Rationale for Timely Insulin Therapy in Type 2 Diabetes Within the Framework of Individualised Treatment: 2020 Update.

Type 2 diabetes is characterised by chronic hyperglycaemia and variable degrees of insulin deficiency and resistance. Hyperglycaemia and elevated fatty acids exert harmful effects on ß-cell function, regeneration and apoptosis (gluco-lipotoxicity). Furthermore, chronic hyperglycaemia triggers a vicious cycle of insulin resistance, low-grade inflammation and a cascade of pro-atherogenic processes. Thus, timely near to normal glucose control is of utmost importance in the management of type 2 diabetes and prevention of micro- and macroangiopathy. The majority of patients are multimorbid and obese, with critical comorbidities such as cardiovascular disease, heart failure and chronic kidney disease. Recently published guidelines therefore recommend patient-centred risk/benefit-balanced use of oral glucose-lowering drugs or a glucagon-like peptide 1 (GLP-1) receptor agonist, or switching to insulin with glycated haemoglobin (HbA1c) out of target. This article covers the indications of early insulin treatment to prevent diabetes-related complications, particularly in subgroups with severe insulin deficit, and to achieve recovery of residual ß-cell function. Furthermore, the individualised, risk/benefit-balanced, timely initiation of insulin as second and third option is analysed. Timely insulin initiation may prevent diabetes progression, reduce diabetes-related complications and has less serious adverse effects. Basal insulin is the preferred option in most clinical situations with consequences of undertreatment of chronic hyperglycaemia.

Determinants of weight change in patients on basal insulin treatment: an analysis of the DIVE registry.

OBJECTIVE: We aimed to describe patterns of weight change in insulin-naive patients with type 2 diabetes mellitus (T2DM) starting basal insulin (BI) treatment. RESEARCH DESIGN AND METHODS: Diabetes Versorgungs-Evaluation (DIVE) is an observational, multicenter, prospective registry in patients with T2DM. Patients were divided into those initiating BI therapy for the first time (with optional oral antidiabetic drugs (OADs)) and those initiating OADs only (OADo). RESULTS: 521 patients were included in the analysis, 113 in the BI arm and 408 in the OADo arm. Relative to baseline, the BI group gained an average of 0.98±7.1 kg at 1 year, compared with a loss of 1.52±11.8 kg in the OADo group (p<0.001). This difference remained statistically significant when expressed as a proportional change from baseline (+0.014±0.08 vs -0.015±0.12, respectively (p<0.001)). Baseline weight (regression coefficient (RC) 0.89; 95% CI 0.81 to 0.97; p<0.001) and diabetes duration (RC 2.52; 95% CI 0.53 to 4.52; p=0.01) were the only factors identified as significant predictors of weight gain between baseline and 1 year follow-up in BI patients. CONCLUSIONS: Though BI therapy leads to modest weight gain over the subsequent year, this may be limited by BI initiation at an early stage of the disease. As such, delaying the start of insulin therapy based on fears of weight gain appears counter-productive, and should be reconsidered.

Addition of once daily prandial lixisenatide to basal insulin therapy in patients with type-2 diabetes results in a reduction of HbA1c as an effect of postprandial glucose lowering.

AIMS: Basal insulin has been shown to effectively reduce fasting blood glucose (FBG), but postprandial plasma glucose (PPG) excursions may remain higher than normal. Glucagon-like peptide (GLP)-1 receptor agonists such as the short-acting lixisenatide are able to control such excursions by slowing gastric emptying. However, data regarding its use in a real world clinical setting are scarce. METHODS: 24 week, prospective, multicentre, non-interventional study in 1437 patients with type-2 diabetes receiving 20µg lixisenatide once daily in combination with basal insulin. The per-protocol set (PPS) comprised 540 patients. RESULTS: HbA1c levels were found to decrease significantly over 24 weeks of treatment in the PPS (0.94±0.99% [7.9±8.5]; p≤0.001). An HbA1c of <7% (53mmol/mol) was achieved in 26.9% of patients, with 9.8% reaching <6.5% (48mmol/mol) and 30.0% reaching their individual treatment goal. There was a slight decrease in FBG (2.84±30.4mg/dl; p≤0.001), and a significant reduction in PPG, with levels decreasing by between 35mg/dl (1.9mmol/l) and 38mg/dl (2.1mmol/l), respectively on average after all main meals in basal optimised patients (PPS; ≤140mg/dl). Body weight decreased from 101 to 98kg with a mean difference of 3.10±4.10kg (p≤0.001). There were few reports of hypoglycaemia and no reports of serious hypoglycaemia and need for external help. AEs were infrequent, and were in line with previous studies. CONCLUSIONS: Lixisenatide in combination with basal insulin was shown to be an effective treatment strategy for patients with type 2 diabetes, controlling HbA1c levels by reduction of PPG excursions during the whole day.

Real-world therapeutic benefits of patients on insulin glargine versus NPH insulin.

AIMS: The addition of a single injection of insulin to the oral drugs (basal supported oral therapy; BOT) has been shown to greatly reduce blood glucose levels. The intermediate-acting NPH insulin (NPH) and the long-acting insulin glargine (Lantus(®)) have been compared for use in BOT in numerous clinical trials; however, their efficacy and safety in a real-life setting have not been described. METHODS: TIP (therapeutic benefits of patients on insulin glargine vs. NPH insulin being poorly controlled on prior short-time basal-insulin supported therapy with NPH insulin or insulin glargine) is a non-interventional, multicentre, observational study over 24 weeks. A total of 2629 patients were enrolled and 1931 were fully evaluable (1614 insulin glargine, 303 NPH insulin). Propensity scoring (PSM) was used to match 570 patients into 2 similar cohorts of 285 patients. RESULTS: In the PSM cohort, a slightly greater reduction in FBG and HbA1c levels was seen in the insulin glargine group compared to the NPH group. A weight loss, which was slightly more pronounced in insulin glargine patients despite receiving a lower insulin dose relative to the NPH group, was seen in both the groups. Additionally, hypoglycaemia, including nocturnal and severe events, was more prevalent in the patients receiving BOT with NPH. The occurrence of new micro- or macro-vascular complications and adverse events was low for both groups. A large proportion of patients changed from NPH therapy to insulin glargine therapy during the study, which was mainly attributable to insufficient glucose modulation. Improvements in quality of life and treatment satisfaction were found for both types of insulin. CONCLUSIONS: This observational study provides evidence from a real-life setting that BOT with insulin glargine provides slightly greater reductions in weight, FBG and HbA1c levels, with a lower risk of hypoglycaemia than patients receiving NPH. This conclusion indicates that insulin glargine may be preferable to NPH insulin for BOT.

Basal insulin combined incretin mimetic therapy with glucagon-like protein 1 receptor agonists as an upcoming option in the treatment of type 2 diabetes: a practical guide to decision making.

The combination of basal insulin and glucagon-like protein 1 receptor agonists (GLP-1 RAs) is a new intriguing therapeutic option for patients with type 2 diabetes. In our daily practice we abbreviate this therapeutic concept with the term BIT (basal insulin combined incretin mimetic therapy) in a certain analogy to BOT (basal insulin supported oral therapy). In most cases BIT is indeed an extension of BOT, if fasting, prandial or postprandial blood glucose values have not reached the target range. In our paper we discuss special features of combinations of short- or prandial-acting and long- or continuous-acting GLP-1 RAs like exenatide, lixisenatide and liraglutide with basal insulin in relation to different glycemic targets. Overall it seems appropriate to use a short-acting GLP-1 RA if, after the near normalization of fasting blood glucose with BOT, the prandial or postprandial values are elevated. A long-acting GLP-1 RA might well be given, if fasting blood glucose values are the problem. Based on pathophysiological findings, recent clinical studies and our experience with BIT and BOT as well as BOTplus we developed chart-supported algorithms for decision making, including features and conditions of patients. The development of these practical tools was guided by the need for a more individualized antidiabetic therapy and the availability of the new BIT principle.

Predictors of response to early basal insulin treatment in patients with type 2 diabetes--the EARLY experience.

BACKGROUND: It was the aim of this study to assess baseline predictors for glycosylated hemoglobin (HbA1c) reduction, treatment-to-target, and insulin glargine dose in patients with an HbA1c level of ≥ 7.5% (58 mmol/mol) at baseline despite 3 months of maximum tolerated dose of metformin under daily conditions. SUBJECTS AND METHODS: This was an open, multicenter, prospective observational study with a 6-month follow-up including 1,438 patients with type 2 diabetes. Baseline variables independently associated with HbA1c (overall reduction and achievement of target values) and insulin glargine dose used were determined using a stepwise multivariate linear regression analysis. RESULTS: In a multivariate linear regression analysis (R(2)=0.545) baseline HbA1c (ß=-0.722; P<0.001) and retinopathy (ß=-0.064; P=0.007) were associated with a greater HbA1c reduction at 6 months, whereas duration of diabetes was associated with a lesser HbA1c reduction (ß=0.084; P<0.001). In another multivariate linear regression analysis, weight (odds ratio [OR] 0.99; 95% confidence interval [CI] 0.98 to <1.00), duration of diabetes (OR 0.96; 95% CI 0.93-0.99), and baseline HbA1c (OR 0.65; 95% CI 0.56-0.76) were associated with a reduced likelihood of achieving an HbA1c level of <7% (53 mmol/mol); baseline HbA1c (OR 0.66; 95% CI 0.51-0.85) was the only variable associated with a reduced likelihood of achieving an HbA1c level of <6.5% (48 mmol/mol). In a further analysis (R(2)=0.135) the insulin dose needed was increased in those with a higher body weight (ß=0.230; P<0.001), a longer duration of diabetes (ß=0.134; P<0.001), a higher baseline HbA1c level (ß=0.205; P<0.001), and the presence of microalbuminuria (ß=0.096; P=0.003). CONCLUSIONS: Identified predictors of greater HbA1c reduction, target goal achievement, and insulin dose needed may help to optimize the balance of benefits and risks with the use of insulin glargine.