An exploratory analysis of the cost-effectiveness of insulin glargine 300 units/mL versus insulin glargine 100 units/mL over a lifetime horizon using the BRAVO diabetes model.

BACKGROUND: This analysis assessed the cost-effectiveness of insulin glargine 300 units/mL (Gla-300) versus insulin glargine 100 units/mL (Gla-100) in insulin-naïve adults with type 2 diabetes (T2D) inadequately controlled with oral antidiabetic drugs (OADs). METHODS: Costs and outcomes for Gla-300 versus Gla-100 from a US healthcare payer perspective were assessed using the BRAVO diabetes model. Baseline clinical data were derived from EDITION-3, a 12-month randomized controlled trial comparing Gla-300 with Gla-100 in insulin-naïve adults with inadequately controlled T2D on OADs. Treatment costs were calculated based on doses observed in EDITION-3 and 2020 US net prices, while costs for complications were based on published literature. Lifetime costs ($US) and quality-adjusted life-years (QALYs) were predicted and used to calculate incremental cost-effectiveness ratio (ICER) estimates; extensive scenario and sensitivity analyses were conducted. RESULTS: Lifetime medical costs were estimated to be $353,441 and $352,858 for individuals receiving Gla-300 and Gla-100 respectively; insulin costs were $52,613 and $50,818. Gla-300 was associated with a gain of 8.97 QALYs and 21.12 life-years, while Gla-100 was associated with a gain of 8.89 QALYs and 21.07 life-years. This resulted in an ICER of $7522/QALY gained for Gla-300 versus Gla-100. Thus, Gla-300 was cost-effective versus Gla-100 based on a willingness-to-pay threshold of $50,000/QALY. Compared with Gla-100, Gla-300 provided a net monetary benefit of $3290. Scenario and sensitivity analyses confirmed the robustness of the base case. CONCLUSION: Gla-300 may be a cost-effective treatment option versus Gla-100 over a lifetime horizon for insulin-naïve people in the United States with T2D inadequately controlled on OADs.

Real-World Analysis of Long-Acting and NPH-Containing Insulins on Glycemic Control.

Introduction Affordability of insulin products has become a concern in the past several years as the average price of various insulin products has increased. While awaiting legislation at the federal level that would address issues leading to high insulin costs, providers may have shifted prescribing practices to prescribe the lowest-priced insulin products to achieve patients' treatment goals. Objective To compare the prevalence of hypoglycemic events between patients receiving lower-cost neutral protamine Hagedorn (NPH)-containing human insulins and higher-cost long-acting insulin analogs in Medicare Part D enrollees within a management services organization, as well as assessing glycemic control and changes in body mass index. Methods This was a multicenter, retrospective study conducted at three primary care clinics. The co-primary outcomes were percent difference of documented mild and severe hypoglycemic events between individuals receiving NPH-containing human insulin and long-acting insulin. Results A total of 72 patients met inclusion criteria and were receiving NPH-containing human insulins or the long-acting insulin analogs, 15 and 57 patients, respectively. Severe hypoglycemic events occurred in 3.5% vs 0% of the long-acting insulin analog and NPH-containing human insulin group, respectively (P = 0.999). Mild hypoglycemic episodes were experienced by 31.6% versus 33.3% of long-acting insulin analog and NPH, respectively (P = 0.539). For secondary outcomes, no difference was observed in glycemic control outcomes across insulin groups. Conclusion Among Medicare Part D patients with type 2 diabetes mellitus, the use of NPH-containing human insulins was not associated with an increased risk of mild or severe hypoglycemia-related episodes or reduced glycemic control compared with long-acting insulin. Study findings suggest that lower-cost, NPH-containing human insulins may be an alternative to higher-cost, long-acting insulin analogs.

Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: A model-based cost-effectiveness analysis using real-world data.

AIMS: To evaluate the cost-effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) in patients with type 2 diabetes (T2D) using real-world data. METHODS: A Markov model was utilized to estimate healthcare costs (US$) and quality-adjusted life-years (QALYs) of receiving treatments over 10 years from the healthcare sector perspective. Model inputs were derived from the analyses of Taiwan's National Health Insurance Research Database or published literature on Taiwanese T2D populations. Base-case analysis was performed for the overall study cohort and subgroup analyses were stratified by the presence or absence of established cardiovascular diseases (CVDs) or chronic kidney diseases (CKDs). RESULTS: Overall, using GLP-1RAs versus LAIs cost $6,053 per QALY gained. Results were robust across sensitivity and scenario analyses. Among patients with established CVDs and CKDs, GLP-1RA versus LAI therapy saved $673 (cost-saving) and cost $1,675 per QALY gained, respectively. Among patients without established CVDs and CKDs, GLP-1RA versus LAI therapy cost $9,093 and $7,659 per QALY gained, respectively. CONCLUSIONS: Using GLP-1RAs versus LAIs for T2D patients represented good economic value in real-world practice. Pronounced economic benefits of GLP-1RA therapy among those with prior CVDs or CKDs support rational treatment decisions and optimal healthcare resource allocation for these patients.

The Non-Human Primate in Safety Assessment of a Bifunctional Long-Acting Insulin Analogue.

Species selection plays a pivotal part during non-clinical safety assessment in drug development. If possible, use of non-human primates (NHPs) should be avoided due to ethical considerations. However, limiting factors as lack of pharmacologic activity in other species could necessitate use of NHPs. LAI-PCSK9i is a bi-functional molecule combining a long-acting insulin analogue with a PCSK9 inhibitor peptide aiming to provide glycaemic control and to reduce plasma LDL concentrations. The NHP was chosen for the safety assessment of LAI-PCSK9i being the most relevant species with basal levels and plasma lipid composition closest to humans, while the dog and initially also the minipig were deemed irrelevant due to lack of pharmacologic activity on LDL-lowering and biological differences in lipid profiles. An in vivo tolerability and toxicokinetic study of LAI-PCSK9i in NHPs showed recurrent and severe hypoglycaemia at very low doses. Therefore, the minipig was re-evaluated and a follow-up study thoroughly assessing blood glucose and cholesterol levels and clinical signs illustrated that minipigs dosed with LAI-PCSK9i, tolerated the compound and LAI-PCSK9i decreased glucose and LDL over time. This work underlines that careful consideration is required when selecting species during safety assessment in drug development. The tolerability issue in NHPs led to the subsequent selection of the minipig for safety evaluation of LAI-PCSK9i although as a suboptimal alternative, which unexpectedly had a measurable pharmacologic response on LDL lowering. In conclusion, the NHPs may be unsuitable as test species for safety assessment of long-acting insulin analogues due to high sensitivity to recurring hypoglycaemic episodes.

Assessment of the Effect of Timing of Insulin Glargine Administration (Bedtime versus Morning) on Glycemic Control in Children with Type 1 Diabetes in Cairo, Egypt: A Single Centre Experience.

BACKGROUND: Diabetes control without developing hypoglycemia is challenging in Type 1 diabetes (T1D) management, with few studies evaluating the effect of insulin glargine timing on glucoregulation. OBJECTIVES: The aim is to compare glycemic control using continuous glucose monitoring (CGM) in children with T1D receiving bedtime versus morning glargine and to assess CGM effect on glycemia. METHODS: This cross-sectional observational study was conducted on 30 pediatric patients with T1D receiving glargine (19 at bedtime and 11 in the morning). CGM sensor was applied for 3-5 days using the I-Pro2 blood glucose sensor. RESULTS: Total daily dose of glargine showed a significant correlation with HbA1C (p=0.006) and percentage of glucose readings within average (p=0.039). HbA1C correlated significantly with time in range (TIR) (p=0.049). Nocturnal hypoglycemia was significantly higher in the bedtime glargine group than in the morning one (p=0.016). The morning glargine group showed better control in terms of lower HbA1C and higher TIR, but these did not reach statistical significance. Follow- up after 3 months revealed significant improvement in the percentage of hyperglycemia, BG readings within average, as well as HbA1c (p:0.001). CONCLUSIONS: Bedtime glargine administration was associated with a higher frequency of occurrence of nocturnal hypoglycemia. No statistically significant difference in glycemic control between both groups was found. CGM use improved glycemic control.

The price paradox of biosimilar-like long-acting insulin.

OBJECTIVES: To describe the uptake and out-of-pocket (OOP) costs of Basaglar, the first long-acting insulin biosimilar, in a commercially insured population in the United States. STUDY DESIGN: Retrospective analysis of commercial pharmacy claims and pharmacy co-payment offsets. METHODS: We assessed Basaglar uptake by examining trends in the composition of the long-acting insulin market in the United States from 2014 to 2018. As patient demographics and plan type may be important determinants of biosimilar uptake, we also assessed characteristics of all long-acting insulin users by drug. We examined Basaglar OOP costs by assessing mean OOP costs per claim for users of Basaglar and other long-acting insulins, overall and by plan type, and the number and source of co-payment offsets for Basaglar and other insulin glargine products from Basaglar market entry through 2018. We used multivariate linear models to examine the relationship between Basaglar OOP expenditures and insurer-negotiated amounts, overall and by plan type. RESULTS: Basaglar experienced a rapid uptake. However, there was no evidence that Basaglar users had lower OOP costs than reference product (Lantus) users. CONCLUSIONS: Given our results and the approval of the first interchangeable biosimilar, we recommend the empirical evaluation of biosimilar cost savings to patients and insurers prior to promoting their automatic substitution.

Safety, efficacy, and cost-effectiveness of insulin degludec U100 versus insulin glargine U300 in adults with type 1 diabetes: a systematic review and indirect treatment comparison.

BACKGROUND: Clinical differences between degludec U100 (Deg-100) and glargine U300 (Gla-300) in type 1 diabetes (T1D) were unknown. AIM: To indirectly compare the safety, efficacy, and cost-effectiveness between Deg-100 and Gla-300 in T1D adults via systematic review. METHOD: Medline, the Cochrane Library, ClinicalTrials.gov, and Google Scholar were searched (October 2021). Randomized controlled trials comparing Deg-100 or Gla-300 vs. glargine U100 in T1D adults (follow-up ≥ 12 weeks) were selected and analyzed using a frequentist network meta-analysis. Cost-effectiveness analysis (CEA) was conducted over a 1-year time horizon from societal perspectives. RESULTS: Nine trials were included. Efficacy analysis suggested that Deg-100 was non-inferior to Gla-300 in reducing HbA1c (MD 0.03 [95% CI - 0.09 to 0.15]; P = 0.60), FPG (MD - 1.12 [- 2.19 to - 0.04]; P = 0.04), and pre-breakfast SMBG (MD - 0.71 [- 1.46 to 0.03]; P = 0.06). Safety analysis suggested that Deg-100 appeared to have lower rates of both severe (HR 0.44 [0.25-0.78]; P = 0.005) and nocturnal severe (HR 0.19 [0.08-0.44]; P < 0.001) hypoglycemia, with lower total (MD - 0.07 [- 0.13 to - 0.01]; P = 0.02) and basal (MD - 0.08 [- 0.12 to - 0.04]; P < 0.001) insulin doses compared with Gla-300. No significant differences were observed for other hypoglycemia outcomes, adverse events, serious adverse events, bolus insulin dose, and body weight. The CEA showed that Deg-100 appeared to be a dominant treatment in Japan (+ 0.0283 QALYs, ¥26,266 [$228] per patient) and the United States (+ 0.0267 QALYs, $986 per patient). CONCLUSION: Low-certainty indirect evidence suggested that Deg-100 appeared to have a favorable reduction in rates of severe hypoglycemia and more cost-effective compared with Gla-300 in T1D adults.

The Cost-Effectiveness of Intermediate-Acting, Long-Acting, Ultralong-Acting, and Biosimilar Insulins for Type 1 Diabetes Mellitus: A Systematic Review.

OBJECTIVES: The incidence of type 1 diabetes mellitus is increasing every year requiring substantial expenditure on treatment and complications. A systematic review was conducted on the cost-effectiveness of insulin formulations, including ultralong-, long-, or intermediate-acting insulin, and their biosimilar insulin equivalents. METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, HTA, and NHS EED were searched from inception to June 11, 2021. Cost-effectiveness and cost-utility analyses were included if insulin formulations in adults (≥ 16 years) with type 1 diabetes mellitus were evaluated. Two reviewers independently screened titles, abstracts, and full-text articles, extracted study data, and appraised their quality using the Drummond 10-item checklist. Costs were converted to 2020 US dollars adjusting for inflation and purchasing power parity across currencies. RESULTS: A total of 27 studies were included. Incremental cost-effectiveness ratios ranged widely across the studies. All pairwise comparisons (11 of 11, 100%) found that ultralong-acting insulin was cost-effective compared with other long-acting insulins, including a long-acting biosimilar. Most pairwise comparisons (24 of 27, 89%) concluded that long-acting insulin was cost-effective compared with intermediate-acting insulin. Few studies compared long-acting insulins with one another. CONCLUSIONS: Long-acting insulin may be cost-effective compared with intermediate-acting insulin. Future studies should directly compare biosimilar options and long-acting insulin options and evaluate the long-term consequences of ultralong-acting insulins.

Hospitalization costs with degludec versus glargine U100 for patients with type 2 diabetes at high cardiovascular risk: Canadian costs applied to SAEs from a randomized outcomes trial.

OBJECTIVES: The present cost-consequence analysis compared estimated hospitalization costs in a Canadian setting with insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. METHODS: Medical terms were mapped across the different vocabularies, in order to assign unit costs from eligible hospital abstracts in Canadian Institute for Health Information data (International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada) to serious adverse events (SAEs; Medical Dictionary for Regulatory Activities) from the randomized DEVOTE trial comparing the two insulins degludec and glargine. Mean annual costs of SAE-related hospitalizations were estimated by treatment, the cost difference (degludec - glargine U100) was bootstrapped to compute confidence intervals (CIs) and p-values, and the cost ratio (degludec/glargine U100) was estimated using a Tweedie distribution. RESULTS: The mean annual cost per patient for SAE-related hospitalizations was 4,074 CAD with degludec and 4,569 CAD with glargine U100 (cost difference: -495, 95% confidence interval [CI]: -966; -24, p = .039), for a cost ratio of 0.89 (95% CI: 0.81; 0.98, p = .016). Overall, cost ratios from sensitivity analyses varying individual methodological assumptions were consistent with the main analysis. Of the system organ classes from DEVOTE SAEs, cardiac disorders were the largest contributor to the costs savings with degludec versus glargine U100. CONCLUSIONS: In patients with T2D at high CV risk, our findings suggest that there are likely to be lower hospitalization costs with degludec versus glargine U100 based on the SAEs observed in DEVOTE and in a Canadian setting.

Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe: Findings and Implications.

BACKGROUND: Diabetes mellitus rates and associated costs continue to rise across Europe enhancing health authority focus on its management. The risk of complications is enhanced by poor glycaemic control, with long-acting insulin analogues developed to reduce hypoglycaemia and improve patient convenience. There are concerns though with their considerably higher costs, but moderated by reductions in complications and associated costs. Biosimilars can help further reduce costs. However, to date, price reductions for biosimilar insulin glargine appear limited. In addition, the originator company has switched promotional efforts to more concentrated patented formulations to reduce the impact of biosimilars. There are also concerns with different devices between the manufacturers. As a result, there is a need to assess current utilisation rates for insulins, especially long-acting insulin analogues and biosimilars, and the rationale for patterns seen, among multiple European countries to provide future direction. Methodology. Health authority databases are examined to assess utilisation and expenditure patterns for insulins, including biosimilar insulin glargine. Explanations for patterns seen were provided by senior-level personnel. RESULTS: Typically increasing use of long-acting insulin analogues across Europe including both Western and Central and Eastern European countries reflects perceived patient benefits despite higher prices. However, activities by the originator company to switch patients to more concentrated insulin glargine coupled with lowering prices towards biosimilars have limited biosimilar uptake, with biosimilars not currently launched in a minority of European countries. A number of activities were identified to address this. Enhancing the attractiveness of the biosimilar insulin market is essential to encourage other biosimilar manufacturers to enter the market as more long-acting insulin analogues lose their patents to benefit all key stakeholder groups. CONCLUSIONS: There are concerns with the availability and use of insulin glargine biosimilars among European countries despite lower costs. This can be addressed.

Association between industry payments and prescriptions of long-acting insulin: An observational study with propensity score matching.

BACKGROUND: The rapidly increased spending on insulin is a major public health issue in the United States. Industry marketing might be one of the upstream determinants of physicians' prescription of long-acting insulin-the most commonly used and costly type of insulin, but the evidence is lacking. We therefore aimed to investigate the association between industry payments to physicians and subsequent prescriptions of long-acting insulin. METHODS AND FINDINGS: Using the databases of Open Payments and Medicare Part D, we examined the association between the receipt of industry payments for long-acting insulin in 2016 and (1) the number of claims; (2) the costs paid for all claims; and (3) the costs per claim of long-acting insulin in 2017. We also examined the association between the receipt of payments and the change in these outcomes from 2016 to 2017. We employed propensity score matching to adjust for the physician-level characteristics (sex, years in practice, specialty, and medical school attended). Among 145,587 eligible physicians treating Medicare beneficiaries, 51,851 physicians received industry payments for long-acting insulin worth $22.3 million. In the propensity score-matched analysis including 102,590 physicians, we found that physicians who received the payments prescribed a higher number of claims (adjusted difference, 57.8; 95% CI, 55.8 to 59.7), higher costs for total claims (adjusted difference, +$22,111; 95% CI, $21,387 to $22,836), and higher costs per claim (adjusted difference, +$71.1; 95% CI, $69.0 to $73.2) of long-acting insulin, compared with physicians who did not receive the payments. The association was also found for changes in these outcomes from 2016 to 2017. Limitations to our study include limited generalizability, confounding, and possible reverse causation. CONCLUSIONS: Industry marketing payments to physicians for long-acting insulin were associated with the physicians' prescriptions and costs of long-acting insulin in the subsequent year. Future research is needed to assess whether policy interventions on physician-industry financial relationships will help to ensure appropriate prescriptions and limit overall costs of this essential drug for diabetes care.

A comprehensive stability assessment of insulin degludec using New customized validated RP-HPLC and SEC-HPLC methods in an orthogonal testing protocol.

Stress testing of biopharmaceuticals plays an important role in preparation of their stability profiles through investigation of possible degradation pathways and identification of degradation products, so in this study Insulin Degludec which is a new generation ultra-long-acting basal insulin is subjected to stress conditions as different temperatures, different pH, oxidation, mechanical agitation, and repeated freeze and thaw cycles to generate possible degradation products and aggregation that are investigated by two new validated RP-HPLC and SEC-HPLC methods in addition to dynamic light scattering (DLS) and native polyacrylamide gel electrophoresis (Nu-PAGE). SEC-HPLC was used to investigate formation of aggregates whose results were correlated with those obtained from DLS and Nu-PAGE, while RP-HPLC was used to investigate any possible chemical modifications. The Proposed RP-method had limit of detection (LOD) and limit of quantitation (LOQ) of 0.012 mg/mL and 0.045 mg/mL respectively and accuracy of 99.22 ± 1.07 %, while the SEC methods had limit of detection (LOD) and limit of quantitation (LOQ) of 0.012 mg/mL and 0.031 mg/mL, respectively. The degradation pattern due to high temperature effect and oxidation is investigated by LC- tandem mass spectrometry. Results showed that Insulin degludec is highly stable under low temperature, mechanical agitation and repeated freeze and thaw stress conditions but elevated temperature and high acidic condition lead to formation of aggregates and also chemical modifications including deamidation, isomerization and oxidation. Such different chemical degradation pathways are due to presence of variable reactive moieties in Insulin degludec structure. Insulin degludec is highly vulnerable to oxidation at the sulfur containing cysteine residue in B chain in position B7 forming trioxidation derivative when exposed to hydrogen peroxide. Formation of A21-Asp and A18-Asp deamidated variants as well as B3-Asp and B3-isoAsp deamidated variants are prominent degradation pathways at neutral pH but at elevated temperature.

Ongoing efforts to improve the management of patients with diabetes in Bangladesh and the implications.

BACKGROUND: Prevalence rates of patients with diabetes are growing across countries, and Bangladesh is no exception. Associated costs are also increasing, driven by costs associated with the complications of diabetes including hypoglycemia. Long-acting insulin analogues were developed to reduce hypoglycemia as well as improve patient comfort and adherence. However, they have been appreciably more expensive, reducing their affordability and use. Biosimilars offer a way forward. Consequently, there is a need to document current prescribing and dispensing rates for long-acting insulin analogues across Bangladesh, including current prices and differences, as a result of affordability and other issues. METHODS: Mixed method approach including surveying prescribing practices in hospitals coupled with dispensing practices and prices among community pharmacies and drug stores across Bangladesh. This method was adopted since public hospitals only dispense insulins such as soluble insulins free-of-charge until funds run out and all long-acting insulin analogues have to be purchased from community stores. RESULTS: There has been growing prescribing and dispensing of long-acting insulins in Bangladesh in recent years, now accounting for over 80% of all insulins dispensed in a minority of stores. This increase has been helped by growing prescribing and dispensing of biosimilar insulin glargine at lower costs than the originator, with this trend likely to continue with envisaged growth in the number of patients. Consequently, Bangladesh can serve as an exemplar to other low- and middle-income countries struggling to fund long-acting insulin analogues for their patients. CONCLUSIONS: It was encouraging to see continued growth in the prescribing and dispensing of long-acting insulin analogues in Bangladesh via the increasing availability of biosimilars. This is likely to continue benefitting all key stakeholder groups.

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus.

BACKGROUND: People with type 1 diabetes mellitus (T1DM) need treatment with insulin for survival. Whether any particular type of (ultra-)long-acting insulin provides benefit especially regarding risk of diabetes complications and hypoglycaemia is unknown. OBJECTIVES: To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues to NPH insulin (neutral protamine Hagedorn) or another (ultra-)long-acting insulin analogue in people with type 1 diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We explored the US Food and Drug Administration (FDA) and European Medical Agency (EMA) web pages. We asked pharmaceutical companies, EMA and investigators for additional data and clinical study reports (CSRs). The date of the last search of all databases was 24 August 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 24 weeks or more comparing one (ultra-)long-acting insulin to NPH insulin or another (ultra-)long-acting insulin in people with T1DM. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias using the new Cochrane 'Risk of bias' 2 (RoB 2) tool and extracted data. Our main outcomes were all-cause mortality, health-related quality of life (QoL), severe hypoglycaemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse events (SAEs) and glycosylated haemoglobin A1c (HbA1c). We used a random-effects model to perform meta-analyses and calculated risk ratios (RRs) and odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) and 95% prediction intervals for effect estimates. We evaluated the certainty of the evidence applying the GRADE instrument. MAIN RESULTS: We included 26 RCTs. Two studies were unpublished. We obtained CSRs, clinical study synopses or both as well as medical reviews from regulatory agencies on 23 studies which contributed to better analysis of risk of bias and improved data extraction. A total of 8784 participants were randomised: 2428 participants were allocated to NPH insulin, 2889 participants to insulin detemir, 2095 participants to insulin glargine and 1372 participants to insulin degludec. Eight studies contributing 21% of all participants comprised children. The duration of the intervention varied from 24 weeks to 104 weeks. Insulin degludec versus NPH insulin: we identified no studies comparing insulin degludec with NPH insulin. Insulin detemir versus NPH insulin (9 RCTs): five deaths reported in two studies including adults occurred in the insulin detemir group (Peto OR 4.97, 95% CI 0.79 to 31.38; 9 studies, 3334 participants; moderate-certainty evidence). Three studies with 870 participants reported QoL showing no true beneficial or harmful effect for either intervention (low-certainty evidence). There was a reduction in severe hypoglycaemia in favour of insulin detemir: 171/2019 participants (8.5%) in the insulin detemir group compared with 138/1200 participants (11.5%) in the NPH insulin group experienced severe hypoglycaemia (RR 0.69, 95% CI 0.52 to 0.92; 8 studies, 3219 participants; moderate-certainty evidence). The 95% prediction interval ranged between 0.34 and 1.39. Only 1/331 participants in the insulin detemir group compared with 0/164 participants in the NPH insulin group experienced a NFMI (1 study, 495 participants; low-certainty evidence). No study reported NFS. A total of 165/2094 participants (7.9%) in the insulin detemir group compared with 102/1238 participants (8.2%) in the NPH insulin group experienced SAEs (RR 0.95, 95% CI 0.75 to 1.21; 9 studies, 3332 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 70/1823 participants (3.8%) in the insulin detemir group compared with 60/1102 participants (5.4%) in the NPH insulin group (RR 0.67, 95% CI 0.39 to 1.17; 7 studies, 2925 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin detemir with NPH insulin was 0.01%, 95% CI -0.1 to 0.1; 8 studies, 3122 participants; moderate-certainty evidence. Insulin glargine versus NPH insulin (9 RCTs): one adult died in the NPH insulin group (Peto OR 0.14, 95% CI 0.00 to 6.98; 8 studies, 2175 participants; moderate-certainty evidence). Four studies with 1013 participants reported QoL showing no true beneficial effect or harmful effect for either intervention (low-certainty evidence). Severe hypoglycaemia was observed in 122/1191 participants (10.2%) in the insulin glargine group compared with 145/1159 participants (12.5%) in the NPH insulin group (RR 0.84, 95% CI 0.67 to 1.04; 9 studies, 2350 participants; moderate-certainty evidence). No participant experienced a NFMI and one participant in the NPH insulin group experienced a NFS in the single study reporting this outcome (585 participants; low-certainty evidence). A total of 109/1131 participants (9.6%) in the insulin glargine group compared with 110/1098 participants (10.0%) in the NPH insulin group experienced SAEs (RR 1.08, 95% CI 0.63 to 1.84; 8 studies, 2229 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 69/938 participants (7.4%) in the insulin glargine group compared with 83/955 participants (8.7%) in the NPH insulin group (RR 0.83, 95% CI 0.62 to 1.12; 6 studies, 1893 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin glargine with NPH insulin was 0.02%, 95% CI -0.1 to 0.1; 9 studies, 2285 participants; moderate-certainty evidence. Insulin detemir versus insulin glargine (2 RCTs),insulin degludec versus insulin detemir (2 RCTs), insulin degludec versus insulin glargine (4 RCTs): there was no evidence of a clinically relevant difference for all main outcomes comparing (ultra-)long-acting insulin analogues with each other. For all outcomes none of the comparisons indicated differences in tests of interaction for children versus adults. AUTHORS' CONCLUSIONS: Comparing insulin detemir with NPH insulin for T1DM showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). However, the 95% prediction interval indicated inconsistency in this finding. Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia. For all other main outcomes with overall low risk of bias and comparing insulin analogues with each other, there was no true beneficial or harmful effect for any intervention. Data on patient-important outcomes such as QoL, macrovascular and microvascular diabetic complications were sparse or missing. No clinically relevant differences were found between children and adults.

Assessment of basal insulin adherence using 2 methodologies among Texas Medicaid enrollees with type 2 diabetes.

BACKGROUND: Basal insulin is often recommended as the initial therapy for patients with type 2 diabetes who require insulin treatment. Adequate adherence is critical to diabetes management, yet suboptimal insulin adherence has been reported. Second-generation long-acting (SGLA) insulin has higher dosing flexibility and lower hypoglycemia risk and may improve adherence. However, little is known regarding adherence to SGLA insulin and how adherence to SGLA insulin compares with intermediate-acting neutral protamine Hagedorn (NPH) and first-generation long-acting (FGLA) insulin. Measurement of insulin adherence is challenging because of the inaccuracies of recorded days supply of insulin, and traditional medication possession ratio (MPR) may be negatively affected. Adjusted MPR (aMPR) has been developed in an effort to address this issue. OBJECTIVE: To examine the unadjusted and adjusted associations between basal insulin type and adherence to basal insulin using MPR and aMPR. METHODS: This retrospective database study used Texas Medicaid prescription claims from January 1, 2014, through June 30, 2017. The index date was the date of the first basal insulin prescription without the same prescription 6 months before (pre-index), and all patients were followed for 12 months (post-index). Patients aged 18-63 years with ≥ 1 pre-index prescription of an oral hypoglycemia agent (OHA) or a glucagon-like peptide-1 receptor agonist (GLP-1 RA), without any post-index prescription of premixed insulin or a basal insulin different from index insulin, and with continuous enrollment throughout the pre- and post-index periods, were included. The dependent variable was basal insulin adherence over 12 months, measured using MPR and aMPR. Unadjusted and adjusted adherence comparisons were conducted by basal (background) insulin type (NPH, FGLA, and SGLA). Covariates included age, gender, baseline use of basal insulins and comorbid medications, total number of medications, OHA adherence, post-index number of OHAs, and use of bolus insulins and GLP-1 RAs. Analysis of variance, chi-square tests, and multiple logistic regression analyses were performed. RESULTS: Of the 5,034 patients included, NPH, FGLA, and SGLA insulin users accounted for 3.7%, 89.8%, and 6.5%, respectively. The overall mean (SD) age was 50.9 (9.9) years, and 65.9% were female. In the unadjusted bivariate analyses, SGLA insulin users had significantly higher adherence, using either MPR (SGLA 0.68 [0.25] vs. FGLA 0.59 [0.27] vs. NPH 0.55 [0.27]; P < 0.0001) or aMPR (0.83 [0.23] vs. 0.78 [0.26] vs. 0.73 [0.28]; P = 0.0001). After controlling for covariates, insulin type was not significantly associated with the likelihood of being adherent (MPR or aMPR ≥ 0.8) using either measure. CONCLUSIONS: Adherence to SGLA insulin was not different from adherence to other basal insulins after controlling for patient characteristics. Yet, MPR and aMPR have limitations and warrant further confirmation of the study findings. Before new adherence measures for insulin therapy are developed, MPR and aMPR should be used with caution. DISCLOSURES: No specific funding was received for this manuscript. The authors report no potential conflicts of interest. Part of the data from this study was presented as posters at the American Pharmacists Association 2020 Annual Meeting & Exposition, March 20-23, 2020, in National Harbor, MD, and at the International Society for Pharmacoeconomics and Outcomes Research 2020 Conference, May 16-20, 2020, in Orlando, FL.

Using 2nd generation basal insulins in type 2 diabetes: Costs and savings in a comparative economic analysis in Italy, based on the BRIGHT study.

BACKGROUND AND AIMS: To evaluate the economic impact of using 2nd generation basal insulin analogs, Glargine 300 Units/ml (Gla-300) vs Degludec 100 Units/ml (IDeg-100), in patients with type 2 diabetes (T2D). METHODS AND RESULTS: An economic analysis was conducted using findings from the BRIGHT study (the first controlled, head-to-head study comparing Gla-300 vs IDeg-100), and costs for the Italian National Healthcare Service (NHS). A cost-minimization analysis (CMA) and a budget impact analysis (BIA) were conducted. Only pharmacological costs were included in the analysis. The CMA estimated patient treatment costs at 24 weeks and 1 year; the BIA assessed the economic impact of treating the overall Italian population of T2D insulin-naïve patients, who initiated insulin treatment during the period September 2017-August 2018 (N = 55 318). In the BIA, four different scenarios were compared: i) all patients receive IDeg-100 (Scenario A); ii) 61% of patients receive Gla-300, 39% IDeg-100 (Scenario B); iii) 80% of patients receive Gla-300, 20% IDeg-100 (Scenario C); iv) all patients treated with Gla-300 (Scenario D). The average treatment costs per patient were lower with Gla-300 vs IDeg-100 (at 24 weeks: €129 vs €161; at 1 year: €324 vs €409, respectively). Results of the BIA showed that comparing Scenario D vs Scenario A, total savings would amount to €1.76 million at 24 weeks, €4.73 million at 1 year, €5.53 million at 2 years. CONCLUSION: A larger use of Gla-300 vs IDeg-100 for the treatment of T2D patients would lead to a relevant reduction of therapy costs in Italy.

Real-world cost-effectiveness of insulin degludec in type 1 and type 2 diabetes mellitus from a Swedish 1-year and long-term perspective.

BACKGROUND AND AIMS: The ReFLeCT study demonstrated that switching to insulin degludec from other basal insulins was associated with reductions in glycated hemoglobin and hypoglycemic events in type 1 (T1D) and type 2 diabetes (T2D), and reductions in insulin doses in T1D. The aim of the present analysis was to assess the short- and long-term cost-effectiveness of switching to insulin degludec in Sweden. METHODS: Short-term outcomes were evaluated over 1 year in a Microsoft Excel model, while long-term outcomes were projected over patient lifetimes using the IQVIA CORE Diabetes Model. Cohort characteristics and treatment effects were sourced from the ReFLeCT study. Costs (in 2018 Swedish krona [SEK]) encompassed direct medical expenditure and indirect costs from loss of workplace productivity. In the long-term analyses, patients were assumed to receive insulin degludec or continue prior insulin therapy (primarily insulin glargine U100) for 5 years, before all patients intensified to once-daily degludec and mealtime aspart. RESULTS: Switching to insulin degludec was associated with improved quality-adjusted life expectancy of 0.04 and 0.02 quality-adjusted life years (QALYs) over 1 year, and 0.16 and 0.08 QALYs over patient lifetimes, in T1D and T2D. Combined costs in T1D and T2D were estimated to be SEK 1,249 lower and SEK 1,181 higher over the short-term, and SEK 157,258 and SEK 2,114 lower over the long-term. Benefits were due to lower insulin doses in T1D, reduced rates of hypoglycemia, and lower incidences of diabetes-related complications. Insulin degludec was associated with an incremental cost-effectiveness ratio of SEK 64,298 per QALY gained for T2D over 1 year and considered dominant for T1D and T2D in all other comparisons. CONCLUSIONS: Insulin degludec was projected to be cost-effective or dominant versus other basal insulins for the treatment of T1D and T2D in Sweden.

Cost-Effectiveness of Insulin Degludec Versus Insulin Glargine U300 in the Netherlands: Evidence From a Randomised Controlled Trial.

INTRODUCTION: This study aimed to evaluate the short-term cost-effectiveness of insulin degludec 200 units/mL (degludec) versus insulin glargine 300 units/mL (glargine U300) from a Dutch societal perspective. METHODS: A previously published model estimated costs [2018 euros (EUR)] and effectiveness [quality-adjusted life years (QALYs)] with degludec compared with glargine U300 over a 1-year time horizon. The model captured hypoglycaemia rates and insulin dosing. Clinical outcomes were informed by CONCLUDE (NCT03078478), a head-to-head randomised controlled trial in insulin-experienced patients with type 2 diabetes. RESULTS: Treatment with degludec was associated with mean annual cost savings (EUR 24.71 per patient) relative to glargine U300, driven by a lower basal insulin dose and lower severe hypoglycaemia rate with degludec compared with glargine U300. Lower rates of non-severe nocturnal and severe hypoglycaemia resulted in improved effectiveness (+ 0.0045 QALYs) with degludec relative to glargine U300. In sensitivity analyses, changes to the vast majority of model parameters did not materially affect model outcomes. CONCLUSIONS: This short-term analysis, informed by the latest clinical trial evidence, demonstrated that degludec was a cost-effective treatment option relative to glargine U300. As such, our modelling analysis suggests that degludec would represent an efficient use of Dutch public healthcare resources in this patient population.

Cost-effectiveness of switching to insulin degludec from other basal insulins in real-world clinical practice in Italy.

Aims: The costs associated with insulin therapy and diabetes-related complications represent a significant and growing economic burden for healthcare systems. The aim of this study was to evaluate the cost-effectiveness of switching to insulin degludec (degludec) vs continuing previous basal insulin, in Italian patients with type 1 (T1D) or type 2 (T2D) diabetes, using a long-term economic model.Materials and methods: Data were retrieved from a real-world population of patients from clinical practice in Italy. Clinical parameters included in the base-case model were change from baseline in HbA1c, rates of hypoglycemia, and basal and bolus insulin dose, at 6 months following switch to degludec. Costs of treatments were taken from official Italian pharmaceutical list prices and costs of hypoglycemia were based on the literature. The data were used to populate a long-term (lifetime) IQVIA CORE Diabetes Model to evaluate the incremental cost-effectiveness ratio (ICER) - cost per quality-adjusted life-year (QALY). The robustness of these results was tested with extensive sensitivity analyses by varying the time horizons and abolishing each of the treatment differences and previous basal insulins.Results: The total incremental cost for degludec vs previous basal insulin was €-6,310 and €-2,682 for patients with T1D and T2D, respectively; the switch to degludec resulted in a QALY gain of 0.781 and 0.628. The long-term ICER for degludec vs continuing the previous basal insulin regimen showed that degludec was dominant for both T1D and T2D, meaning that patient health was improved in terms of QALYs with lower healthcare costs. Sensitivity analyses showed that degludec remained dominant in most scenarios including after elimination of any benefit in non-severe hypoglycemia and insulin dose, in both T1D and T2D.Conclusions: Under routine care, switching to degludec is dominant, compared with continuing previous basal insulin, in Italian patients with T1D or T2D.