Rising to the challenge of cardio-renal-metabolic disease in the 21st century: Translating evidence into best clinical practice to prevent and manage atherosclerosis.

Rising rates of obesity-associated cardiometabolic disorders allied to ageing populations are driving increases in cardiovascular morbidity and mortality. These adverse trends present challenges for healthcare systems that are struggling to prevent and manage the burgeoning cardiometabolic nexus of multiple long-term conditions. While potent new medications and non-pharmacological interventions have ushered in a promising new therapeutic era, translating clinical trial data to real-world clinical practice is often suboptimal. Postgraduate training and narrowly focused clinical specialisations reflect the traditional siloed approach to managing cardiovascular-metabolic disease that appears increasingly outmoded in the 21st century. It is our contention that greater inter-disciplinary collaboration allied to increased awareness of the continuum of cardiometabolic disease should enable clinicians to address this global public health threat more effectively. With this aim in mind, we have established an International Cardiometabolic Working Group. It is our hope to stimulate the interest of clinicians and clinical researchers across a range of medical specialties who share the vision of better care for people living with cardiometabolic diseases.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Prioritizing obesity treatment: expanding the role of cardiologists to improve cardiovascular health and outcomes.

Obesity is a major risk factor for cardiovascular disease, yet management remains poor. Cardiologists and healthcare professionals treating people with high cardiovascular risk are in a position to address overweight and obesity to improve cardiovascular health. There are several treatment options for obesity, which are associated with numerous health benefits. Modest weight reductions of 5-10% improve cardiovascular risk factors, with greater weight loss bringing about greater benefits. Anti-obesity medications can support weight reduction when lifestyle modifications alone are insufficient. The weight loss induced by these treatments can improve cardiovascular risk, and some therapies - such as glucagon-like-peptide-1 analogues - may promote these benefits independently of weight loss. Bariatric surgery can induce greater weight losses than other treatment modalities and is associated with numerous health benefits, but newer medications such as semaglutide and those in development, such as tirzepatide, produce robust weight loss efficacy that is approaching that of bariatric surgery. Healthcare professionals must approach this disease with compassion and collaborate with patients to develop sustainable plans that improve health and maintain weight loss over the long term.

Real-World Use of Once-Weekly Semaglutide in Type 2 Diabetes: Results from SemaglUtide Real-world Evidence (SURE) Germany.

CONTEXT: Efficacy and safety of once-weekly semaglutide in type 2 diabetes were established in the phase 3 SUSTAIN trials, which included patients across the continuum of type 2 diabetes care. It is useful to complement these findings with real-world evidence. OBJECTIVE: SURE Germany evaluated once-weekly semaglutide in a real-world type 2 diabetes patient population. DESIGN/SETTING: The prospective observational study was conducted at 93 clinical practices in adults with+≥ 1 documented glycated haemoglobin value ≤12 weeks before initiation of semaglutide. INTERVENTION: Once-weekly semaglutide was prescribed at the physicians' discretion. MAIN OUTCOMES: The primary endpoint was change in glycated haemoglobin from baseline to end-of-study (~30 weeks). Secondary endpoints included changes in body weight and patient-reported outcomes. All adverse events were systematically collected and reported, including patient-reported documented and/or severe hypoglycaemia. RESULTS: Of 779 patients in the full analysis set, 669 (85.9%) completed the study on treatment with semaglutide, comprising the effectiveness analysis set. In this data set, estimated mean changes in glycated haemoglobin and body weight from baseline to end-of-study were -1.0%point (-10.9 mmol/mol; P<0.0001) and -4.5 kg (-4.2%; P<0.0001). Sensitivity analyses supported the primary analysis. Improvements were observed in other secondary endpoints, including patient-reported outcomes. No new safety concerns were identified. CONCLUSIONS: In a real-world population in Germany, patients with type 2 diabetes treated with once-weekly semaglutide experienced clinically significant improvements in glycaemic control and body weight. These results support the use of once-weekly semaglutide in routine clinical practice in adult patients with type 2 diabetes in Germany.

Effect of once-weekly semaglutide versus thrice-daily insulin aspart, both as add-on to metformin and optimized insulin glargine treatment in participants with type 2 diabetes (SUSTAIN 11): A randomized, open-label, multinational, phase 3b trial.

AIM: To compare the efficacy and safety of once-weekly (OW) semaglutide versus thrice-daily (TID) insulin aspart (IAsp) in participants with inadequately controlled type 2 diabetes (T2D) treated with insulin glargine (IGlar) and metformin. MATERIALS AND METHODS: SUSTAIN 11 (NCT03689374) was a randomized (1:1), parallel, open-label, multinational, phase 3b trial. After a 12-week run-in to optimize once-daily IGlar U100, 1748 adults with T2D (HbA1c >7.5% to ≤10.0%) were randomized to OW semaglutide or TID IAsp as add-on to optimized IGlar and metformin for 52 weeks. The primary outcome was change in HbA1c from randomization to week 52. Confirmatory secondary endpoints included the occurrence of severe hypoglycaemic episodes and change in body weight (BW). Safety was assessed. RESULTS: HbA1c (randomization: 8.6% [70.0 mmol/mol]) decreased by 1.5% points (16.6 mmol/mol) and 1.2% points (13.4 mmol/mol) with semaglutide (n = 874) and IAsp (n = 874), respectively (estimated treatment difference [ETD] -0.29% points [95% confidence interval {CI} -0.38; -0.20]; P < .0001 for non-inferiority). Few severe hypoglycaemic episodes were recorded in either group, with no statistically significant difference between the groups. Change in BW from randomization (87.9 kg) to week 52 was in favour of semaglutide (-4.1 kg) versus IAsp (+2.8 kg) (ETD -6.99 kg [95% CI -7.41; -6.57]). A higher proportion of participants experienced adverse events with semaglutide (58.5%) versus IAsp (52.1%); most were mild to moderate. CONCLUSIONS: In this basal insulin-treated population, OW semaglutide improved glycaemic control to a greater extent than TID IAsp and provided numerically greater weight loss.

Efficacy and safety of efpeglenatide in key patient subgroups from the BALANCE randomized trial, stratified by pre-diabetes status, BMI, and age at baseline.

INTRODUCTION: Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being developed to improve glycemic control in type 2 diabetes (T2D). In the BALANCE 205 study (NCT02075281), efpeglenatide significantly reduced body weight versus placebo in patients with obesity, or overweight with comorbidities, and without T2D. These subanalyses explore the efficacy and safety of efpeglenatide in subgroups of patients with pre-diabetes and stratified by body mass index (BMI) or age from the BALANCE study. RESEARCH DESIGN AND METHODS: The 20-week BALANCE study randomized patients with BMI ≥30 kg/m2 or ≥27 kg/m2 with comorbidities, and without diabetes, to efpeglenatide 4 mg or 6 mg once weekly, 6 mg or 8 mg once every 2 weeks, or placebo. For these subanalyses, patients were stratified by pre-diabetes status (glycated hemoglobin (HbA1c) 5.7%-6.4% (39-46 mmol/mol) or fasting plasma glucose (FPG) 100-125 mg/dL) and by BMI or age < or ≥ median values (34.9 kg/m2 and 44 years, respectively) at baseline. RESULTS: In patients with pre-diabetes at baseline, all efpeglenatide doses led to greater proportions of patients reverting to normoglycemia (40.6%-64.3%) versus placebo (10.0%), and greater reductions in HbA1c (0.30%-0.38%), FPG (7.7-14.1 mg/dL), and weight (5.6-7.3 kg) versus placebo (nominal p<0.05 for all). In patients with BMI or age < or ≥ median, greater reductions in weight were observed with all efpeglenatide doses versus placebo (nominal p<0.01 for all). The most common adverse events in patients receiving efpeglenatide across patient subgroups were gastrointestinal adverse events. CONCLUSIONS: These results are consistent with the overall BALANCE population and suggest beneficial effects of efpeglenatide on glycemic control and body weight regardless of pre-diabetes status, age, or BMI at baseline. The effects of efpeglenatide on glycemic control in patients with pre-diabetes suggest it might help reduce the likelihood of at-risk patients developing diabetes.

Evolution of Type 2 Diabetes Management from a Glucocentric Approach to Cardio-Renal Risk Reduction: The New Paradigm of Care.

For many years, clinical studies could not show that lowering glucose in patients with type 2 diabetes leads to better macrovascular outcomes. In the past few years, new data have shown that treatment with two classes of dugs developed as "glucose-lowering agents," SGLT2 inhibitors and GLP-1 receptor agonists, can reduce macrovascular and renal complications. These studies have prompted debate about the main aim of type 2 diabetes management. In this review, three eras of diabetes management are described according to the treatment recommendations, such as the ADA/EASD consensus, moving from a pure glucocentric view into the present cardio-renal outcome-oriented approach, this has been endorsed by major diabetes and cardiology societies. While in the first era normalizing HbA1c was the only focus (e.g., UK Prospective Diabetes Study), failing to show a reduction in cardiovascular morbidity and mortality, further studies analyzing the pros and cons of intensified control such as ACCORD, VADT, ADVANCE recognized that treatment intensification was associated with weight gain and hypoglycemia, thereby potentially reducing the benefits of glycemic control. Therefore, the focus in the second area was on controlling HbA1c without these unwanted effects. The consistent beneficial results of several cardiovascular outcome trials with SGLT2 inhibitors and GLP-1 receptor agonists showing significantly improved cardio-renal outcomes, induced a paradigm shift: a change from (only) control of HbA1c to an organ-protective approach with the main focus now on cardio-renal risk; this is now considered as the third era. Recent data indicating beneficial effects of glucose-lowering agents in particular SGLT2 inhibitors even in subjects without diabetes, improving hospitalization for heart failure and renal outcomes might reveal another new era, which could then be considered a fourth era. While current international guidelines call for this paradigm shift, registry data show that we are still far from translating this objective into real-world practice.

Cardiovascular outcome trials in obesity: A review.

Obesity is a global epidemic associated with over 200 health complications and a significant risk of developing cardiovascular disease (CVD), partly by increasing classical risk factors such as lipid and glucose levels and blood pressure. Weight loss through lifestyle interventions, pharmacotherapy and/or bariatric surgery improves CV risk factors. Cardiovascular outcome trials (CVOTs) of anti-obesity medications aim to evaluate the CV safety and benefits of pharmacotherapy. Many CVOTs in obesity have either failed to demonstrate a CV benefit or have been terminated prematurely because of safety issues, prompting regulatory agencies to define new requirements (based on those for CVOTs in type 2 diabetes [T2D]). CVOTs of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in T2D have demonstrated that some GLP-1RAs reduce CV risk and may help inform future CVOTs in obesity, given the approval of liraglutide 3.0 mg for obesity. In this review, the evidence for the link between obesity and CVD is considered in the context of studies showing that weight loss improves markers of CV risk and risk of adverse CV events. The review also examines the CVOTs in obesity that have been conducted to date and those under way, such as the SELECT trial with subcutaneous semaglutide of 2.4 mg.

Body weight management and safety with efpeglenatide in adults without diabetes: A phase II randomized study.

AIM: To evaluate the safety of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), and its effects on body weight management in adults without diabetes. MATERIALS AND METHODS: In this phase II, randomized, placebo-controlled, double-blind trial, participants with a body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 with comorbidity were randomized 1:1:1:1:1 to efpeglenatide (4 mg once weekly, 6 mg once weekly, 6 mg once every 2 wk, or 8 mg once every 2 wk; n = 237) or placebo (n = 60) in combination with a hypocaloric diet. The primary endpoint was body weight change from baseline after 20 wk of treatment, assessed using a mixed-effect model with repeated measures with an unstructured covariance matrix over all post-screening visits; treatment comparisons were based on least squares mean estimates. RESULTS: Over 20 wk, all doses of efpeglenatide significantly reduced body weight from baseline versus placebo (P < 0.0001), with placebo-adjusted reductions ranging between -6.3 kg (6 mg once every 2 wk) and -7.2 kg (6 mg once weekly). Greater proportions of efpeglenatide-treated participants had body weight loss of ≥5% or ≥10% versus placebo (P < 0.01, all comparisons). Efpeglenatide led to significant improvements in glycaemic variables (fasting plasma glucose and glycated haemoglobin) and lipid profiles (cholesterol, triglycerides) versus placebo. Rates of study discontinuations as a result of adverse events ranged from 5% to 19% with efpeglenatide. Gastrointestinal effects were the most common treatment-emergent adverse events. CONCLUSIONS: Efpeglenatide once weekly and once every 2 wk led to significant body weight reduction and improved glycaemic and lipid variables versus placebo. It was also well tolerated for weight management in adults without diabetes.

Long-term efficacy and safety of combined insulin and glucagon-like peptide-1 therapy: Evidence from the LEADER trial.

AIM: Glucagon-like peptide-1 receptor agonist (GLP-1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long-term data are lacking. The aim was to assess the long-term efficacy of the GLP-1RA liraglutide in subgroups by insulin use in the LEADER trial. MATERIALS AND METHODS: LEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal-only insulin, other insulin or no insulin). Insulin was a non-random treatment allocation as part of standard of care therapy. RESULTS: At baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal-only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no-insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal-only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal-only and no-insulin subgroups. CONCLUSIONS: In patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes.

Triple therapy with low-dose dapagliflozin plus saxagliptin versus dual therapy with each monocomponent, all added to metformin, in uncontrolled type 2 diabetes.

AIM: To evaluate the efficacy and safety of triple therapy with low-dose dapagliflozin plus saxagliptin added to metformin in uncontrolled type 2 diabetes. MATERIALS AND METHODS: This 24-week, double-blind trial (NCT02681094) randomized 883 patients (glycated haemoglobin [HbA1c] 7.5-10.0%) on metformin ≥1500 mg/d to add-on dapagliflozin 5 mg/d plus saxagliptin 5 mg/d or to add-on of either monocomponent. The primary endpoint was change in HbA1c from baseline. RESULTS: Baseline mean ± SD patient characteristics were: age 56.7 ± 10.5 years; HbA1c 8.2 ± 0.9%; and diabetes duration 7.6 ± 6.1 years. Triple therapy significantly decreased HbA1c versus dual therapy (-1.03% vs. -0.63% [dapagliflozin] vs. -0.69% [saxagliptin]; P < .0001). More patients achieved HbA1c <7.0% with triple versus dual therapy (41.6% vs. 21.8% [dapagliflozin; P < .0001] vs. 29.8% [saxagliptin; P = .0018]). Triple therapy significantly decreased fasting plasma glucose (-1.5 mmol/L vs. -1.1 mmol/L [dapagliflozin; P = .0135] vs. -0.7 mmol/L [saxagliptin; P < .0001]) and body weight (-2.0 kg vs. -0.4 kg [saxagliptin; P < .0001]), and ß-hydroxybutyrate levels were lower than with dapagliflozin plus metformin (mean difference -0.51; P = .0009). Urinary tract/genital infections and hypoglycaemia occurred in <5.0% and 5.8% of patients, respectively, with triple therapy. CONCLUSIONS: Triple therapy with once-daily dapagliflozin 5 mg, saxagliptin 5 mg and metformin significantly improved glycaemic control versus dual therapy with either agent added to metformin in uncontrolled type 2 diabetes, and was generally well tolerated.

Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with type 2 diabetes.

OBJECTIVE: To compare the efficacy and safety of dapagliflozin and dapagliflozin plus saxagliptin vs glimepiride as add-on to metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 52-week, multicentre, double-blind, active-controlled study (NCT02471404) randomized (1:1:1) patients (n = 939; HbA1c 7.5%-10.5%) on metformin monotherapy (≥1500 mg/day) to add-on dapagliflozin 10 mg, dapagliflozin 10 mg plus saxagliptin 5 mg, or glimepiride 1 to 6 mg (titrated). The primary efficacy end point was change in HbA1c from baseline to Week 52. RESULTS: Baseline mean age, diabetes duration and HbA1c were 58.4 years, 7.0 years and 8.3%, respectively. Adjusted mean HbA1c change from baseline was -1.20% with dapagliflozin plus saxagliptin and -0.82% with dapagliflozin, vs -0.99% with glimepiride (mean dose at Week 52, 4.6 mg). Changes in body weight (-3.2 kg and -3.5 kg vs +1.8 kg) and systolic blood pressure (SBP; -6.4 mm Hg and -5.6 mm Hg vs -1.6 mm Hg) were significantly greater with dapagliflozin plus saxagliptin and dapagliflozin than with glimepiride. FPG decreased significantly with dapagliflozin plus saxagliptin compared with glimepiride (-2.1 mmol/L vs -1.5 mmol/L) and was similar with dapagliflozin (-1.6 mmol/L) compared with glimepiride. Confirmed incidence of hypoglycaemia was lower with dapagliflozin regimens than with glimepiride (0 and 1 vs 13 patients) and fewer patients required rescue. Genital infections were more frequent with dapagliflozin; other AE profiles were similar. CONCLUSIONS: Dapagliflozin, saxagliptin and metformin improved glycaemic control compared with glimepiride plus metformin; add-on of dapagliflozin alone showed efficacy similar to that of glimepiride. Both dapagliflozin regimens decreased body weight and SBP, with a lower incidence of hypoglycaemia compared with glimepiride.

'Knowing what Matters in diabetes: Healthier below 7': results of the campaign's first 10 years (part 2), participants without known diabetes history.

INTRODUCTION: Type 2 diabetes represents a major problem in many societies. Early detection and, even better, prevention could help to reduce the burden of the disease. Therefore, increased awareness of disorders of glucose metabolism is important. During the campaign 'Knowing what Matters in diabetes: Healthier below 7', in the last few years, more than 31 000 shopping mall visitors in Germany were voluntarily checked for their potential diabetes risk. METHODS: With a modified FINDRISK questionnaire, demographic, anthropometric and anamnestic data relevant for the estimation of the potential diabetes risk were collected. In addition, medical data such as plasma glucose, blood pressure (BP), BMI and waist circumference were obtained. Furthermore, lifestyle habits were documented. Hemoglobin (Hb)A1c was assessed randomly in a subgroup of individuals (n=4133). In total, data from 26 522 valid questionnaires were collected and evaluated over 10 years (2005-2014) from 45 single locations throughout Germany. Results from participants with manifest diabetes have already been published in this journal. Here, we report on the results from participants without a previous history of diabetes mellitus. RESULTS: Among the 26 522 participants with a completed questionnaire, 21 055 (79.4%) participants did not have a previous history of diabetes. Characteristic risk factors for diabetes were common in this group. With about 17% being obese and 40% being overweight, more than half of these individuals were thus beyond the normal BMI range. In addition, waist circumference exceeded common thresholds in 44% of the participants. As expected, many of them followed an unhealthy lifestyle as 35% reported no regular physical activity and 20% reported an unhealthy diet. The mean BP was 141/85 mmHg. More than half (51%) half of the patients in the nondiabetic group had a systolic BP above 140 mmHg, but only one-third (35%) reported concomitant treatment with antihypertensives. In the questionnaire, 14% of the participants had a FINDRISK sum score of 15 points and above, indicating a moderate or high risk of potentially developing type 2 diabetes within 10 years. Surprisingly, in the subgroup with HbA1c measurements (n=4133), 18.5% of the participants without a diagnosis or a history of diabetes were found to have an HbA1c value of at least 6.5% indicating manifest, previously undetected type 2 diabetes. CONCLUSION: The data collected in individuals without a known history of diabetes indicate a considerable prevalence of typical risk factors associated with diabetes. In addition, the data confirmed that screening of apparently healthy individuals consistently shows a significant proportion of individuals with previously undetected type 2 diabetes which, in the subgroup, was surprisingly high. As there is convincing evidence for the beneficial effect of relatively simple lifestyle interventions such as an increase of physical activity and avoidance of unfavourable diets, and weight reduction, campaigns such as 'Knowing what Matters in diabetes: Healthier below 7' can be an appropriate option to encourage primary prevention among the sedentary population as well as a suitable tool for early disease recognition. Therefore, campaigns such as this should be intensified and options for early preventive intervention should be offered to reduce long-term disease burden and healthcare costs.

Usability Evaluation of a Blood Glucose Monitoring System With a Spill-Resistant Vial, Easier Strip Handling, and Connectivity to a Mobile App: Improvement of Patient Convenience and Satisfaction.

BACKGROUND: Proper management of diabetes mellitus requires regular self-monitoring of blood glucose (SMBG). This research evaluated the usability of the Accu-Chek® Guide Meter that includes a spill-resistant vial, easier strip handling, and wireless connectivity to a mobile app. METHODS: A total of 197 participants were allowed to experience typical blood glucose testing tasks on the Accu-Chek Guide Meter, review data such as last result, patterns, and target percentage on the meter and on the mobile app, and then evaluate their experience through a human factors usability survey. Participants used a 6-point agree/disagree scale to rate 34 market statement questions. RESULTS: The results of a Pearson chi-square proportions test for each of the 34 market statement questions showed a significant difference (P < .0001) between the disagree responses (1-3) and agree responses (4-6). An overwhelming majority of participants found all aspects of the system, including the test strips, strip vial, and data analysis on the meter and the mobile app, to be a good fit for their lifestyle and to provide a better testing experience. CONCLUSIONS: This study found superior usability of the new meter system over the participants' current meters in both the United States and France.

[Insulin therapy: as late as possible]. / Insulintherapie bei Typ-2-Diabetes--so spät wie möglich!

While in the past non insulin treatment options were limited, and a progressive beta cell loss was thought to happen over time, (early )insulin supplementation was believed to be necessary. Many data however now indicate that there is rather a beta cell dysfunction, and that a better life style management and the new medication can help to maintain a good glycemic control without insulin supplementation, and less problems with weight management and most importantly less hypoglycemia. Furthermore, studies could not provide evidence for a benefit by early insulin treatment.