Introduction
Deficits in biphasic and pulsatile insulin secretion play a key role for manifestation and progression of type 2 diabetes. In the natural history of type 2 diabetes, impaired insulin secretion occurs long before diabetes is diagnosed [
1,
2]. Timely insulin therapy has been demonstrated to represent one of the most effective tools to protect pancreatic β-cell function, endothelium and other end-organs from harmful effects of hyperglycaemia [
3,
4]. Even in patients with severe hyperglycaemia (HbA
1c > 9–10%) at diagnosis, insulin is able to control gluco- and lipotoxicity within a few days of therapy by downregulating excessive peripheral insulin resistance, hepatic glucogenesis, lipolytic activity of adipose tissue, and subclinical inflammation [
3‐
10].
There is substantial evidence that insulin treatment can lead to long-lasting recovery of residual pancreatic β-cell function [
6,
7]. With early insulin therapy, durable remission of dysglycaemia was achieved in up to 50% of cases [
8‐
11]. Moreover, in the ORIGIN study [
12] and some other clinical trials it was shown that with early insulin treatment progression of diabetes was significantly reduced in comparison to standard of care [
13,
14]. A detailed analysis of the pathophysiology, underlying clinical reasoning and indication for early insulin treatment in type 2 diabetes has been given previously [
3,
15]. Of note, in obese patients with metabolic syndrome and insulin resistance, insulin therapy may also have adverse effects such as hypoglycaemia, weight gain and possibly increased risk of cardiovascular (CV) events, heart failure and arrhythmias. Moreover, insulin therapy needs professional medical care and may be associated with inconveniences for elderly patients.
In advanced diabetes with a duration of more than 10 to 15 years, residual pancreatic β-cell function is critically impaired as a consequence of long-lasting gluco-lipotoxicity leading to imbalance between β-cell regeneration and apoptosis [
14,
16]. Protection and recovery of residual β-cell secretory capacity, however, can reduce the risk of severe hypoglycaemia (SH) [
17,
18]. Consequently, there is evidence that timely insulinisation can prevent diabetes-related complications, improve endothelial function and myocardial blood flow, and may protect end-organs from oxidative stress and glycosylation [
19‐
22].
In 2008, the US Food and Drug administration (FDA) published its “Guidance for Industry” mandatory recommendations how new glucose-lowering drugs must to have proven CV safety in cardiovascular outcome trials (CVOTs) with major cardiovascular events (MACE) as primary outcome as a prerequisite for approval.
After initial neutral results of safety studies for MACE [
23‐
27] with dipeptidyl peptidase 4 (DPP4) inhibitors and some glucagon-like peptide 1 receptor agonists (GLP-1RAs), recently published CVOTs, i.e. EMPA-REG with the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin [
28], CANVAS and CREDENCE with canagliflozin [
29,
30], DECLARE with dapagliflozin [
31], LEADER with the GLP-1RA liraglutide [
32], SUSTAIN-6 with semaglutide [
33], HARMONY-OUTCOMES with albiglutide [
34] and REWIND with dulaglutide [
35], have substantially changed the recommended stepwise approach to manage glycaemic control in type 2 diabetes [
36,
37]. Insulin at this stage is only recommended as part of triple therapy or even only if triple therapy fails as “last option” after an initial therapeutic trial with a GLP-1RA. Furthermore, in current recommendations the dysglycaemic level for initiation of insulin therapy was set to a glycated haemoglobin (HbA
1c) target of 10% or 11%, or a fasting blood glucose in older individuals and people at risk of hypoglycaemia of 300 mg/dL [
38]. These recommendations, however, may result in an inadequate delay of timely insulin treatment with harmful effects not only on metabolic memory [
39] but also on quality of life as well as the mental and physical fitness of patients. Moreover, with clear evidence for CV and renal benefit of SGLT2 inhibitors and GLP-1RAs, the European Society of Cardiology (ESC) 2019 guidelines recommend these drugs even as first-line treatment before metformin in patients with atherosclerotic vascular disease, heart failure and chronic kidney disease (CKD) [
40]. Thus, at present, we envision a substantial risk that in the light of favourable results of CVOTs with SGLT2 inhibitors and GLP-1RAs in special populations with high CV risk, clinical inertia with respect to improving glucose control by insulin therapy may be facilitated. Thereby, the notion that good glucose control early in diabetes history with timely initiation of insulin can protect pancreatic β-cells and reduce the development of microangiopathy and diabetes-related complications must not be neglected. In this overview, we will analyse the risk/benefit balance of timely insulin in type 2 diabetes therapy derived from appropriate trials. This approach aims to provide a rationale for individualised insulin therapy in conjunction with the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus recommendations of 2018 (updated in 2019 [
41]) and the ESC guidelines in 2019 [
38,
40,
42].
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Rationale for Timely Insulin Treatment
As a result of the progressive nature of type 2 diabetes, many patients will eventually become insulin-dependent [
43‐
45]. Neither the latest guidelines for anti-hyperglycaemic treatment of patients with type 2 diabetes nor recent other literature exactly defines the threshold to initiate insulin therapy in type 2 diabetes. In contrast, in all available guidelines and recommendations, the necessity for insulin therapy is defined by the inability to reach an individualised HbA
1c goal. Real-world data show that individual HbA
1c targets are not achieved in the majority of cases, especially when insulin treatment is delayed [
45]. Moreover, according to real-world studies, insulin-treated patients also do not reach individual glycaemic targets in many cases [
46]. Thus, the potential of a start with insulin therapy in a timely manner should be rethought strategically.
Most of the evidence implies that timely insulin treatment has two major advantages for glycaemic control: (1) potent glucose-lowering efficacy, and timely treatment may protect pancreatic β-cells, thereby providing an insulin-sparing strategy in the long run (2) which may pose lower risk of hypoglycaemia and weight gain [
47].
An HbA1c below 7% is the accepted gold standard for diabetes control. In addition, stable glucose homeostasis avoiding peaks and hypoglycaemic episodes has been demonstrated to be of important clinical relevance, not least in relation to risk of CV and cerebral complications, as well as for fitness in daily life.
Several oral antidiabetic drugs (OADs) have proven high glucose-lowering potency, being in some randomised clinical trials equivalent to the efficacy of insulin therapy [
42]. In these studies, HbA
1c baseline values were between 7.5% and 9.1%. In this range, GLP-1RAs in particular showed comparable results to insulin with a similar percentage of participants achieving individualised goals [
48]. Nevertheless, it should be reconciled that most of these randomised trials lasted only 26 weeks, only few with extension to 52 weeks. The 26-week trials frequently allowed not enough time to titrate insulin properly. In some trials comparing therapy with insulin vs. GLP-1RAs, maximum HbA
1c reduction had been reached after 12 or 18 weeks with the highest dosage of GLP-1RA. In parallel, insulin titration was stopped per protocol at 20 or 24 IU followed by HbA
1c worsening in the weeks thereafter [
49‐
51]. Comparable results were seen within the ORIGIN trial with other newer glucose-lowering drugs (e.g. DDP4 or SGLT2 inhibitors) [
12]. Avogaro et al. [
52] showed in a meta-analysis of DPP4 inhibitors an apparently accepted mean increase in HbA
1c of 0.22% after 52 weeks of usage. Long-term loss of glycaemic control of 0.30% over 4 years of treatment was observed with dapagliflozin [
53]. A declining efficacy for SGLT2 inhibitors was also observed in a meta-analysis by Monami et al. [
54] over 104 weeks, but these compounds were more effective than DDP4 inhibitors over this period. According to another meta-analysis, HbA
1c reduction was smaller when DDP4 inhibitors were used in monotherapy as opposed to a combination with metformin [
55]. All these trials revealed decreasing efficacy of these compounds over time, due to “progression” of β-cell failure.
Only intensive insulin treatment is able to reliably correct hyperglycaemia and lipotoxicity within 1 to 2 days of treatment [
10]. This has been shown for insulin glargine and insulin degludec. Furthermore, insulin glargine has been demonstrated to keep glucose to a near normal range over an extended period of more than 6 years [
56]. While there are no specific head-to-head trials testing long-term efficacy and durability of insulin versus SGLT2 inhibitors and/or GLP-1RAs, it has been demonstrated that both insulin glargine and insulin degludec are able to constantly maintain glycaemic control over extended periods of more than 3 years in the DEVOTE, BRIGHT and CONCLUDE trials [
57‐
59].
When looking at possible pancreatic β-cell protective effects of insulin, it is important to distinguish between β-cell function, i.e. insulin biosynthesis and secretion, and β-cell mass. While most of the data on pancreatic β-cell mass are derived from in vitro or animal studies, evidence on β-cell function is derived from surrogate measures e.g. in glucose clamp analyses or mathematical calculations (homoeostatic model assessment, HOMA).
Berard et al. [
60] estimated that a minimum of 15% or 20% of pancreatic β-cell function is needed for an adequate glucose-lowering effect of most of the OADs. However, it does not seem to be reasonable to wait until β-cell failure exists to such a high degree, especially when some oral drugs lose more and more effectiveness with declining β-cell function. Although some OADs have shown the ability to maintain or even improve β-cell function and critical loss of β-cell mass [
61], many of them depend on preserved β-cell function, which becomes an issue in later stages of type 2 diabetes. In contrast, insulin can be used at any stage in type 2 diabetes management, independent of more or less insufficient β-cell function. Studies with long-term insulin use have demonstrated very stable glycaemic levels at target, indirectly suggesting that insulin therapy is the most appropriate way to induce pancreatic β-cell rest as an important precondition of long-term preserved endogenous insulin biosynthesis [
12,
62]. In a meta-analysis of short-term intensive insulin therapy, Kramer et al. [
63] calculated a mean increase in β-cell function (HOMA-B) of 1.13 (95% confidence interval [CI] 1.02–1.25) and a decrease in insulin resistance (HOMA-IR) of 0.57 (95% CI − 0.84 to 0.29) as an insulin effect. Remission of diabetes was still observed in 42% of patients after 2 years.
Particularly in early stages, but also up to 5 years after manifestation, pathophysiological important improvements of β-cell function and hepatic insulin resistance were shown under insulin therapy owing to rapid improvement of gluco- and lipotoxicity [
11,
64,
65]. Insulin supports improvement of physiological pancreatic β-cell function (“increased readily releasable insulin pool” close to the cell membrane of the β-cell) [
65]. In addition, many studies demonstrated the interrelation of low residual β-cell function as a driver of glucotoxicity [
66] and elevated hypoglycaemic risk. Thus, progression of type 2 diabetes may be associated with higher risk of SH. The higher the β-cell reserve (C-peptide) is, the lower the risk of hypoglycaemia. Furthermore, SH and weight gain are more expressed when starting insulin (too) late or at high HbA
1c levels [
67]. Here, timely combination of insulin with SGLT2 inhibitors or GLP-1RAs may be considered [
12,
68,
69].
Prevention of Microvascular Complications with Insulin Treatment
With significant progress in the prevention of CV disease and overall increase in life expectancy of patients with type 2 diabetes, microvascular complications and other diabetes-related diseases become more and more prominent determinants of the fate of people with long-term diabetes. As shown by Bergenstal and colleagues, in the post-DCCT area reaching HbA
1c ≤ 7.0% was associated with an impressive decline in MACE but less impressive decline in severe kidney disease [
82]. Unfortunately, among people with long-term type 2 diabetes, treatment “not-to-target” frequently prevails [
83]. Even worse, to minimise potential adverse effects of insulin (hypoglycaemia and weight gain), in CVOTs with intensified glucose control treatment with insulin was targeted to inadequate HbA
1c levels (> 8–10%), particularly in older patients.
There exists, however, consistent evidence from CVOTs with neutral outcome for primary objectives (MACE) that HbA
1c is a strong and independent predictor for microvascular disease. In the UKPDS, intensified treatment with insulin had a significant effect on microvessel disease with a close relationship between HbA
1c and retinopathy down to HbA
1c < 6% after 10 years of follow-up [
72].
Of note, in the UKPDS early addition of insulin to oral treatment reduced the risk of complications [
84]. The landmark study of benefit of early and timely insulin treatment—ORIGIN—demonstrated a significant reduction of CKD and retinopathy in participants with HbA
1c ≥ 6.4% at baseline. The HR of composite hard endpoints of kidney and eye disease was 0.90 (95% CI 0.81–0.99). The strongest effect was observed on reduction of microalbuminuria [
85]. With respect to quality of life, it is remarkable that in the ORIGIN study basal insulin glargine also improved muscular strength in the handgrip test and erectile dysfunction [
86].
Relevance of Potential Adverse Effects of Insulin Treatment
Safety and quality of life are major issues to be considered at initiation of insulin treatment [
87]. Hypoglycaemia and weight gain are serious adverse effects of any glucose-lowering therapy addressed in recently published guidelines and treatment recommendations. Interestingly, prevalence and harmful consequences of hypoglycaemic events during glucose-lowering treatment with insulin seem to depend on several factors, and should be appraised also in the context of improvements in glycaemia and comedications. For example, it was demonstrated very early that weight gain can be attenuated if metformin is used or continued when initiating basal insulin [
88]. Further, the time point of initiation in medical history of diabetes is one of the best-known variables especially when insulin was used in randomised clinical trials by heterogeneous subgroups of patients with type 2 diabetes. In the INSIGHT trial, starting at 7.6 years of diabetes duration, the HbA
1c reduction was − 0.3% (
P = 0.0007, 8.6% at baseline). There was, however, no difference in hypoglycaemic events as compared to treatment with an additional OAD [
89]. In the TULIP study with 10 years of diabetes duration at baseline, HbA
1c could be lowered using insulin glargine by − 0.8 ± 0.7% (from 7.6 ± 0.3%), but resulted in 20.3% more patients with symptomatic hypoglycaemia and weight gain of + 1.89 kg in the insulin arm. The LANMET trial showed for patients with 9 years of type 2 diabetes a reduction in HbA
1c of − 2.4% (from 9.6% at baseline) with 5.4 hypoglycaemic episodes per patient year and a weight gain of + 2.6 ± 0.6 kg. Of importance, obese patients with insulin resistance frequently needed insulin dosages of more than 100 IU/day (so-called insulin failures) [
90,
91].
Evidence for fewer hypoglycaemic drug events and less weight gain if insulinisation starts earlier than later in progression of type 2 diabetes also comes from real-world data. In the EARLY trial, patients with type 2 diabetes and failure in OAD therapy who started basal insulin within 5 years after diagnosis had a weight difference of − 0.4 kg as compared to those with diagnosis 5 years or more before [
68]. Another non-interventional longitudinal study on insulinisation revealed that the mean weight increase of + 1.78 kg after 1 year was highly dependent on baseline HbA
1c and insulin dosage needed to improve glycaemic control [
92,
93]. Many studies show the highest weight gain among insulin therapies with premix formulations [
94‐
96]. By contrast, Lingvay et al. [
97] found a higher weight gain with triple OAD therapy of + 7.15 kg vs. + 4.5 kg premix insulin twice a day.
Severe hypoglycaemic episodes are serious adverse events of inappropriate insulin treatment. They are associated with increased risk of CV complications, heart failure, arrhythmias and mortality [
80,
98‐
103]. However, a causal relationship and the relevance of SH for MACE is a matter of debate. Of note, the DCCT, a landmark trial in patients with type 1 diabetes that evaluated the effect of intensified insulin treatment over 7 years on micro- and macroangiopathy, showed that better HbA
1c control with more insulin resulted in higher incidence of SH, but achieved a significant reduction in CV [
104] and all-cause mortality [
105] at 30 years follow-up. The DEVOTE study was a CV safety study comparing basal insulin glargine vs. basal insulin degludec in a high-risk type 2 diabetes cohort. While significantly fewer SHs were registered with degludec in comparison to the glargine arm (4.9 vs. 6.6), the rates of MACE and overall serious adverse events (SAEs) were equal between both groups. Thus, while SH has a non-significant causal relationship, if any, to CV complications and death, it represents an SAE that labels a very high-risk group for MACE, arrhythmias and cancer. Nevertheless, the question remains whether patients with type 2 diabetes treated with insulin may be exposed to higher risk if SH happens. A nationwide registry study in Sweden compared second-line addition of insulin to metformin vs. DPP4 inhibitors during 2007 and 2014. Objectives were incidence of CVD, mortality and hypoglycaemia. Insulin compared to DPP4 inhibitors was associated with higher risk of mortality, CVD and SH (HR 1.69, 1.39, 4.35, respectively). The increased HR persisted after adjustment by propensity score matching [
106]. Zhuang et al. [
107] performed a meta-analysis including 170 trials with all novel glucose-lowering drugs and a total of 166,371 international participants with MACE, all-cause mortality and hypoglycaemia as objectives. In this largest database of controlled studies with sulfonylurea as reference, SGLT2 inhibitors, insulin, GLP-1RA and DPP4 inhibitors were superior with respect to MACE, whereas SGLT2 inhibitors and insulin were better for mortality outcome. Of importance, MACE and all-cause mortality were associated with SH risk.
Thus, by extrapolation, SH is a serious risk factor for MACE, heart failure, cardiac arrhythmias and overall mortality with a bidirectional relationship. Inappropriate insulin treatment is associated with an odds ratio of 2–3 for SH. However, there is no evidence for a specific risk associated with timely and adequately titrated insulin treatment.
Combinations with SGLT2 Inhibitors and GLP-1 Receptor Agonists
With level Ia evidence for CV and renal benefit of two novel glucose-lowering drug groups, SGLT2 inhibitors and GLP-1RAs, the ESC/EASD guidelines 2019 recommend these compounds as first-line therapy before metformin in patients with CVD and CKD [
40]. At present and in the near future we will not see outcome data from controlled trials with triple and multiple combinations with insulin. Therefore, decisions on the use of insulin in the framework of multiple drug combinations must be based on phase III clinical trials sponsored by the pharmaceutical industry with respect to control of HbA
1c and provide safety as primary objectives, clinical experience, plausibility and eventually results from big data registries.
Insulin in Combination with GLP-1RAs
Initiation of insulin if GLP-1RA plus metformin treatment does not achieve targets is a rational approach that uses synergistic and complementary actions of this triad.
A systematic review of additional treatment of an existing basal insulin therapy with several GLP-1RAs (exenatide, liraglutide, lixisenatide, albiglutide) as most common in clinical trials [
122] highlighted the advantages of these effective and safe combinations. Advantages were lower hypoglycaemic risk, reduction in insulin dosages and improvements in patient compliance. Quality of glycaemic control of a basal insulin plus GLP-1RA was comparable to an addition of titrated prandial insulin [
123‐
125]. In favour of the GLP-1RA/insulin combination it should be taken into account that the GLP-1RA has pleiotropic effects on the heart, liver and adipose tissue [
126,
127]. As compared to the addition of prandial insulin, a weight loss of − 5.66 kg was observed; and compared to other basal insulin combinations, a weight reduction of − 3.22 kg was observed. In a review and systemic meta-analysis, the reduction in relative risk of hypoglycaemic events by GLP-1RAs was − 33% as compared to prandial insulin combinations [
127]. The meta-analysis included 15 studies with a diabetes duration of 6.7–17.1 years (mean 12.2 years) and baseline HbA
1c values of 7.4–8.8% (mean 8.13%). The combination of basal insulin with a GLP-1RA “yielded a 92% higher likelihood of achieving target HbA
1c of 7.0% or lower by the end of the intervention, as compared with other glucose-lowering treatments”.
As mentioned above, only few studies evaluated the sequential addition of basal insulin to an insufficient GLP-1RA therapy [
122]. The poorly controlled (HbA
1c ≥ 7%) participants in the so-called Liraglutide–Detemir Study were uptitrated to the maximum liraglutide dosage of 1.8 mg for 12 weeks and separated into responders (61%, HbA
1c < 7%) and non-responders (39%) which were still above the target [
128]. The problem of unsolved response/non-response or persistency to GLP-1RAs is well known, not only from randomised clinical trials but also from daily clinical practice [
129]. During the following period over 26 weeks, responders in the Liraglutide–Detemir Study were maintained on 1.8 mg liraglutide, and to evaluate the additional effect of basal insulin, non-responders were randomised to be treated further with liraglutide 1.8 mg or combined with basal insulin titrated according to label (end dosage 0.41 IU/kg). The liraglutide non-responders stayed stable in HbA
1c, but the group with additional basal insulin reached a statistically significant efficacy difference of − 0.52% HbA
1c. Interestingly, HbA
1c in the responder group increased from run-in to study end by + 0.2% and it was lowest at − 1.12% in total compared to − 1.13% in the combined treatment group (liraglutide + basal insulin). Thus, addition of basal insulin to liraglutide was effective to treat patients to target and was safe and well tolerated without SHs and weight gain. In an open-label trial with two basal insulins, the combination with the GLP-1RA exenatide and OADs was effective to achieve HbA
1c targets with low rates of symptomatic hypoglycaemic events and only minimal weight gain [
130].
HbA
1c and glucose monitoring in clinical trials reveal an inherent tendency of an increase in HbA
1c after 6–8 months [
50,
131‐
133]. Therefore, timely addition of insulin should be considered to protect pancreatic β-cells from gluco-lipotoxicity and exploit anabolic effects on musculature. As a consequence, flexible fixed ratio combinations of insulins with a GLP-1RA have been developed: insulin glargine/lixisenatide (iGlarLixi [
134]) and insulin degludec/liraglutide (iDegLira [
135]). With these fixed-ratio combinations, pen applications that require only one injection per day have been provided. Clinical studies with iGlarLixi compared with its single components have revealed better efficacy, safety and compliance with the fixed combinations [
134,
136]. Improved efficacy, safety and compliance were also shown for iDegLira vs. single components [
137,
138]. By extrapolation, these new fixed combinations have several advantages: superiority for HbA
1c and post-prandial glucose control, lower risk of hypoglycaemia, less weight gain and better adherence to therapy [
134,
138‐
140]. Furthermore, a reduced insulin dosage is required and care for frail patients may be simplified [
141].
Another approach to rational, timely use of insulin in multiple combinations with incretins must be clinical experience in multimorbid patients. Table
1 gives clinical characteristics that indicate a priority of insulin substitution. Again, insulin has the advantage that dysglycaemia can be controlled flexibly within a short period of time. Only insulin has anabolic effects of benefit in frail, multimorbid individuals with sarcopenia. In international surveys we see a rapid increase in the prescription of new drugs [
142,
143].
There are, however, large national differences in the introduction of GLP-1RAs and SGLT2 inhibitors within Europe. At the moment, we could not find reliable epidemiological data comparing outcome and adverse effects of multiple oral combinations with GLP-1RAs vs. combination with insulin.
Insulin in Combinations with SGLT2 Inhibitors
SGLT2 inhibitors were the first novel class of glucose-lowering medications with level Ia evidence for prevention of MACE, heart failure and CKD [
28,
30,
31]. Mechanistic studies reveal a complementary effect of insulin added to SGLT2 inhibitors [
144] counteracting enhanced hepatic gluconeogenesis, and providing inhibition of lipolysis and prevention of ketosis [
145]. Furthermore, insulin adds anabolic effects and reduces incidence of urogenital infections [
146‐
150]. In a meta-analysis of seven phase III studies in insulin-treated patients, SGLT2 inhibitors caused an HbA
1c reduction of 0.56% and a reduction of body weight by 2.6 kg associated with 8.7 IU less insulin compared to placebo [
151].
Similar reductions in HbA
1c (between − 0.6% and − 0.7%) were shown for empagliflozin for the long period of 78 weeks in addition to an uncontrolled basal insulin therapy (glargine U100, detemir, NPH insulin) [
151] with similar hypoglycaemic events in all groups including placebo. The main reductions occurred during the first 12 weeks and remained stable especially with the 25 mg dose in the following 56 weeks owing to an almost stable basal insulin dosage (− 1.2 to − 0.5 IU from baseline), whereas in the placebo group the insulin dosage rose up by + 5.5 IU. The advantage of adding SGLT2 inhibitors to basal insulin therapy vs. an ongoing monotherapy was recently confirmed in a meta-analysis by Monami et al. [
54].
The risk of genital mycotic infections increases with the development of glucosuria. Clinical experience suggests that timely insulin addition with near to normal glucose control has preventive effects on genital candidiasis [
152,
153].
There are no outcomes available on benefit of insulin when added to SGLT2 inhibitors plus metformin and/or other OADs. Thus, timely initiation in the framework of multiple combinations with SGLT2 inhibitors as first-line drug depends on pathophysiological and clinical reasoning of risk/benefit and not least the unmet needs of our patients.
In summary, while SGLT2 inhibitors and GLP-1RAs show strong evidence for early use, for combination therapy of insulin with SGLT2 inhibitors and/or GLP1-RAs, it is reasonable to recommend an early add-on of insulin to those drugs in order to get to target, improve long-term persistence on HbA1c and reduce microvascular disease risk.
Conclusions
Type 2 diabetes is a progressive chronic disease with deficits in pancreatic β-cell function and insulin resistance in muscle, liver and adipose tissue as core defects together with low-grade inflammation. Gluco- and lipotoxicity have harmful effects on residual β-cell function and islet cell regeneration. Therefore, timely initiation of insulin to achieve near to normal glucose homeostasis and to control lipotoxicity and inflammation is an option at any time to protect β-cells and to avoid harmful remodelling of the metabolic memory. Insulin treatment, however, is a double edged sword that may have serious adverse effects such as hypoglycaemia and weight gain. Thus, an individualised approach to start insulin therapy is essential on the basis of risk/benefit balance.
In principle, we recommend two strategies for insulin use: (1) insulin (as first-line drug) at diagnosis of diabetes. The indication is severe hyperglycaemia with HbA1c ≥ 9–10% and subtypes with severe insulin deficit and clinical disease. This strategy is most effective to control gluco-lipotoxicity, favours revival of β-cell function, avoids harmful effects on metabolic memory and has a high rate of diabetes remission; (2) insulin as a combination with OADs and/or GLP-1RAs at the time when HbA1c is out of target or the patient develops diabetes-related complications, or suffers from infections, sarcopenia etc. that benefit from the pleiotropic effects of insulin.
Acknowledgements
The content published herein represents the views and opinions of the various contributing authors and does not necessarily represent the views or opinion of Sanofi-Aventis Deutschland GmbH and/or its affiliates.
Disclosures
Markolf Hanefeld: Boards: Sanofi SC for ORIGIN, Lilly SC for REWIND, AstraZeneca SC for EXSCEL; Lecture fees: Bayer, AstraZeneca, Lilly, Sanofi, Abbott, Novo Nordisk. Holger Fleischmann: former employee of Sanofi-Aventis Deutschland GmbH. Thorsten Siegmund: Boards: Abbott, Ascensia, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Janssen, Medtronic, MSD, Novo Nordisk, Sanofi; Lecture fees: Abbott, Ascensia, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Lilly, Medtronic, MSD, Novartis, Novo Nordisk, Sanofi. Jochen Seufert: Advisory board member Abbott, AstraZeneca, Boehringer Ingelheim, GI Dynamics, Janssen, LifeScan Mundipharma Novartis, Novo Nordisk, Sanofi. Speaker Abbott, AstraZeneca, Bayer, Berlin Chemie Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Eli Lilly, Merck Sharp Dohme (MSD) MedScape Novartis, Novo Nordisk, Omniamed, Sanofi, Research support AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GI Dynamics, Intarcia Ipsen, Janssen, Novartis, Novo Nordisk, Sanofi, Ypsomed.