeks. This glycemic lowering effect is greater than that observed in previous studies [9,10]. In addition, the HbA1c lowering effect of sitagliptin was more pronounced in non-obese patients and in patients with decreased insulin secretion compared with the non-responder group. This potent effects of sitagliptin are expected in Korean diabetic patients who have quantitative pancreatic deficiencies. Asian T2DM patients have relatively lower level of pancreatic secretory dysfunction than patients of European descent. Most studies of sitagliptin have demonstrated significant improvements in β-cell function [11,12]. Therefore, sitagliptin appears to be effective for the treatment of T2DM, and may become a first-line treatment in the future. As Dr. Oh noted, our study has some limitations. It is retrospective, and did not control for other factors such as exercise and diet. Despite these limitations, the results of our study indicate that sitagliptin treatment greatly reduces glucose level in younger, non-obese Korean T2DM patients. Further prospective studies with larger sample sizes are needed to determine the specific effects of sitagliptin.