Cost-Effectiveness of Dipeptidylpeptidase-4 Inhibitors Added to Metformin in Patients With Type 2 Diabetes in China.

Purpose: Dipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context. Materials and Methods: In this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters. Results: Of the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022 versus linagliptin 5 mg, saxagliptin 5 mg, sitagliptin 100 mg and vildagliptin50 mg, respectively. The sitagliptin 100 mg strategy was the cheapest option. The ICER of alogliptin 25 mg against sitagliptin 100 mg strategy was $6,952 per additional QALY gained, and the rest of the strategies were dominated or extended dominated. The most influential parameters were the cost of DPP-4 inhibitors and their treatment efficacy. Conclusions: These results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.

Comparative assessment of in vitro BBB tight junction integrity following exposure to cigarette smoke and e-cigarette vapor: a quantitative evaluation of the protective effects of metformin using small-molecular-weight paracellular markers.

BACKGROUND: The blood-brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) from blood-borne agents and potentially harmful xenobiotics. Our group's previous data has shown that tobacco smoke (TS) and electronic cigarettes (EC) affect the BBB integrity, increase stroke incidence, and are considered a risk factor for multiple CNS disorders. Metformin was also found to abrogate the adverse effects of TS and EC. METHODS: We used sucrose and mannitol as paracellular markers to quantitatively assess TS and EC's impact on the BBB in-vitro. Specifically, we used a quantitative platform to determine the harmful effects of smoking on the BBB and study the protective effect of metformin. Using a transwell system and iPSCs-derived BMECs, we assessed TS and EC's effect on sucrose and mannitol permeability with and without metformin pre-treatment at different time points. Concurrently, using immunofluorescence (IF) and Western blot (WB) techniques, we evaluated the expression and distribution of tight junction proteins, including ZO-1, occludin, and claudin-5. RESULTS: Our data showed that TS and EC negatively affect sucrose and mannitol permeability starting after 6 h and up to 24 h. The loss of barrier integrity was associated with a reduction of TEER values. While the overall expression level of ZO-1 and occludin was not significantly downregulated, the distribution of ZO-1 was altered, and discontinuation patterns were evident through IF imaging. In contrast to occludin, claudin-5 expression was significantly decreased by TS and EC, as demonstrated by WB and IF data. CONCLUSION: In agreement with previous studies, our data showed the metformin could counteract the negative impact of TS and EC on BBB integrity, thus suggesting the possibility of repurposing this drug to afford cerebrovascular protection.

Assessment of safety and tolerability of remogliflozin etabonate (GSK189075) when administered with total daily dose of 2000 mg of metformin.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are characterized by an elevated glycemic index and are at a higher risk for complications such as cardiovascular disease, nephropathy, retinopathy and peripheral neuropathy. Normalization of glycemic index can be achieved by dosing combinations of metformin with other anti-diabetic drugs. The present study (Clintrials number NCT00519480) was conducted to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of remogliflozinetabonate, an SGLT2 inhibitor, withdoses (500 mg and 750 mg BID) greater than the commercial dose (100 mg BID)in combination with metformin with minimum daily dose of 2000 mg given in two divided doses. METHODS: This was a randomized, double-blinded, repeat dose study in 50 subjects with T2DM. The study was conducted in three phases; run-in, randomization, and treatment. All subjects were on a stable metformin dosing regimen. Cohort 1 subjects were randomly allocated to receive either remogliflozin etabonate 500 mg BID or placebo BID (2:1) in addition to metformin. Cohort 2 subjects were administered with either remogliflozin etabonate 750 mg BID or placebo BID (2:1) in addition to metformin for 13 days. All the subjects were assessed for safety (adverse events, lactic acid levels, vital signs, electrocardiogram [ECG]), pharmacokinetic evaluation, and pharmacodynamics (Oral Glucose Tolerance Testing) parameters. RESULTS: Co-administration of remogliflozin etabonate and metformin was well tolerated in all subjects during the observation period. There were no severe or serious adverse events (SAEs) and no increase in lactic acid concentration was reported during the study. The statistical results showed that concomitant administration of remogliflozin etabonate, either 500 mg or 750 mg BID, with metformin had no effect on the pharmacokinetics of metformin. The accumulation ratios, Day 13 vs. Day 1, for AUC values of remogliflozin etabonate and its metabolites were all very close to 1, indicating no accumulation in plasma concentrations of remogliflozin etabonate and its metabolites. Mean glucose values from baseline and glucose and insulin values following oral glucose tolerance test (OGTT) were decreased in all treatment groups. CONCLUSION: Co-administration of doses of remogliflozin etabonate (500 mg BID or 750 mg BID) greater than the commercial dose (100 mg BID) with metformin (2000 mg BID) was shown to be safe and effective during the observation period. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00519480 . Registered:22 August 2007.

Cost-effectiveness analysis of polycystic ovary syndrome management and the risk of gestational diabetes in pregnant women: a decision-tree model.

BACKGROUND: This study estimated the cost-effectiveness of metformin to reduce the risk of gestational diabetes mellitus (GDM) in pregnant women with polycystic ovary syndrome (PCOS) from the US health-care payer perspective. METHODS: A decision tree was developed to simulate the progression of PCOS in a hypothetical cohort of 10,000 pregnant women diagnosed with PCOS and two scenarios were tested. Normal glucose regulation without developing GDM, average cost-effectiveness ratios (ACER), and the incremental cost-effectiveness ratios (ICERs) were the outcome measures assessed through pregnancy. Evidence from randomized clinical trials and other published literature were used to assess disease progression and its associated health-care costs. Sensitivity analyses that varied key model parameters were conducted. RESULTS: Management of PCOS with metformin was associated with lowest ACER ($669.78 per normal glucose regulation without GDM) as compared to 'no intervention' strategy. Metformin use is the most cost-effective strategy to manage PCOS during pregnancy with average cost savings of $7,593,372.97 and an average effect gain of 2271 of normal glucose regulation without GDM among pregnant women with PCOS. Sensitivity analyses determined that the results are robust. CONCLUSIONS: Management of PCOS during pregnancy may be a cost-effective strategy to reduce GDM risk and its associated complications.

Association between prior use of anti-diabetic medication and breast cancer stage at diagnosis.

BACKGROUND: Knowledge regarding antidiabetic medication (ADM) use prior to breast cancer (BC) diagnosis remains limited. The objectives were to (1) evaluate if the prior use of ADM was associated with BC stage at diagnosis and (2) identify and compare patient characteristics among BC patients using different ADMs. RESEARCH DESIGN AND METHODS: Newly diagnosed female BC patients exposed to any medication during one year prior to cancer diagnosis were identified in 2008-2013 Linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Stage at diagnosis, categorized as early and advanced, was the primary outcome. Chi-square tests were used to compare characteristics and logistic regression models were applied to examine the effect while controlling for patient's characteristics. RESULTS: A total of 1,719 female BC patients used ADM while 6,084 patients were non-ADM users. Although a higher proportion of ADM users (20.36%) were diagnosed with advanced stage compared to the non-ADM users (14.46%), the difference was not statistically significant after adjusting for the patients' characteristics. Besides, insulin users were more likely to be diagnosed with advanced stage (adjusted odds ratio 1.69; 95% CI 1.15, 2.48) compared to metformin users. CONCLUSIONS: The association between ADM use and BC diagnostic characteristics varied based on different treatments.

Metformin adherence in patients with type 2 diabetes and its association with glycated haemoglobin levels.

INTRODUCTION Metformin is the initial medication of choice for most patients with type 2 diabetes. Non-adherence results in poorer glycaemic control and increased risk of complications. AIM The aim of this study was to characterise metformin adherence and association with glycated haemoglobin (HbA1c) levels in a cohort of patients with type 2 diabetes. METHODS Prescription and dispensing data were used for this study. Primary care clinical and demographic data were collected from 10 general practices (October 2016-March 2018) and linked to pharmaceutical dispensing information. Metformin adherence was initially measured by calculating the proportion of patients who had optimal medication cover for at least 80% of days (defined as a medication possession ratio (MPR) of ≥0.8), calculated using dispensing data. Prescription adherence was assessed by comparing prescription and dispensing data. The association between non-adherence (MPR <0.8) and HbA1c levels was also assessed. RESULTS Of the 1595 patients with ≥2 metformin prescriptions, the mean MPR was 0.87. Fewer Maori had an MPR ≥0.8 than New Zealand European (63.8% vs. 81.2%). Similarly, Maori received fewer metformin prescriptions (P=0.02), although prescription adherence did not differ by ethnicity. Prescription adherence was lower in younger patients (P=0.002). Mean HbA1c levels were reduced by 4.8 and 5.0mmol/mol, respectively, in all and Maori patients with an MPR ≥0.8. Total prescription adherence reduced HbA1c by 3.2mmol/mol (all P<0.01). DISCUSSION Ethnic disparity exists for metformin prescribing, leading to an overall reduction in metformin coverage for Maori patients. This needs to be explored further, including understanding whether this is a patient preference or health system issue.

Luteolin cooperated with metformin hydrochloride alleviates lipid metabolism disorders and optimizes intestinal flora compositions of high-fat diet mice.

Luteolin (LU) is a flavonoid compound and metformin hydrochloride (MH) is a kind of drug. Studies have shown that both LU and MH have the function of hypoglycemic effect. However, there are few reports indicating that LU cooperated with MH (LU·MH) can relieve lipid metabolism disorders and optimize intestinal flora compositions of high-fat diet mice. In this research, we investigated the effects of LU, MH and LU·MH on lipid metabolism disorders and intestinal flora composition in high-fat diet mice. The study found that compared with high-fat diet (HFD) alone, LU, MH and LU·MH could significantly reduce the lipid metabolism disorder. Furthermore, compared with LU or MH alone, the biochemical indicators of LU·MH were significantly improved and the results of the histopathological section also showed that LU·MH has stronger liver repair ability. It revealed that the potential mechanisms of the LU·MH alleviating lipid metabolism disorders were involved in the simultaneous regulation of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1. In addition, LU·MH could regulate the intestinal flora compositions. This includes significantly reducing the ratio of Firmicutes and Bacteroidetes(F/B) and at the family level, increasing the relative abundance of Lachnospiraceae, Helicobacteraceae, Marinifilaceae and Peptococcaceae to relieve lipid metabolism disorders. In conclusion, the work found that LU·MH regulates the signal pathway of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1 simultaneously and decreases the ratio of F/B, as well as increases the relative abundance of certain microbiota to alleviate the lipid metabolism disorders of HFD-fed mice.

Cost-utility analysis of second-line anti-diabetic therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin.

BACKGROUND: There are significant differences in costs and effectiveness among the second-line treatment options for type 2 diabetes (T2DM). We aimed to evaluate the cost-effectiveness of the second-line anti-diabetic therapy in T2DM patients inadequately controlled on metformin (MET) in Taiwan from the perspective of the National Health Insurance (NHI). METHODS: The Cardiff T2DM model was used to predict the occurrence of mortality, diabetes-related complications, and drug adverse events. Five second-line treatments were selected for the analysis: sodium-glucose cotransporter 2 inhibitors (SGLT-2-i), glucagon-like peptide-1 receptor agonists (GLP-1-RA), dipeptidyl peptidase-4 inhibitor (DPP-4-i), sulfonylurea (SU), and insulin (INS). Treatment efficacy data were obtained from meta-analyses and randomized clinical trials, whereas cost data were derived from the NHI databases. RESULTS: The analysis found that SU + MET (DPP-4-i as triple therapy) had the lowest cost, and SU + MET (SGLT-2-i as triple therapy) was associated with a mean incremental benefit of 0.47 quality-adjusted life years (QALYs) at an incremental cost of NT$2769, resulting in an incremental cost-effectiveness ratio (ICER) of NT$5840/QALY. Compared to their next less costly strategies, SGLT-2-i + MET (SU as triple therapy) and SGLT-2-i + MET (DPP-4-i as triple therapy) had ICER values of NT$63,170/QALY and NT$64,090/QALY, respectively. These results were fairly robust to extensive sensitivity analyses, but were relatively sensitive to baseline HbA1c, HbA1c threshold, and utilities. CONCLUSION: The addition of either SU or SGLT-2-i to MET was found to be cost-effective, using the 2019 forecast for GDP per capita of Taiwan (NT$770,770) as the willingness to pay (WTP) threshold.

Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin.

We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial.

Metformin Usage Index and assessment of vitamin B12 deficiency among metformin and non-metformin users with type 2 diabetes mellitus.

AIM: The present study aimed to evaluate the combined effect of both dose and duration of metformin therapy on vitamin B12 levels in patients with type 2 diabetes mellitus (T2D). METHODS: We recruited 2887 patients with T2D between January 2018 and November 2019 and categorized them into two groups (metformin and non-metformin users) matched for age, mean duration of diabetes, and BMI. We calculated the "Metformin Usage Index" (MUI) which was defined as the product of the dose of metformin (mg) used and its duration divided by 1000. Vitamin B12 levels were compared between the two groups, and its association with MUI was assessed using correlation and multistep logistic regression analyses. RESULTS: Vitamin B12 levels < 200 pg/ml and between 200 and 300 pg/ml were noted among 24.5% and 34.5% metformin users, respectively; this was significantly higher than among non-metformin users (17.3% and 22.6%, respectively) [P < 0.001]. Overall, a vitamin B12 level < 300 pg/ml was found in 52.2% of the subjects. There was a significant association between an MUI > 5 and a high risk of vitamin B12 deficiency [P < 0.01]. The highest risk was observed among patients with an MUI > 15 [odds ratio (OR) 6.74, 95% CI 4.39-10.4] followed by patients with an MUI > 10 (OR 5.12, 95% CI 3.12-8.38). CONCLUSIONS: The MUI can be employed as a risk assessment tool for evaluation of vitamin B12 deficiency in patients with T2D. Further prospective studies are required to determine the MUI thresholds in populations with good nutritional statuses and low prevalence of vitamin B12 deficiency.

Efficacy and safety of generic exenatide injection in Chinese patients with type 2 diabetes: a multicenter, randomized, controlled, non-inferiority trial.

AIMS: This study aimed to compare the efficacy and safety of generic exenatide with branded exenatide Byetta® in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on monotherapy or combination therapy of metformin and insulin secretagogues. METHODS: A multicenter, randomized, controlled, non-inferiority trial was performed. A total of 240 patients with T2DM and glycated hemoglobin (HbA1c) ≥ 7% (53 mmol/mol) to ≤ 9.0% (75 mmol/mol) on monotherapy or combination therapy of metformin and insulin secretagogues for at least 3 months were randomized into generic exenatide or branded exenatide groups with a 1:1 ratio for 16 weeks of treatment. The primary endpoint was the change in HbA1c levels from baseline at week 16, with a non-inferiority margin of - 0.35% (- 3.83 mmol/mol) (lower bound of one-sided 95% confidence interval (CI) > - 0.35% (- 3.83 mmol/mol)). Secondary endpoints included the proportion of participants achieving HbA1c < 7% (53 mmol/mol), the changes in fasting plasma glucose (FPG), 2-h postprandial glucose (2hPG) following a standard meal, 7-point self-monitoring blood glucose (SMBG) profiles, body weight change from baseline at week 16 and the change in HbA1c levels from baseline at week 8. Safety issues were also evaluated. RESULTS: After 16 weeks of treatment, HbA1c levels decreased significantly from baseline in the two groups, with a reduction of - 1.10% ± 1.31% (- 12.0 mmol/mol ± 14.3 mmol/mol) in the generic exenatide group and - 1.08% ± 1.11% (- 11.8 mmol/mol ± 12.1 mmol/mol) in the branded exenatide group (both P < 0.001). The least-squares mean difference of HbA1c reduction between the two groups was - 0.03% (- 0.33 mmol/mol), with a lower one-sided 95% CI limit of - 0.27% (- 2.95 mmol/mol), which was higher than the prespecified non-inferiority margin of - 0.35% (- 3.83 mmol/mol). Moreover, there were no significant differences in the proportion of participants achieving HbA1c < 7% (53 mmol/mol) and the changes in FPG, 2hPG, 7-point SMBG profiles and body weight at week 16 and the change in HbA1c levels from baseline at week 8 (all P > 0.05) between the two groups. The incidence of adverse events, including the incidence of hypoglycemia (18.3% and 17.5%, respectively), was similar for the generic and branded exenatide groups (P > 0.05). CONCLUSIONS: In patients with T2DM inadequately controlled on monotherapy or combination therapy of metformin and insulin secretagogues, add-on treatment with generic exenatide demonstrated non-inferiority to branded exenatide in terms of improvements in HbA1c after 16 weeks of treatment. Furthermore, the two drugs were also similar for other efficacy endpoints and safety profile. Trial registration Chinese Clinical Trial Registry: ChiCTR-IPR-15006558, Date registered May 27, 2015.

Cost-effectiveness of diabetes treatment sequences to inform step therapy policies.

OBJECTIVES: Cost-effectiveness estimates are useful to a health plan when they are specific to a utilization management policy question. To help inform a step therapy policy decision, this study assessed the 3-year cost-effectiveness of adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor versus switching to a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with type 2 diabetes who are on metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor from both private and public payer perspectives in the United States. STUDY DESIGN: Cost-effectiveness analysis. METHODS: A decision-analytic model was built incorporating goal glycated hemoglobin (A1C) achievement as the effectiveness measure, as well as adverse effect and discontinuation rates from clinical trial data. One-way, scenario, and probabilistic sensitivity analyses were performed. RESULTS: In a cohort of 1000 patients, adding an SGLT2 inhibitor led to $3.9 million more in spending and 93 more patients reaching goal A1C compared with switching from a DPP-4 inhibitor to a GLP-1 RA. This resulted in an incremental cost-effectiveness ratio (ICER) of $42,125 per patient to achieve goal A1C from the private payer perspective. Using a public payer perspective led to an ICER of $103,829. These results were most sensitive to changes in drug costs and the proportion of patients achieving A1C goal or discontinuing. CONCLUSIONS: Assuming a $50,000 willingness-to-pay threshold, adding an SGLT2 inhibitor was cost-effective compared with switching from a DPP-4 inhibitor to a GLP-1 RA from a private payer perspective but not from a public payer perspective. This study highlights how differences in payer reimbursement rates for medications can lead to contrasting results.

Reducing the Burden of Diabetes Treatment: A Review of Low-cost Oral Hypoglycemic Medications.

BACKGROUND: The vast majority of individuals diagnosed with diabetes are low/middle income and may have access to only three of the 11 oral hypoglycemic medications (OHMs) due to cost: metformin intermediate release (IR) or extended release (ER), sulfonylureas (glimepiride, glipizide, glyburide), and pioglitazone. Sulfonylureas and pioglitazone have had significant controversy related to potential adverse events, but it remains unclear whether these negative outcomes are class, drug, or dose-related. OBJECTIVE: We conducted a narrative review of low-cost OHMs. METHODS: We evaluated the maximum recommended (MAX) compared to the most effective (EFF) daily dose, time-to-peak change in HbA1c levels, and adverse events of low-cost oral hypoglycemic medications. RESULTS: We found that the MAX was often greater than the EFF: metformin IR/ER (MAX: 2,550/2,000 mg, EFF: 1,500-2,000/1,500-2,000 mg), glipizide IR/ER (MAX: 40/20 mg, EFF: 20/5 mg), glyburide (MAX: 20 mg, EFF: 2.5-5.0 mg), pioglitazone (MAX: 45 mg, EFF: 45 mg). Time-to-peak change in HbA1c levels occurred at weeks 12-20 (sulfonylureas), 25-39 (metformin), and 25 (pioglitazone). Glimepiride was not associated with weight gain, hypoglycemia, or negative cardiovascular events relative to other sulfonylureas. Cardiovascular event rates did not increase with lower glyburide doses (p<0.05). Glimepiride and pioglitazone have been successfully used in renal impairment. CONCLUSION: Metformin, glimepiride, and pioglitazone are safe and efficacious OHMs. Prescribing at the EFF rather than the MAX may avoid negative dose-related outcomes. OHMs should be evaluated as individual drugs, not generalized as a class, due to different dosing and adverse-event profiles; Glimepiride is the preferred sulfonylurea since it is not associated with the adverse events as others in its class.

A Safety Comparison of Metformin vs Sulfonylurea Initiation in Patients With Type 2 Diabetes and Chronic Kidney Disease: A Retrospective Cohort Study.

OBJECTIVE: To compare the safety of metformin vs sulfonylureas in patients with type 2 diabetes by chronic kidney disease (CKD) stage. PATIENTS AND METHODS: This retrospective cohort study included adults in Manitoba, Canada, with type 2 diabetes, an incident monotherapy prescription for metformin or a sulfonylurea, and a serum creatinine measurement from April 1, 2006, to March 31, 2017. Patients were stratified by estimated glomerular filtration rate (eGFR) into the following groups: eGFR of 90 or greater, 60 to 89, 45 to 59, 30 to 44, or less than 30 mL/min/1.73 m2. Outcomes included all-cause mortality, cardiovascular events, and major hypoglycemic episodes. Baseline characteristics were used to calculate propensity scores and perform inverse probability of treatment weights analysis, and eGFR group was examined as an effect modifier for each outcome. RESULTS: The cohort consisted of 21,996 individuals (19,990 metformin users and 2006 sulfonylurea users). Metformin use was associated with lower risk for all-cause mortality (hazard ratio [HR], 0.48; 95% CI, 0.40-0.58; P<.001), cardiovascular events (HR, 0.67; 95% CI, 0.52-0.86; P=.002), and major hypoglycemic episodes (HR, 0.14; 95% CI, 0.09-0.20; P<.001) when compared with sulfonylureas. CKD was a significant effect modifier for all-cause mortality (P=.002), but not for cardiovascular events or major hypoglycemic episodes. CONCLUSION: Sulfonylurea monotherapy is associated with higher risk for all-cause mortality, major hypoglycemic episodes, and cardiovascular events compared with metformin. Although the presence of CKD attenuated the mortality benefit, metformin may be a safer alternative to sulfonylureas in patients with CKD.

The cost-effectiveness of metformin in pre-diabetics: a systematic literature review of health economic evaluations.

Objectives: Our aim was to systematically identify and appraise cost-effectiveness studies of metformin in prediabetic subjects.Methods: A systematic literature review was conducted and reported according to standard guidlines. The search was conducted in PubMed, Embase, International Society for Pharmacoeconomics and Outcomes Research (ISPOR) presentation database and the Cost-Effectiveness Analysis (CEA) and Center for Reviews and Dissemination (CRD) registries. All cost-effectiveness studies assessing metformin in prediabetic patients were included.Results: Twenty-three reports were included. Metformin and intensive lifestyle changes (ILC) interventions were always cost-effective compared to placebo. ILC was cost-effective and sometimes dominant compared to metformin. Metformin was cost-saving compared to ILC in the short and medium-term. Although, in the long term, metformin was more expensive than ILC in terms of direct medical costs, when indirect non-medical costs are included, metformin less expensive than ILC. One study reported that for patients with Body Mass Index (BMI) higher than 30 kg/m2, metformin is a cost-effective strategy compared to placebo and ILC. However, this finding was not confirmed by other retrieved studies.Conclusion: ILC is cost-effective compared to metformin and, both of them are cost-effective compared to placebo. Metformin may be cost-saving in the short- to medium-term and possibly in the long-term.

Intensification of medical management in type 2 diabetes: A real-world look at primary care practice.

AIMS: To determine which drugs were selected to be added to metformin for patients on dual anti-diabetic medication in the management of type 2 diabetes and to assess HbA1c and BMI outcomes at 6 and 12 months after the initiation of a second anti-diabetic medication. METHODS: A retrospective chart review of electronic medical record data. Second line anti-diabetic medication added to metformin between 7/1/2012 to 8/31/2017 in the primary care practice in Fairview Health System in Minnesota. RESULTS: 3413 patients met the selection criteria of type 2 diabetes, 18 years and older, dual anti-diabetes therapy with metformin being the first prescribed. The most frequently prescribed medications added to metformin were sulfonylurea and basal insulin accounting for 51% (1724/3413) and 37% (1268/3413) respectively. Mean HbA1c reductions at 6 and 12 months among 2134 patients with baseline and follow-up HbA1c data respectively were: GLP-1 agonist (-1.3, P < 0.001; -1.2, P < 0.001), sulfonylurea (-1.1, P < 0.001; -0.9, P < 0.001), basal insulin (-1.1, P < 0.001; -1.0, P < 0.001), DPP4 inhibitor (-0.7, P = 0.223; -0.8, P = 0.049). Patients prescribed a GLP-1 agonist had a higher mean baseline BMI (BMI =40.3 kg/m2) and this was the only group with a statistically significant BMI reduction from baseline at 6 and 12 months (-1.5, P = 0.049 and -1.8, P = 0.041). CONCLUSION AND RELEVANCE: Type 2 diabetes patients treated with sulfonylurea, basal insulin and GLP-1 agonist as an add on to metformin had significant reductions in HbA1c. Patients prescribed a GLP-1 agonist had a significant BMI reduction.

Evaluation of the Short-Term Cost-Effectiveness of IDegLira Versus Basal Insulin and Basal-Bolus Therapy in Patients with Type 2 Diabetes Based on Attainment of Clinically Relevant Treatment Targets.

BACKGROUND: Effective glycemic control can reduce the risk of complications and their related costs in patients with type 2 diabetes (T2D). Many patients fail to reach hemoglobin A1c (HbA1c) ≤ 6.5% or < 7.0%, often due to adverse effects of treatment, such as hypoglycemia and weight gain. Glycemic targets should be individualized and consider multiple factors, including the risk of adverse events and the patient's characteristics and comorbid conditions. OBJECTIVE: To compare the odds and annual cost of achieving treatment targets, which incorporate HbA1c targets of < 7.5%, < 8.0%, and ≤ 9.0%, with insulin degludec/liraglutide (IDegLira) versus basal insulin and basal-bolus therapy. METHODS: This is a post hoc analysis of the DUAL V and DUAL VII 26-week trials, which randomized patients with T2D uncontrolled (HbA1c 7%-10%) on insulin glargine 100 units/mL (IGlar U100) and metformin to IDegLira or continued IGlar U100 titration (DUAL V) or IGlar U100 + insulin aspart (DUAL VII), all with metformin. Proportions of patients achieving HbA1c targets (< 7.5%, < 8.0%, and ≤ 9.0%) by the end of trial were assessed via 3 outcomes: alone, without either hypoglycemia or weight gain (double composite outcome), or without a combination of hypoglycemia and weight gain (triple composite outcome). The cost per patient achieving the triple composite outcome at each HbA1c target (< 7.5%, < 8.0%, and ≤ 9.0%) was calculated by dividing the annual cost of treatment by the proportion of patients achieving the target. This short-term (1-year) cost-effectiveness analysis was conducted from the perspective of a U.S. health care payer. RESULTS: More patients achieved HbA1c < 7.5% (P < 0.0001) and < 8.0% (P = 0.0003), and a similar percentage achieved HbA1c ≤ 9.0% with IDegLira versus IGlar U100 (DUAL V). Similar proportions of patients achieved all 3 HbA1c targets with IDegLira compared with basal-bolus therapy (DUAL VII). The odds of achieving double or triple composite outcomes were significantly higher for IDegLira versus IGlar U100 or basal-bolus for all 3 HbA1c targets (P < 0.0001 in each case) in both trials. For each $1 spent on IDegLira, the equivalent annual costs per patient to achieve HbA1c targets of < 7.5%, < 8.0%, or ≤ 9.0% without hypoglycemia and without weight gain were $2.43, $2.10, and $2.05, respectively, for IGlar U100 and $6.33, $5.80, and $6.06, respectively, for basal-bolus therapy. CONCLUSIONS: Based on data from DUAL V and DUAL VII, this analysis showed that a greater or similar proportion of patients with T2D reached HbA1c targets with IDegLira compared with IGlar U100/basal-bolus therapy. Odds of achieving double or triple composite outcomes of HbA1c reduction without hypoglycemia and/or without weight gain were greatest for IDegLira. Short-term cost analyses based on the triple composite outcomes suggest that IDegLira is a cost-effective treatment option in the United States compared with either uptitration of IGlar U100 or basal-bolus therapy. DISCLOSURES: This study was supported by Novo Nordisk A/S. The analysis was based on the DUAL V (NCT01952145) and DUAL VII (NCT02420262) trials, which were funded and conducted by Novo Nordisk. This post hoc analysis was conceived and interpreted by the authors and drafted with medical writing support that was funded by Novo Nordisk. Novo Nordisk also reviewed the manuscript for medical accuracy. Hunt and Malkin are employees of Ossian Health Economics and Communications, which received consulting fees from Novo Nordisk during the conduct of this study and has received consulting fees from Novo Nordisk, unrelated to this study. Mocarski, Ranthe, and Schiffman are employees of Novo Nordisk and Novo Nordisk A/S. Cannon has received speaker fees/honoraria from Abbvie, Amgen, and Janssen; speaker fees from Novo Nordisk; and has stock ownership in Novo Nordisk. Bargiota has received speaker fees/honoraria from AstraZeneca, Eli Lilly, MSD, Novo Nordisk, Sanofi, Boehringer Ingelheim, and Novartis. Billings has received personal fees from Novo Nordisk, Sanofi, and Dexcom, unrelated to this study. Leiter reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Servier, and GSK, unrelated to this study. Doshi has no relevant conflicts of interest to disclose. Parts of this study were presented as a poster at the AMCP Managed Care & Specialty Pharmacy Annual Meeting; April 23-26, 2018; Boston, MA.

Drug price, dosage and safety: Real-world evidence of oral hypoglycemic agents.

OBJECTIVES: Drug price reduction is one of the major policies to restrain pharmaceutical expenses worldwide. This study explores whether there is a relationship between drug price and clinical quality using real-world data. METHODS: Patients with newly-diagnosed type 2 diabetes receiving metformin or sulfonylureas during 2001 and 2010 were identified using the claim database of the Taiwan universal health insurance system. Propensity score matching was performed to obtain comparable subjects for analysis. Pharmaceutical products were categorized as brand-name agents (BD), highpriced generics (HP) or low-priced generics (LP). Indicators of clinical quality were defined as the dosage of cumulative oral hypoglycemic agents (OHA), exposure to other pharmacological classes of OHA, hospitalization or urgent visit for hypoglycemia or hyperglycemia, insulin utilization and diagnosis of diabetic complications within 1 year after diagnosis. RESULTS: A total of 40,152 study subjects were identified. A generalized linear mix model showed that HP and BD users received similar OHA dosages with comparable clinical outcomes. By contrast, LP users had similar outcomes to BD users but received a 39% greater OHA dosage. A marginally higher risk of poor glycemic control in LP users was also observed. CONCLUSIONS: Drug price is related to indicators of clinical quality. Clinicians and health authorities should monitor the utilization, effectiveness and clinical safety indicators of generic drugs, especially those with remarkably low prices.

[De-escalation of antihyperglycemic treatment in patients with type 2 diabetes - when less is more]. / Az antihyperglykaemiás terápia deeszkalációja 2-es típusú diabetesben ­ amikor a kevesebb több.

Type 2 diabetes - due to its natural course - should be considered as a progressive chronic disease. Owing to this fact, antihyperglycemic treatment should be continuously increased stepwise in order to achieve proper glycemic control. Lifestyle modification should be initiated immediately after manifestation, shortly followed by metformin monotherapy, and later, dual or triple combinations and, finally, injectable derivatives - only insulin in the past - should be used for appropriate glycemic control. Guidelines about treatment approach of patients with type 2 diabetes unequivocally emphasize and describe in detail the need of treatment intensification, in other words, stepwise escalation in clinical practice. In the last couple of years, evidences provided that step down therapy, simplification of complex treatment regimens should also be considered in certain cases. This approach was generally called de-escalation in antihyperglycemic treatment which should be considered in patients with type 2 diabetes 1) after bariatric (metabolic) surgery; 2) with significant weight reduction irrespective of its origin; 3) with complex insulin regimens where re-evaluation of this treatment was missed; 4) with continuously decreasing renal function; 5) among elderly patients with comorbidities; 6) in social deprivation. In this article, data about therapeutic de-escalation of antihyperglycemic treatment in patients with type 2 diabetes and first experiences with this treatment approach are summarized. Orv Hetil. 2019; 160(31): 1207-1215.