Diethelm Tschöpe

Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension

Objective. To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension. Methods. In this double-blind, multicentre trial, 837 patients with diabetes mellitus and hypertension (mean sitting diastolic blood pressure [BP] > 95 and < 110 mmHg) were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination (n=277) for eight weeks. Efficacy variables were cuff mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP); 24-hour ambulatory BP, plasma renin activity (PRA) and plasma renin concentration (PRC) were also assessed. Results. At week 8, aliskiren, ramipril and aliskiren/ramipril lowered msDBP (mean±SEM) by 11.3±0.5, 10.7±0.5 and 12.8±0.5 mmHg, and msSBP by 14.7±0.9, 12.0±0.9 and 16.6±0.9 mmHg, respectively. Aliskiren/ramipril provided superior msDBP reductions to ramipril (p=0.004) or aliskiren (p=0043) monotherapy; adding aliskiren to ramipril provided an additional mean BP reduction of 4.6/2.1 mmHg. Aliskiren monotherapy was non-inferior to ramipril for msDBP reduction (p=0.0002) and superior for msSBP reduction (p=0.021).All treatments significantly lowered mean 24-hour ambulatory BP. Aliskiren significantly reduced PRA from baseline as monotherapy (by 66%, p<0.0001) or in combination with ramipril (by 48%, p<0.0001), despite large increases in PRC in all treatment groups. Aliskiren was well tolerated as monotherapy or in combination with ramipril. Conclusions. Combining aliskiren with ramipril provided a greater reduction in msDBP than either drug alone in patients with diabetes and hypertension.

High prevalence and poor control of hypertension in primary care: cross-sectional study.

Objective To report: (1) on the background, design and methods of the Hypertension and Diabetes Risk Screening and Awareness (HYDRA) study, (2) on the point prevalence of hypertension in primary care and (3) on the proportion of treated, controlled, and uncontrolled hypertension. Design Cross-sectional point prevalence study. Setting Representative nationwide sample of 1912 primary care practices in Germany. Participants A total of 45 125 unselected primary care attendees. Main outcome measures Prevalence of hypertension based on doctors diagnosis, self-reported diagnosis, and blood pressure (BP) measurements. Results A total of 39% of all patients and 67% of patients aged 60 years or older, respectively, were diagnosed by their doctors as having hypertension. Eighty-four percent of diagnosed patients were on antihypertensive medication, 57% of which were rated by the physician as well controlled. When hypertension was defined as either current BP levels ⩾ 140/90 mmHg and/or current antihypertensive medication, the total point prevalence increased to 50%, while treatment and control rates (BP < 140/90 mmHg) dropped to 64 and 19%, respectively. Conclusions Extrapolation of these findings to the entire primary care patient population seen in the over 20 000 primary care practices in Germany suggests that on an average day, over 700 000 patients with elevated BP are seen by primary care physicians, but that only around 132 000 of these patients are well controlled. Thus, this study not only documents the enormous burden of hypertensive patients in the primary health system, but also highlights the alarming lack of BP control in the vast majority of hypertensive patients.

Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia

BackgroundWe aimed at identifying variables predicting hypoglycemia in elderly type 2 diabetic patients and the relation to HbA1c values achieved.DesignProspective, observational registry in 3810 patients in primary care. Comparison of patients in different age tertiles: with an age < 60 (young, n=1,253), age 60 to < 70 (middle aged, n=1,184) to those ≥ 70 years (elderly, n=1,373). Odds Ratios (OR) with 95% confidence intervals (CI) were determined from univariable and multivariable regression analyses.ResultsElderly patients had a later diabetes diagnosis, a longer diabetes duration, better glucose control and more frequent co-morbid disease conditions. Overall 10.7% of patients experienced any severity hypoglycemia within the last 12 months prior to inclusion. Higher rates of hypoglycemia were observed in the elderly than in the young after adjusting for differences in HbA1c, fasting and post-prandial blood glucose (OR 1.68; 95%CI 1.16-2.45). This was particularly true for hypoglycemic episodes without specific symptoms (OR 1.74; 95%CI 1.05-2.89). In a multivariate model stroke / transitory ischemic attack, the presence of heart failure, clinically relevant depression, sulfonylurea use and blood glucose self-measurement were associated with hypoglycemic events.ConclusionElderly patients are at an increased risk of hypoglycemia even at comparable glycemic control. Therefore identified variables associated with hypoglycemia in the elderly such as heart failure, clinically relevant depression, the use of sulfonylurea help to optimize the balance between glucose control and low levels of hypoglycemia. Asymptomatic hypoglycemia should not be disregarded as irrelevant but considered as a sign of possible hypoglycemia associated autonomic failure.

Good Manufacturing Practice-Compliant Expansion of Marrow-Derived Stem and Progenitor Cells for Cell Therapy

Ex vivo expansion is being used to increase the number of stem and progenitor cells for autologous cell therapy. Initiation of pivotal clinical trials testing the efficacy of these cells for tissue repair has been hampered by the challenge of assuring safe and high-quality cell production. A strategy is described here for clinical-scale expansion of bone marrow (BM)-derived stem cells within a mixed cell population in a completely closed process from cell collection through postculture processing using sterile connectable devices. Human BM mononuclear cells (BMMNC) were isolated, cultured for 12 days, and washed postharvest using either standard open procedures in laminar flow hoods or using automated closed systems. Conditions for these studies were similar to long-term BM cultures in which hematopoietic and stromal components are cultured together. Expansion of marrow-derived stem and progenitor cells was then assessed. Cell yield, number of colony forming units (CFU), phenotype, stability, and multilineage differentiation capacity were compared from the single pass perfusion bioreactor and standard flask cultures. Purification of BMMNC using a closed Ficoll gradient process led to depletion of 98% erythrocytes and 87% granulocytes, compared to 100% and 70%, respectively, for manual processing. After closed system culture, mesenchymal progenitors, measured as CD105+CD166+CD14–CD45– and fibroblastic CFU, expanded 317- and 364-fold, respectively, while CD34+ hematopoietic progenitors were depleted 10-fold compared to starting BMMNC. Cultured cells exhibited multilineage differentiation by displaying adipogenic, osteogenic, and endothelial characteristics in vitro. No significant difference was observed between manual and bioreactor cultures. Automated culture and washing of the cell product resulted in 181 × 106 total cells that were viable and contained fibroblastic CFU for at least 24 h of storage. A combination of closed, automated technologies enabled production of good manufacturing practice (GMP)-compliant cell therapeutics, ready for use within a clinical setting, with minimal risk of microbial contamination.

Incidence and predictors of hypoglycaemia in type 2 diabetes - an analysis of the prospective DiaRegis registry

BackgroundHypoglycaemia is a serious adverse effect of antidiabetic drug therapy. We aimed to determine incidence rates of hypoglycaemia in type-2 diabetic patients and identify predictors of hypoglycaemia when treatment is intensified.MethodsDiaRegis is a prospective German registry that follows 3810 patients with type-2 diabetes referred for treatment intensification because of insufficient glycaemic control on one or two oral antidiabetic drugs.ResultsOut of a total of 3347 patients with data available for the present analysis 473 (14.1%) presented any severity hypoglycaemia over a follow-up of 12 months. 0.4% were hospitalized (mean of 1.3±0.6 episodes), 0.1% needed medical assistance (1.0±0.0), 0.8% needed any help (1.1±0.5) and 10.1% no help (3.4±3.7), and 8.0% had no specific symptoms (3.6±3.5). Patients with incident hypoglycaemia had longer diabetes duration, higher HbA1c and a more frequent smoking history; more had co-morbid disease conditions such as coronary artery disease, peripheral arterial disease, amputation, heart failure, peripheral neuropathy, diabetic retinopathy and clinically relevant depression at baseline. Multivariable adjusted positive predictors of incident hypoglycaemia over the follow-up were prior anamnestic hypoglycaemia, retinopathy, depression, insulin use and blood glucose self-measurement, but not sulfonylurea use as previously reported for anamnestic or recalled hypogylcaemia. On the contrary, glitazones, DPP-4 inhibitors and GLP-1 analogues were associated with a reduced risk of hypoglycaemia.ConclusionsHypoglycaemia is a frequent adverse effect in ambulatory patients when antidiabetic treatment is intensified. Particular attention is warranted in patients with prior episodes of hypoglycaemia, microvascular disease such as retinopathy and in patients receiving insulin. On the other hand glitazones, DPP-4 inhibitors and GLP-1 analogues are associated with a reduced risk.

Antidiabetic pharmacotherapy and anamnestic hypoglycemia in a large cohort of type 2 diabetic patients--an analysis of the DiaRegis registry.

BackgroundWe aimed to identify predictors of anamnestic hypoglycaemia in type-2 diabetic patients on oral mono- or dual oral combination antidiabetic pharmacotherapy.MethodsDiaRegis is a prospective registry in type-2 diabetic patients in primary care. Odds ratios (OR) with 95% confidence intervals were determined from univariate logistic regression. Using multivariate logistic regression analysis with stepwise backward selection at an alpha of 0.05 independent predictors of hypoglycaemia were determined.Results3,808 patients had data on hypoglycaemia available (median age 65.9 years, 46.6% female). 10.8% had at least one anamnestic hypoglycaemic episode within the previous 12 months. Patients with hypoglycaemia received more sulfonylureas (OR 2.16; 95%CI 1.75-2.67) and less metformin (OR 0.64; 95%CI 0.50-0.82). On top of metformin, patients with thiazolidine (OR 0.50; 95%CI 0.28-0.89) and DPP-4 inhibitor use (OR 0.34; 95%CI 0.16-0.70) had a decreased risk for hypoglycaemia while it was again increased with sulfonylureas (OR 2.08; 95%CI 1.44-2.99). Age < 65 years was an independent predictor of a reduced hypoglycaemia incidence (OR 0.76; 95%CI 0.59-0.96), low HbA1c (OR 1.68; 95%CI 1.31-2.14), stroke/TIA (OR 1.72; 95%CI 1.08-2.72), heart failure (OR 1.77; 95%CI 1.28-2.45), and the use of sulfonylureas (OR 2.58; 95%CI 2.03-3.29) were independent predictors of increased risk.ConclusionsThe results indicate that the risk of hypoglycaemia might be substantially reduced by carefully selecting antidiabetic pharmacotherapy in patients with type-2 diabets in primary care.

NEWLY DIAGNOSED DIABETES AND PREDIABETES IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION PREDICTS ADVERSE OUTCOMES DURING A THREE-YEAR FOLLOW-UP: RESULTS OF THE SWEETHEART REGISTRY

There is a considerable prevalence of glucose abnormalities in patients presenting with an acute myocardial infarction. The present analysis reports the prevalence of dysglycemia and the impact of newly diagnosed diabetes on mortality at the 3-year follow-up. A total of 2,767 consecutive patients

The role of co-morbidity in the selection of antidiabetic pharmacotherapy in type-2 diabetes

Metformin is, if not contraindicated and if tolerated, usually preferred over other antidiabetic drugs for the first line treatment of type-2 diabetes. The particular decision on which antidiabetic agent to use is based on variables such as efficacy, cost, potential side effects, effects on weight, comorbidities, hypoglycemia, risk, and patient preferences. However, there is no guidance how to consider these in the selection of antidiabetic drug treatment. In this work, we aimed to summarize available evidence and tried to give pragmatic treatment recommendations from a clinical practice perspective.There are clear contraindications for some drugs in those with impaired renal and liver function and precautions in those with heart failure for the use of metformin (NYHA III-IV) and glitazones. On the other hand, GLP-1 analogs, DPP-4 inhibitors and acarbose are generally less critical and can be used in the majority of patients. We identified the following gaps with respect to the selection of antidiabetic drug treatment in patients with co-morbid disease conditions: 1) Guidelines fail to give advice on the use of specific antidiabetic drugs in patients with co-morbidity. 2) The literature is deficient in studies documenting antidiabetic drug use in patients with severely impaired renal function, diabetic retinopathy, cerebrovascular disease and systolic heart failure. 3) Further there are no specific data on patients with multiple of these co-morbid disease conditions. We postulate that differential use of antidiabetic drugs in patients with co-morbid disease constellations will help to reduce treatment related complications and might improve prognosis.

Diabetes treatment patterns and goal achievement in primary diabetes care (DiaRegis) - study protocol and patient characteristics at baseline

BackgroundPatients with type 2 diabetes are at an increased risk for disease and treatment related complications after the initial approach of oral mono/dual antidiabetic therapy has failed. Data from clinical practice with respect to this patient group are however scarce. Therefore we set up a registry in primary care documenting the course and outcomes of this patient group.MethodsDiabetes Treatment Patterns and Goal Achievement in Primary Diabetes Care (DiaRegis) is a prospective, observational, German, multicenter registry including patients with type-2 diabetes in which oral mono/dual antidiabetic therapy has failed. Data were recorded at baseline and will be prospectively documented during visits at 6 ± 1, 12 ± 2 and 24 ± 2 months. The primary objective is to estimate the proportion of patients with at least 1 episode of severe hypoglycemia within one year.Results313 primary care offices included 4,048 patients between June 2009 and March 2010 of which 3,810 patients fulfilled the in- and exclusion criteria. 46.7% of patients were female; patients had a median diabetes duration of 5.5 years and most were obese with respect to BMI or waist circumference. HbA1c at baseline was 7.4%, fasting plasma glucose 142 mg/dl and postprandial glucose 185 mg/dl. Co-morbidity in this patient population was substantial with 17.9% having coronary artery disease, 14.4% peripheral neuropathy, 9.9% heart failure and 6.0% peripheral arterial disease. 68.6% of patients received oral monotherapy, 31.4% dual oral combination therapy. The most frequent antidiabetic agent used as monotherapy was metformin (79.0%) followed by sulfonylureas (14.8%).ConclusionsDiaRegis is a large, prospective registry in primary diabetes care to document the course and outcomes of patients with type-2 diabetes in which the initial approach of oral mono/dual antidiabetic therapy has failed. The two year follow-up will allow for a prospective evaluation of these patients during multiple adjustments of therapy.

Prognostic implications of DPP-4 inhibitor vs. sulfonylurea use on top of metformin in a real world setting – results of the 1 year follow-up of the prospective DiaRegis registry

DPP‐4 inhibitors (DPP4‐I) have been shown to provide non‐inferior glycaemic control compared with sulfonylureas (SU), but result in a reduction of body weight and a significantly lower risk of hypoglycaemia in patients with type 2 diabetes. We aimed to validate these results in a large real‐world sample of patients participating in the prospective DiaRegis registry and to assess prognostic implications.