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      Second-Generation Insulin Analogues – a Review of Recent Real-World Data and Forthcoming Head-to-Head Comparisons

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          Abstract

          Insulin analogues play a key role in the effective management of type 2 diabetes. However, there are several behavioural barriers to appropriate early initiation of insulin therapy, despite compelling evidence supporting the benefits of this strategy in those patients for whom oral anti-diabetes agents provide insufficient control. The development of second-generation insulin analogues (insulin glargine 300 U/mL and insulin degludec) has provided physicians with agents that can provide comparable glycaemic control to first-generation insulin, but with a reduced risk of hypoglycaemia and modes of action suited to once-daily regimens. These characteristics may help overcome patient and physician concerns about early insulin use in disease management. To date, there have been no head-to-head comparisons of second-generation insulins: here we consider recent real-world evidence and the forthcoming direct comparison in the BRIGHT randomised controlled study, as presented at the recent 11 th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD) 2018.

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          The burden of treatment failure in type 2 diabetes.

          In type 2 diabetes, therapies to maintain blood glucose control usually fail after several years. We estimated the glycemic burden that accumulates from treatment failure and describe the time course and predictors of failure. A prospective, population-based study using retrospective observational data. We identified all 7208 complete courses of treatment with nondrug therapy, sulfonylurea monotherapy, metformin monotherapy, and combination oral antihyperglycemic therapy between 1994 and 2002, inclusive, among members of the Kaiser Permanente Northwest Region. We calculated mean cumulative glycemic burden, defined as HbA(1c)-months >8.0 or 7.0% for each treatment. We then measured the likelihood that the next HbA(1c) would exceed 8.0 and 7.0% after HbA(1c) exceeded each of ten hypothetical treatment thresholds. Finally, we estimated multivariate logistic regression models to predict when HbA(1c) would continue to deteriorate. In this well-controlled population, the average patient accumulated nearly 5 HbA(1c)-years of excess glycemic burden >8.0% from diagnosis until starting insulin and about 10 HbA(1c)-years of burden >7.0%. Whenever patients crossed the American Diabetes Association-recommended treatment threshold of 8.0%, their next HbA(1c) result was as likely to be 8.0%. Multivariate prediction models had highly statistically significant coefficients, but predicted <10% of the variation in future HbA(1c) results. Clinicians should change glucose-lowering treatments in type 2 diabetes much sooner or use treatments that are less likely to fail. An action point at 7.0% or lower is more likely to prevent additional deterioration than the traditional action point of 8.0%.
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            Glycaemic control and hypoglycaemia burden in patients with type 2 diabetes initiating basal insulin in Europe and the USA

            Aims To evaluate short‐ and long‐term glycaemic control and hypoglycaemia incidence in insulin‐naïve patients ≥30 years of age with type 2 diabetes (T2DM) initiating basal insulin (BI) with or without oral anti‐hyperglycaemic drugs (OADs). Methods This was an observational, retrospective longitudinal analysis of electronic medical records from 5 European countries and the USA. A multivariable logistic regression model assessed baseline and short‐term (0‐3 months post BI initiation) factors associated with long‐term (3‐24 months) glycaemic control and hypoglycaemia. Results Overall, 40 627 patients were included; 20.9% and 27.8% achieved the general HbA1c target of ≤7% at 3 and 24 months post BI initiation, respectively. Failure to achieve HbA1c ≤7% at 3 months was associated with increased risk of failing to achieve target at 24 months (odds ratio [OR], 3.70 [95% CI, 3.41‐4.00]). Over 24 months, 8.9% of patients experienced a recorded hypoglycaemic event. Hypoglycaemia during the initial 3‐month period was associated with longer‐term risk of these events over the ensuing 3 to 24 months (OR, 5.71 [95% CI, 4.67‐6.99]). Conclusions Initiating BI with or without OADs is associated with short‐ and long‐term suboptimal glycaemic control; the majority of patients fail to achieve HbA1c target ≤7% in the first 3 months, or after 2 years of BI treatment. Treatment response and hypoglycaemia incidence by 3 months post BI initiation are associated with longer‐term glycaemic control and hypoglycaemic risk, respectively. These results support the need for early anti‐hyperglycaemic interventions that more effectively control blood glucose levels without increasing the risk of hypoglycaemia.
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              Insulin Therapy for Type 2 Diabetes

              A number of landmark randomized clinical trials established that insulin therapy reduces microvascular complications (1,2). In addition, recent follow-up data from the U.K. Prospective Diabetes Study (UKPDS) suggest that early insulin treatment also lowers macrovascular risk in type 2 diabetes (3). Whereas there is consensus on the need for insulin, controversy exists on how to initiate and intensify insulin therapy. The options for the practical implementation of insulin therapy are many. In this presentation, we will give an overview of the evidence on the various insulin regimens commonly used to treat type 2 diabetes. Secondary analyses of the aforementioned landmark trials endeavored to establish a glycemic threshold value below which no complications would occur. The UKPDS found no evidence for such a threshold for A1C, but instead showed that better glycemic control was associated with reduced risks of complications over the whole glycemic range (“the lower the better”) (4). For the management of type 2 diabetes, this resulted in the recommendation to “maintain glycemic levels as close to the nondiabetic range as possible” (5). However, in contrast to the UKPDS, the Kumamoto study observed a threshold, with no exacerbation of microvascular complications in patients with type 2 diabetes whose A1C was 8.5% at the start of insulin therapy), treatment with once-daily basal insulin alone would not attain glycemic goals (11,32,33). However, the LANMET study proved otherwise. In this clinical trial, A1C levels decreased from 9.1% at baseline to 7.1% with combination therapy of bedtime insulin glargine or NPH insulin and metformin (36). Finally, it seems likely that insulin initiation by means of one (basal) injection may also facilitate patients' acceptance of insulin initiation. Combined therapy with oral agents As discussed at the first Controversies in Obesity, Diabetes and Hypertension (CODHy) meeting, the rationale for combining insulin with oral therapy is minimization of the adverse effects of insulin treatment, i.e., hypoglycemia and weight gain (44). Combination of insulin with metformin is indeed associated with better glycemic control, fewer hypoglycemic events, and less weight gain than treatment with insulin alone (45). Therefore, metformin should be continued when patients are initiated on insulin therapy (i.e., providing there are no intolerable side effects). Data concerning the combination of insulin with either sulfonylureas alone, or with both metformin and sulfonylureas, compared with insulin-alone treatment regimens, are ambiguous (46). The only consistent advantage of such combined therapy is reduced insulin dose requirements, which may result in less daily injections, easier dose titration, and improved compliance (46). However, these potential benefits must be balanced against the side effects and higher cost of continuing sulfonylureas together with metformin compared with treatment with metformin and NPH insulin alone—although not versus long-acting insulin analogs and metformin alone (31,46)—and the possibility of reduced patient adherence when increasing numbers of pills are prescribed (47). An ongoing randomized trial comparing the continuation of sulfonylureas in combination with metformin and insulin glargine versus discontinuation of sulfonylureas with this combination regimen in insulin-naive type 2 diabetic patients will hopefully provide further evidence regarding this issue (ISRCTN29335793: www.controlled-trials.com). INTENSIFICATION OF INSULIN THERAPY When should insulin therapy be intensified? Because of progressive β-cell decline, treatment with once-daily basal insulin alone will eventually fail to maintain glycemic control in a substantial number of patients with type 2 diabetes. When the recommended A1C level of <7.0% is not reached, or maintained despite successful basal insulin dose titration maintaining fasting plasma glucose ≤100 mg/dl, or when aggressive titration is limited by hypoglycemia, treatment should be intensified by adding insulin injections. How should insulin therapy be intensified? The available options for additional insulin injections include a second injection of basal insulin, prandial insulin before one or more meals, or a switch to biphasic insulin. The choice between intensification of basal insulin versus the introduction of prandial or biphasic insulin should be individualized based on patients' diurnal blood glucose profiles. When considering the profiles obtained with NPH insulin or long-acting insulin analog once daily, the effect appears to wane during the day, even in patients starting insulin therapy, i.e., with remaining endogenous insulin secretion (33,37,48). These patients could benefit from adding a second injection of basal insulin (48). However, in the context of declining endogenous insulin secretion, daytime hyperglycemia is usually related to elevated postprandial glucose levels, favoring the initiation of prandial or biphasic insulin. Two recent studies established that in patients not achieving adequate glycemic control with once-daily basal insulin, basal-bolus therapy results in greater A1C reductions than biphasic insulin twice or thrice daily (49,50). However, when a more gradual intensification of insulin treatment is preferred, patients can be switched to biphasic insulin two, and subsequently three, times daily. The latter regimen has been shown to significantly improve A1C levels of patients previously treated with insulin glargine (50). Whether stepwise introduction of meal-time injections is as safe and effective as the rapid initiation of a full basal-bolus regimen is currently under investigation (51). Finally, regarding the choice of prandial insulin, rapid-acting insulin analogs are not superior to regular insulin in reducing A1C levels or rates for overall and nocturnal hypoglycemia, despite improving postprandial control (18). In some studies, treatment with rapid-acting analogs was associated with fewer severe hypoglycemic episodes and improved treatment satisfaction (18), the latter probably being related to increased convenience because of injection immediately before meals. In conclusion, there is no compelling reason to overall favor rapid-acting insulin analogs over regular insulin in type 2 diabetes. Whereas in some countries the price of rapid-acting analogs has been lowered to the level of regular insulin, in others, it remains around twice as high (31). Continuous subcutaneous insulin infusion In patients with type 2 diabetes already using at least one daily insulin injection, the introduction of intensive insulin therapy with continuous subcutaneous insulin infusion resulted in comparable glycemic control, weight gain, and hypoglycemia risk as multiple daily injection therapy (52,53). Although continuous subcutaneous insulin infusion was associated with greater improvements in treatment satisfaction in one study (53), we recommend that its use be restricted to selected patients in experienced centers only. DRAWBACKS OF INSULIN THERAPY Hypoglycemia Intensive glucose-lowering therapy inevitably results in an increased rate of hypoglycemia, which was once again confirmed in the recent ACCORD study with annualized rates of hypoglycemic episodes requiring medical assistance of 3.1 and 1.0% in the intensive and standard therapy groups, respectively (6). Iatrogenic hypoglycemia hampers tight glycemic control and is considered the limiting factor in diabetes management (54). Opinions are divided on the extent of the problem, with cited event rates for severe hypoglycemia in insulin-treated type 2 diabetic patients ranging from between 1 and 3 (5) to between 10 and 73 per 100 patient-years (55). Of note, the relatively low rates were found in clinical trials (2,56), whereas the higher figures were reported in retrospective and population-based studies (57 –59). The difference is probably explained by varying durations of disease or insulin therapy in the cited studies. The risks of mild and severe hypoglycemia are low among type 2 diabetic patients just beginning insulin therapy (30) and appear to increase with increasing durations of diabetes and insulin treatment (57 –59). To conclude, in type 2 diabetes, the frequency of hypoglycemia is generally lower than that in type 1 diabetes (54). This is presumably the result of relative protection of type 2 diabetic patients against hypoglycemia by residual endogenous (i.e., physiologically regulated) insulin and glucagon secretion, insulin resistance, and higher glycemic thresholds for counterregulatory and symptomatic responses to hypoglycemia (60,61). Therefore, when initiating insulin therapy, attempts to attain A1C goals should not be hampered too much by concerns about hypoglycemia. However, iatrogenic hypoglycemia appears to become a more frequent problem at the insulin-deficient stage of the disease, warranting more vigilance as the disease advances (54). Weight gain The ∼2- to 4-kg increase in body weight associated with insulin therapy has traditionally been explained by reductions of glucosuria and resting energy expenditure when glycemic control is improved (5,46). Other explanations are snacking to prevent, or in response to, hypoglycemia or restoration of the weight loss usually preceding insulin initiation to the weight before onset of diabetes. In contrast, a recent study found that the mean weight gain of 1.8 kg in 23 type 2 diabetic patients during the first 6 months of insulin therapy was not accompanied by a change in glucosuria, resting energy expenditure, or physical activity. The authors concluded that increased energy intake was the only plausible explanation for the observed weight increments (62). Although the mechanisms underlying insulin-associated weight gain are still not fully understood, it is thought to be proportional to the number of insulin injections, or the total daily insulin dose (32,45,46). Interestingly, when considering studies investigating basal insulin initiation in type 2 diabetes, we found no evidence for such a dose-response relationship (Fig. 1 C). Finally, when directly comparing the mean increases in body weight during insulin initiation with NPH insulin versus long-acting insulin analogs, insulin glargine is associated with similar weight gain (27,35 –37). Treatment with insulin detemir, on the other hand, appears to result in less weight gain than NPH insulin (28,33). However, considering the limited magnitude of the reported weight-sparing effect, we still recommend NPH insulin for the initiation of insulin therapy in patients with type 2 diabetes. CONCLUSIONS Although insulin has no upper dose limit and numerous trials established that glycemic goals can be attained by using adequate doses, in clinical practice, many patients experience years of uncontrolled hyperglycemia. Because most type 2 diabetic patients have residual endogenous insulin secretion, the rationale for imitating the physiological insulin secretion pattern is less convincing than in type 1 diabetes. Glycemic treatment should be stepwise with swift introduction of successive interventions after treatment failure (i.e., A1C ≥7.0%). Insulin should be initiated when A1C is ≥7.0% after 2–3 months of dual oral therapy. The preferred regimen for insulin initiation in type 2 diabetes is once-daily basal insulin. In addition to timely initiation, rapid titration of the dose is indispensable for successful insulin therapy. Hypoglycemia risk is very low among type 2 diabetic patients just starting insulin therapy, making NPH insulin the most cost-effective drug. When glycemic goals are not attained despite successful basal insulin dose titration (i.e., fasting plasma glucose ≤100 mg/dl), or when titration is limited by hypoglycemia, treatment should be intensified by addition of prandial or biphasic insulin.
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                Author and article information

                Journal
                Eur Endocrinol
                Eur Endocrinol
                EE
                European Endocrinology
                Touch Medical Media
                1758-3772
                1758-3780
                May 2018
                11 May 2018
                : 14
                : Suppl1
                : 2-9
                Affiliations
                [1 ] Hospital de Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
                [2 ] Lawson Research Institute, London, ON, Canada
                Hospital de Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
                Lawson Research Institute, London, ON, Canada
                Author notes
                Corresponding Author: Irene Hramiak, PO Box 5777, Station B, 268 Grosvenor St, London, Ontario, Canada, N6A 4V2. E: Irene.Hramiak@ 123456sjhc.london.on.ca

                Disclosure: Didac Mauricio reports personal fees from Sanofi, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, GlaxoSmithKline, Novo Nordisk, Ferrer, Menarini, AstraZeneca and Janssen, outside the submitted work. Irene Hramiak reports grants from Lexicon Pharmaceuticals and Medtronic; grants and personal fees from Sanofi, GlaxoSmithKline, Janssen Pharmaceuticals and Novo Nordisk; personal fees from Amgen Inc, Boehringer Ingelheim, Roche, Insulet Corp and Takeda; grants, personal fees and non-financial support from Astra Zeneca/Bristol-Myers Squibb; and grants, personal fees and other support from Eli Lilly and Merck, outside the submitted work.

                Article
                10.17925/EE.2018.14supp1.2
                6009413
                30034546
                0f1ea241-69db-45cd-9562-09c7ef386a8d
                © The Author(s) 2018

                This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. © The Authors 2018.

                Review Process: This supplement did not undergo the journal’s standard peer review process but was reviewed by the Editorial Board for scientific accuracy before publication.

                History
                : 30 April 2018
                : 11 May 2018
                Page count
                Pages: 8
                Funding
                Support: The publication of this supplement is supported by Sanofi. The views and opinions are those of the authors and not necessarily those of Sanofi.
                Categories
                Second-Generation Insulin Analogues

                second-generation,insulin glargine 300,once-daily insulin,hypoglycaemia,type 2 diabetes

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