Franz-Werner Dippel

Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis.

BackgroundThere are a number of instruments that describe severity and progression of multiple sclerosis and they are increasingly used as endpoints to assess the effectiveness of therapeutic interventions. We examined to what extent the psychometric properties of two accepted instruments – EDSS and MSFC – meet methodological standards and the value they have in clinical trials.MethodsWe conducted a systematic literature search in relevant databases [MEDLINE (PubMed), ISI Web of Science, EMBASE, PsycINFO & PSYNDEX, CINAHL] yielding 3,860 results. Relevant full-text publications were identified using abstract and then full-text reviews, and the literature was reviewed.ResultsFor evaluation of psychometric properties (validity, reliability, sensitivity of change) of EDSS and MSFC, 120 relevant full-text publications were identified, 54 of them assessed the EDSS, 26 the MSFC and 40 included both instruments. The EDSS has some documented weaknesses in reliability and sensitivity to change. The main limitations of the MSFC are learning effects and the z-scores method used to calculate the total score. However, the methodological criterion of validity applies sufficiently for both instruments.For use in clinical studies, we found the EDSS to be preferred as a primary and secondary outcome measure in recent studies (50 EDSS, 9 MSFC).ConclusionsRecognizing their strengths and weaknesses, both EDSS and MSFC are suitable to detect the effectiveness of clinical interventions and to monitor disease progression. Almost all publications identify the EDSS as the most widely used tool to measure disease outcomes in clinical trials. Despite some limitations, both instruments are accepted as endpoints and neither are discussed as surrogate parameters in identified publications. A great advantage of the EDSS is its international acceptance (e.g. by EMA) as a primary endpoint in clinical trials and its broad use in trials, enabling cross-study comparisons.

Amputation rate and risk factors in type 2 patients with diabetic foot syndrome under real-life conditions in Germany.

AIMS To determine the risk of amputation and the influencing factors for amputation for patients with type 2 diabetes with diabetic foot syndrome. METHODS Longitudinal data from general practices in Germany (Disease Analyzer database, IMS Health) were analyzed. 3892 type 2 diabetes patients (mean age: 66.0 (SD: 10.9 years), 39.1% female) with a first-time diagnosis of diabetic foot syndrome between 01/200 and 12/2004 and at least 5 year follow-up documentation in the practices were included. The analyses of amputation-free survival were carried out using Kaplan-Meier curves and log-rank tests. A multivariate Cox regression model was fitted with the incident of diabetes-associated amputations as the dependent variable and adjusted for clinical and demographic characteristics. RESULT The cumulative incidence of diabetes-associated lower limb amputations was 18.2%. Amputations are independently associated with higher age, male gender, higher HbA1c value and longer diabetes duration but also some other diabetes complications. DISCUSSION The diabetic foot syndrome can but must not lead to a lower limb amputation. Due to the great medical and economic burden on the health system caused by diabetic complications, early therapeutic intervention is essential for patients with diabetic foot syndrome.

Predictors of hypoglycaemia in insulin-treated type 2 diabetes patients in primary care: A retrospective database analysis

AIMS To investigate the frequency and predictors (diabetes care and treatment, comorbidity) of documented hypoglycaemia in primary care patients with insulin-treated type 2 diabetes. METHODS Data from 32,545 patients (mean age: 70 (SD 11) years, 50.3% males) from 1072 practices were retrospectively analyzed (Disease Analyzer database Germany: 09/2011-08/2012). Logistic regression (≥1 documented hypoglyemia) was used to adjust for confounders (age, sex, practice characteristics, diabetes treatment regimen). RESULTS The prevalence of patients (12 months) with at least one reported hypoglycaemia was 2.2% (95% CI: 2.0-2.4%). The adjusted odds of having hypoglycemia were increased for renal failure (OR; 95% CI: 1.26; 1.16-1.37), autonomic neuropathy (1.34; 1.20-1.49), and adrenocortical insufficiency (3.08; 1.35-7.05). Patients with mental disorders including dementia (1.49; 1.31-1.69), depression (1.24; 1.13-1.35), anxiety (1.18; 1.01-1.37), and affective disorders (1.80; 1.36-2.38) also showed an increased odds of having hypoglycemia. Location of the practice in an urban area was associated with a lower odds ratio (0.74; 0.68-0.80). CONCLUSIONS Both individual patient characteristics (e.g. comorbidity) and regional factors (practice location) have a substantial impact on hypoglycaemia in primary care patients with insulin therapy.

Health economic evaluation of insulin glargine vs NPH insulin in intensified conventional therapy for type 1 diabetes in Germany.

Abstract Objective: Basal insulin analogs are well established in the treatment of type 1 diabetes in Germany. However, little is known about their economic impact. The aim of this study for an adult population was to compare, from the perspective of the Statutory Health Insurance (SHI), the cost effectiveness of the long-acting insulin analog glargine (GLA) with intermediate-acting neutral protamine Hagedorn (NPH) insulin in basal bolus therapy, considering the interaction between glycemic control and the rate of hypoglycemia. Methods: A validated discrete event simulation model was adapted to the German setting to project clinical and cost outcomes over 40 years. Resources were valued with German official prices in 2009/2010 Euros. Health-related disutilities were taken from UK sources. Patient characteristics and risk factors were partially extracted from German sources in a sensitivity analysis. Results: In the base-case analysis, GLA was dominant as it increased life expectancy by 0.196 years and improved quality-adjusted life-years (QALYs) by 0.396 units while at the same time leading to savings of €5246 each per patient after 40 years compared to NPH. These results were robust in the sensitivity analyses. Monte Carlo simulation confirmed dominance of GLA in 70% (life-years gained) and 80% (QALYs gained) of the iterations. The price of GLA had the highest impact on savings. In extreme scenarios, incremental cost-effectiveness ratios increased up to €9576 per QALY gained. Limitations of the evaluation included no myocardial re-infarction(s) and no recurrent stroke(s), patient characteristics, risk factors, and disutilities from the UK due to scarce data in Germany, and that not all diabetes-related direct costs were included, namely insulin pens and blood glucose meters. Conclusion: GLA appears to be cost effective or even cost saving among type 1 diabetics with basal bolus therapy from the perspective of SHI compared to NPH depending on the scenario chosen.

Fracture risk in patients with type 2 diabetes under different antidiabetic treatment regimens: a retrospective database analysis in primary care.

Aim Type 2 diabetes is associated with an increased risk of fractures. There are a few studies on the effects of diabetes treatment on fracture risk. The aim was to investigate the fracture risk related to various types of insulin therapy in primary care practices. Methods Data from 105,960 type 2 diabetes patients from 1,072 general and internal medicine practices in Germany were retrospectively analyzed (Disease Analyzer database; 01/2000–12/2013). Fracture risk of the following therapies was compared using multivariate logistic regression models adjusting for age, sex, diabetes care, comorbidity, and glycemic control (HbAlc): 1) incident insulin therapy versus oral antidiabetic drugs, 2) basal-supported oral therapy versus supplementary insulin therapy versus conventional insulin therapy, and 3) insulin glargine versus insulin detemir versus NPH insulin. Results There was a lower odds of having incident fractures in the oral antidiabetic drug group compared to incident insulin users, although not significant (odds ratio [OR]; 95% confidence interval: 0.87; 0.72–1.06). There were increased odds for conventional insulin therapy (OR: 1.59; 95% CI [confidence interval] 0.89–2.84) and supplementary insulin therapy (OR: 1.20; 0.63–2.27) compared to basal-supported oral therapy, which was not significant as well. Overall, there was no significant difference in fracture risk for basal insulins (glargine, detemir, NPH insulin). After a treatment duration ≥2 years, insulin glargine showed a lower odds of having ≥1 fracture compared to NPH users (OR: 0.78; 0.65–0.95) (detemir vs NPH insulin: OR: 1.03; 0.79–1.36). Conclusion Long-standing therapy with insulin glargine was associated with a lower odds of having any fractures compared to NPH insulin. Further studies are required to investigate whether the lower chance is due to a reduced frequency of hypoglycemia.

Treatment persistence after initiating basal insulin in type 2 diabetes patients: A primary care database analysis

AIMS To compare persistence and its predictors in type 2 diabetes patients in primary care, initiating either basal supported oral therapy (BOT) or intensified conventional therapy (ICT) with glargine, detemir, or NPH insulin. METHODS In the BOT cohort, 1398 glargine (mean age: 68 years), 292 detemir (66 years), and 874 NPH (65 years) users from 918 practices were retrospectively analyzed (Disease Analyzer, Germany: 2008-2012). The ICT group incorporated 866 glargine (64 years), 512 detemir (60 years), and 1794 NPH (64 years) new users. Persistence was defined as proportion of patients remaining on the initial basal insulin (glargine, detemir and NPH insulin) over 2 years. Persistence was evaluated by Kaplan-Meier curves (log-rank tests) and Cox regression adjusting for age, sex, diabetes duration, antidiabetic co-therapy, comorbidities, specialist care, and private health insurance. RESULTS In BOT, two-year persistence was 65%, 53%, and 59% in glargine, detemir, and NPH users, respectively (p<0.001). In ICT, persistence was higher without differences between groups: 84%, 85%, 86% in glargine, detemir, and NPH, respectively (p=0.536). In BOT, detemir and NPH users were more likely to discontinue basal insulin compared with glargine (detemir vs. glargine: adjusted Hazard Ratio; 95% CI: 1.56; 1.31-1.87; NPH vs. glargine: 1.22; 1.07-1.38). Heart failure (1.39; 1.16-1.67) was another predictor of non-persistence, whereas higher age (per year: 0.99; 0.98-0.99), metformin (0.61; 0.54-0.69), and sulfonylurea co-medication (0.86; 0.77-0.97) were associated with lower discontinuation. CONCLUSIONS In BOT, treatment persistence among type 2 diabetes patients initiating basal insulin is influenced by type of insulin, antidiabetic co-medication, and patient characteristics.

Predictors of early discontinuation of basal insulin therapy in type 2 diabetes in primary care

AIMS To identify patient-related characteristics and other impact factors predicting early discontinuation of basal insulin therapy in type 2 diabetes in primary care. METHODS A total of 4837 patients who started basal insulin therapy (glargine: n=3175; NPH: n=1662) in 1072 general and internal medicine practices throughout Germany were retrospectively analyzed (Disease Analyser Database: 01/2008-03/2014). Early discontinuation was defined as switching back to oral antidiabetic drugs (OAD) therapy within 90 days after first basal insulin prescription (index date, ID). Patient records were assessed 365 days prior and post ID. Logistic regression models were used to adjust for age, sex, diabetes duration, diabetologist care, disease management program participation, HbA1c, and comorbidity. RESULTS Within 3 months after ID, 202 (6.8%) of glargine patients switched back to OAD (NPH: 130 (8.5%); p<0.05). In multivariable logistic regression, predictors of early basal insulin discontinuation were ≥1 documented hypoglycemia before ID (adjusted Odds ratio; 95% CI: 2.20; 1.27-3.82), diagnosed depression (1.31; 1.01-1.70) and referrals to specialists within 90 days after ID (2.06; 1.61-2.63). Diabetologist care (0.57; 0.36-0.89) and glargine treatment (vs. NPH: 0.78; 0.61-0.98) were related to a lower odds of having early insulin discontinuation. CONCLUSIONS Less than 10% of type 2 diabetes patients switched back to oral antidiabetic drugs within 90 days after start of basal insulin therapy. In particular, patients with baseline depression and frequent or severe hypoglycemia have a higher likelihood for early discontinuation of basal insulin, whereas use of insulin glargine and diabetologist care are related to an increased chance of continuous insulin treatment.

Predictors for the initiation of a basal supported oral therapy (BOT) in type 2 diabetic patients under real-life conditions in Germany.

OBJECTIVE To assess the predictors for the initiation of a basal supported oral therapy (BOT) in type 2 diabetic patients under real-life conditions in Germany. RESEARCH DESIGN AND METHODS A historical cohort study based on representative German real life data (IMS(®) Disease Analyzer) was performed. The study included patients with type 2 diabetes who started an oral antidiabetic drug (OAD) treatment between 01/1995 and 12/2011. Patients with consecutive treatment data for at least 12 months before the initiation of an OAD treatment were eligible for the analysis. The time-dependent rate of patients starting an insulin therapy with a long-acting insulin was calculated by use of the Kaplan-Meier method. Multivariate Cox regression analyses were applied to identify associated factors. RESULTS The study included 194,967 patients with type 2 diabetes mellitus being on OAD therapy. 24,964 patients were switched to BOT during the observational period. The probability of switching to insulin therapy was associated with three main predictors such as (1) poor metabolic control, (2) midlife age and (3) number and type of the OAD before insulinization. The variation of the HbA1c threshold to HbA1c≥7.5 leads to comparable outcomes with significant HR. CONCLUSION The highest probability of initiating a basal supported oral therapy (BOT) under real life conditions was found for patients with poor metabolic control, midlife age and pre-treatment with specific OADs such as SU, GLI or AGI before initiation of insulin therapy.

Predictors of Insulin Initiation in Metformin and Sulfonylurea Users in Primary Care Practices: The Role of Kidney Function

Aims: The aims were to investigate predictors of insulin initiation in new users of metformin or sulfonylureas in primary care practices, in particular, its association with decreased renal function. Methods: Data from 9103 new metformin and 1120 sulfonylurea users with normal baseline glomerular filtration rate (eGFR) >90 ml/min/1.73 m2 from 1072 practices were retrospectively analyzed (Disease Analyzer Germany: 01/2003-06/2012). Cox regression models and propensity score matching was used to adjust for confounders (age, sex, practice characteristics, comorbidity). Results: Insulin treatment was started in 394 (4.3%) metformin and in 162 (14.5%) sulfonylurea users within 6 years (P < .001). Kaplan-Meier curves (propensity score matched patients) showed that the metformin group was at a lower risk of insulin initiation compared to sulfonylurea users throughout the study period. A substantial eGFR decline (category: 15-<30 ml/min/1.73 m2) was significantly associated with a higher likelihood to have insulin initiated (adjusted hazard ratio [HR]: 2.39; 95% CI: 1.09-5.23) in metformin but not in sulfonylurea (HR: 0.45; 95% CI: 0.16-1.30) users. Conclusions: New users of sulfonylurea monotherapy in primary care practices in Germany were about 3-fold more likely to start insulin therapy than those with metformin. Kidney function decline was associated with earlier insulin initiation in metformin but not in sulfonylurea users.

Resource Consumption and Costs of Treatment in Patients with Type 1 Diabetes under Intensified Conventional Therapy under German Real-Life Conditions

Introduction: The aim of this study was to compare, from the perspective of the statutory health insurance, resource consumption and the associated adjusted treatment costs of intensified conventional therapy (ICT) with long-acting insulins in patients with type 1 diabetes mellitus (T1DM). Methods: We identified patients with T1DM who started ICT with either insulin glargine or neutral protamine Hagedorn (NPH) insulin between July 2000 and February 2008 using a representative German database (IMS® Disease Analyzer). The variables age, gender, insurance status, diabetes duration, hemoglobin A1c level, body mass index, and geographic region and specialization of practice were collected. Resource consumption was evaluated over a time period of 12 months and included the quantities of applied basal and bolus insulin, blood glucose test strips, lancets and needles, physician visits (general practitioner, specialist), hospitalization, and antihypoglycemic therapy (intravenous glucose/glucagon). Results: A total of 2297 patients with T1DM were included; 1079 received ICT with insulin glargine and 1218 with NPH insulin. After adjustment, annual cost savings in favor of insulin glargine amounted to £423.94 compared with NPH insulin (p = .3019). Discussion: The adjusted results show that an ICT with insulin glargine results in lower annual costs than ICT with NPH insulin (this difference was not statistically significant). However, in the context of glucose-lowering effect and a lower hypoglycemia rate, insulin glargine is preferred to NPH insulin for patients with T1DM undergoing ICT.