Insulin Analogues Glargine Research Articles

Insulin Analogs and Cancer

Today, insulin analogs are used in millions of diabetic patients. Insulin analogs have been developed to achieve more physiological insulin replacement in terms of time-course of the effect. Modifications in the amino acid sequence of the insulin molecule change the pharmacokinetics and pharmacodynamics of the analogs in respect to human insulin. However, these changes can also modify the molecular and biological effects of the analogs. The rapid-acting insulin analogs, lispro, aspart, and glulisine, have a rapid onset and shorter duration of action. The long-acting insulin analogs glargine and detemir have a protracted duration of action and a relatively smooth serum concentration profile. Insulin and its analogs may function as growth factors and therefore have a theoretical potential to promote tumor proliferation. A major question is whether analogs have an increased mitogenic activity in respect to insulin. These ligands can promote cell proliferation through many mechanisms like the prolonged stimulation of the insulin receptor, stimulation of the IGF-1 receptor (IGF-1R), prevalent activation of the extracellular-signaling-regulated kinase (ERK) rather than the protein kinase B (PKB/AKT) intracellular post-receptor pathways. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar to those of insulin. In contrast, long-acting analogs behave differently. Although not all data are homogeneous, both glargine and detemir have been found to have a decreased binding to receptors for insulin but an increased binding to IGF-1R, a prevalent activation of the ERK pathway, and an increased mitogenic effect in respect to insulin. Recent retrospective epidemiological clinical studies have suggested that treatment with long-acting analogs (specifically glargine) may increase the relative risk for cancer. Results are controversial and methodologically weak. Therefore prospective clinical studies are needed to evaluate the possible tumor growth-promoting effects of these insulin analogs.

Protected Graft Copolymer (PGC) Basal Formulation of Insulin as Potentially Safer Alternative to Lantus® (Insulin-Glargine): A Streptozotocin-Induced, Diabetic Sprague Dawley Rats Study

To develop a long-acting formulation of native human insulin with a similar pharmacodynamics (PD) profile as the insulin analogue insulin glargine (Lantus®, Sanofi-Aventis) with the expectation of retaining native human insulin's superior safety profile as insulin glargine is able to activate the insulin-like growth factor 1 (IGF-1) receptor and is linked to a number of malignancies at a higher rate than regular human insulin. Development of protected graft copolymer (PGC) excipients that bind native human insulin non-covalently and testing blood glucose control obtained with these formulations in streptozotocin-induced diabetic Sprague Dawley rats compared to equally dosed insulin glargine. PGC-formulations of native human insulin are able to control blood glucose to the same extent and for the same amount of time after s.c. injection as the insulin analogue insulin glargine. No biochemical changes were made to the insulin that would change receptor binding and activation with their possible negative effects on the safety of the insulin. Formulation with the PGC excipient offers a viable alternative to biochemically changing insulin or other receptor binding peptides to improve PD properties.

Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus

IntroductionThe goal of insulin therapy in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) is to match as closely as possible normal physiologic insulin secretion to control fasting and postprandial plasma glucose. Modifications of the insulin molecule have resulted in two long-acting insulin analogs (glargine and detemir) and three rapid-acting insulins (aspart, lispro, and glulisine) with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles. These agents can be used together in basal-bolus therapy to more closely mimic physiologic insulin secretion patterns.MethodsThis study reviews effects of the multiple demographic and clinical parameters in the insulin analogs glargine, detemir, lispro, aspart, and glulisine in patients with T2DM. A search was conducted on PubMed for each major topic considered (effects of injection site, age, race/ethnicity, obesity, renal or hepatic dysfunction, pregnancy, exercise, drug interactions) using the topic words and name of each type of insulin analog. Information was also obtained from the prescribing information for each insulin analog.ResultsThe PK/PD profiles for insulin analogs may be influenced by many variables including age, weight, and hepatic and renal function. However, these variables do not have equivalent effects on all long-acting or rapid-acting insulin analogs.ConclusionRapid-acting and long-acting insulin analogs represent major advances in treatment for patients with T2DM who require insulin therapy. However, there are potentially important PK and PD differences between the two long-acting agents and among the three rapid-acting insulin analogs, which should be considered when designing treatment regimens for special patient groups.

Critical appraisal of the recent data published on the link between insulin and cancer

Recent publications indicate a possible association between newer analogue insulin Glargine and cancer. However all these data were observational in nature and subject to lot of methodological errors. It is practically impossible to derive at a cause and effect relationship based on these observational studies. There are several confounding factors like hyperinsulinemia, obesity and smoking, which independently can be associated with cancer risk. This review looks into the recently published observational studies from the methodological point of view and whether such a negative association can indeed be drawn as a conclusion. Several methodological defects were identified in the process of scrutiny and we concluded it is not possible to conclude that there is an association between Glargine use and cancer. However long-term prospective data is required to come to definite conclusion.

Pharmacotherapy of diabetes and cancer risk

Lines of reports published recently analyzing the association between pioglitazone use and bladder cancer and the subsequent actions taken by regional regulatory agencies and international diabetes organizations rekindle a longrunning controversy over diabetes treatment and cancer risk. An interim report of an ongoing cohort study, one of the representative papers published in the April issue of Diabetes Care, examined the association between pioglitazone therapy and the risk of bladder cancer in 193,099 diabetic patients in the Kaiser Permanente Northern California (KPNC) Diabetes Registry between 1997 and 2002. The patients were C40 years of age and the group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among those who did not use pioglitazone. Overall, the short-term use of pioglitazone was not associated with a risk of bladder cancer [HR 1.2 (95% CI 0.9–1.5)], but its use for more than 2 years was weakly associated with an increased risk (OR 1.4, 95% CI 1.03–2.0) [1]. Surprisingly, France suspended the use of pioglitazone at the beginning of June 2011 and Germany has recommended that pioglitazone should not be started in new patients, based on a recently conducted retrospective cohort study by the French National Health Insurance Agency (Caisse National d’Assurance Maladie) which followed diabetic patients taking antidiabetic medicines between 2006 and 2009. The US Food and Drug Administration (FDA) soon issued a Drug Safety Communication on June 15, 2011 (updated on August 5) regarding the ongoing safety review of pioglitazone and the increased risk of bladder cancer [2]. Based on a review of the data from the KPNC epidemiological study, FDA stated that the long-term use of pioglitazone ([1 year) may be associated with an increased risk of bladder cancer. The FDA acknowledged that the finding was still of nominal statistical significance, and is advising health-care professionals not to use it in patients with active bladder cancer and to prescribe the drug with caution for patients with a prior history of bladder cancer, weighing the benefits of blood glucose control against the unknown risks of cancer recurrence. One month after the FDA’s communication, the European Medicines Agency (EMA) issued a recommendation and the EMA’s Committee for Medicinal Products for Human Use concluded that the benefits of pioglitzone outweigh its risks in a limited population of type 2 diabetes patients, despite the small risk of bladder cancer with this drug. The Committee has made recommendations to reduce the risk of bladder cancer in patients taking the medicines [3]. The series of events mentioned above reminded us of a recent outbreak of controversy related to a possible association between the long-acting insulin analog glargine and an increased risk of cancer. On June 2009, the diabetes community was suddenly shaken with a story relevant to patients with diabetes treated with insulin, when four registry studies that analyzed the association of insulin glargine with the risk of cancer were published in Diabetologia. The American Diabetes Association (ADA) immediately released a statement noting that ‘‘findings from these research papers are conflicting and inconclusive, and the ADA cautions against over-reaction and advises patients using insulin not to stop taking it until more information is available.’’ Regulatory agencies such as the EMA and FDA, international organizations such as the International Diabetes Federation (IDF), K. Kaku (&) M. Hashiramoto Division of Diabetes, Metabolism, and Endocrinology, Kawasaki Medical School, Kurashiki, Japan e-mail: kka@med.kawasaki-m.ac.jp

Diabetes and Ramadan: An Update On Use of Glycemic Therapies During Fasting

The fasting of Ramadan is observed by a large proportion of Muslims with diabetes. Recommendations for the management of diabetes during Ramadan were last published in 2005 by the American Diabetes Association. Several studies in this field have since been published, some addressing the use of new pharmacological agents in managing diabetes during Ramadan. The incritin memetics are potentially safe during Ramadan; the DPP4 inhibitors vildagliptin and sitagliptin provide an effective and safe therapeutic option, administered either alone or in combination with metformin or sulfonylureas. There are no published studies on the use of GLP-1 receptor agonists during Ramadan. Among the sulfonylureas, gliclazide MR (modified release) and glimepride can be safely used during Ramadan, but glibenclamide should be avoided due to the associated risk of hypoglycemia. In selected patients with type 1 and type 2 diabetes, the long-acting insulin analogues glargine and detemir, as well as the premixed insulin analogues, can be used with minimal risk of metabolic derangement or hypoglycemia; the risk is higher in type 1 diabetes. Insulin pumps can potentially empower patients with diabetes and enable safe fasting during the month of Ramadan. Further clinical trials are needed to evaluate the safety and efficacy of new antidiabetic agents and new diabetes-related technologies during Ramadan.

Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years

In order to provide comprehensive information on the differences in bioactivity between human insulin and insulin analogues, published in vitro comparisons of human insulin and the rapid acting analogues insulin lispro (Humalog®), insulin aspart ( NovoRapid®), insulin glulisine (Apidra®), and the slow acting analogues insulin glargine (Lantus®), and insulin detemir (Levemir®) were gathered from the past 20 years (except for receptor binding studies). A total of 50 reports were retrieved, with great heterogeneity among study methodology. However, various differences in bioactivity compared to human insulin were obvious (e.g. differences in effects on metabolism, mitogenesis, apoptosis, intracellular signalling, thrombocyte function, protein degradation). Whether or not these differences have clinical bearings (and among which patient populations) remains to be determined.

Incidence of malignancies in patients with diabetes mellitus and correlation with treatment modalities in a large Israeli health maintenance organization: a historical cohort study

It has been hypothesized that incidence of and mortality from several malignancies are increased among diabetic patients. Whether certain treatment modalities, including use of metformin, sulfonylureas, or insulins, affect cancer incidence or mortality and whether use of long-acting insulin analogues glargine and detemir may increase cancer incidence more than traditional human insulins are debated. The objective was to investigate the association between specific glucose-lowering agents and cancer incidence in diabetic members of an Israeli health maintenance organization. We studied a cohort of 36,342 diabetic patients aged at least 18 years with no history of cancer or treatment with insulin as of January 1, 2003. For the period from January 2003 to December 2007, we searched pharmacy records for purchases of glucose-lowering agents, including metformin, sulfonylureas, human insulin, and analogue insulins. Incident cancer diagnoses were identified from the health maintenance organization cancer registry. We studied the association of cancer incidence with the use of specific glucose-lowering agents, controlling for age, sex, and baseline glycohemoglobin measurement. Cancer was diagnosed in 6% of the study cohort during 164,652 person-years of follow-up time. Cancer incidence increased with age and varied with medication purchasing patterns. On multivariate analysis, age (hazard ratio [HR], 1.049; confidence interval [CI], 1.045-1.052), male sex (HR, 1.16; CI, 1.065-1.264), and number of insulin purchases (HR, 1.007; CI, 1.001-1.012) were significantly associated with increased cancer risk, whereas number of metformin purchases was associated with reduced cancer risk (HR, 0.996; CI, 0.994-0.998). Male sex, age, and human insulin purchases were associated with increased cancer incidence, whereas metformin purchases were associated with decreased cancer risk. There was a trend for increased cancer incidence associated with use of long-acting insulin analogues, but the number of long-acting insulin analogue users was too small for risk estimates to be conclusive.

Therapeutic effects of metformin in breast cancer: involvement of the immune system?

Breast cancer and associated diabetes mellitus have gained raising interest as an elevated risk of breast cancer prognosis resulting in increased mortality in diabetic patients. In this context, the long-acting insulin analog glargine and other antidiabetics have been discussed to promote tumorigenesis. In contrast, the biguanide class oral antidiabetic metformin has been shown capable of enhancing cell cycle arrest and inducing apoptosis as well as reducing growth factor signaling. Consequently, several studies are underway to evaluate a possible role of metformin in breast cancer treatment. Although mechanisms involved are not definitely clear yet, here, we discuss metformin's anticancer effects including the potential impact of the immune system.

Insulin Preparations with Prolonged Effect

The discovery of insulin and its clinical application early in the last century dramatically improved the prospects of people with diabetes. However, the limitations of those initial, unmodified insulin preparations were quickly recognized; most notably, their relatively "short action" meant that multiple daily subcutaneous injections were required. This stimulated a concerted effort to modify the properties of insulin in order to extend the duration of its blood glucose-lowering effect, minimize dosing frequency, and decrease the burden of treatment. The first successful attempts to prolong insulin's action were achieved by modifying its formulation with additives such as protamine and zinc, culminating in the production of "intermediate-acting" neutral protamine Hagedorn (NPH) insulin in the 1940s and the lente family of insulins in the 1950s. However, NPH and lente insulins were still associated with several limitations, including considerable variability of effect and a pronounced peak in their time-action profile. In the 1980s, the focus of research moved toward the modification of insulin itself with the aim of producing a "long-acting" insulin that would better satisfy basal insulin requirements over the entire day. Once-daily insulin glargine was the first "long-acting" insulin analog in clinical practice, followed by once- or twice-daily insulin detemir and, more recently, insulin degludec, which is now being evaluated for administration at less frequent intervals. These analogs demonstrate several benefits over "intermediate-acting" insulins, including a lower risk of both overall hypoglycemia and nocturnal hypoglycemia and reduced day-to-day glucose variability, making it more feasible to achieve better fasting and overall glycemic control. Long-acting insulin analogs (insulin glargine and insulin detemir) are now firmly established as key tools in the battle against diabetes, and ongoing clinical research of insulin-based therapy should focus on treatment strategies to maximize their benefits. To date, the clinical experience with insulin degludec is limited but demonstrates it has comparable efficacy to insulin glargine.

How Basal Insulin Analogs Have Changed Diabetes Care

How Basal Insulin Analogs Have Changed Diabetes Care

Italian toasted bread (‘bruschetta’) should be carefully evaluated by people with type 1 diabetes

Several studies focused the effect on glycemic index (GI) of bread on blood glucose either in healthy individuals or in diabetes [1] since post-prandial glycemia (PPG) and glycemic variability have important impact on diabetes complications [2]. The amount and composition of carbohydrates (CHO) affects PPG, together with fibres, chemical state of the starch and food cooking. In fact, high temperature of food processing increases the starch gelatinization with an easier enzymatic accessibility, faster digestion and higher PPG [3]. Mediterranean diet is a model of healthful eating habits in diabetes for its content of starch, mainly pasta and bread. However, no data are available on toasted bread (‘bruschetta’) which is frequently present in breakfast Mediterranean diet. Thus, we evaluated in type 1 diabetes (DM1) the PPG spikes after ingestion of white and dark bread served fresh and toasted. Eighteen (12 F, 6 M) DM1 clinical outpatients, nonsmokers, without any diabetes complications or malabsorptive disorders, aged 38.4 ± 3.7 years, with HbA1c 7.2 ± 0.8% and duration of diabetes of 22.8 ± 7.8 years, were selected. All patients were treated with intensive insulin regimen with 22.1 ± 10.1 IU and 22.3 ± 7.0 IU daily of rapid (Lispro)and long-acting insulin analogue (Glargine), respectively. All patients gave their informed consent to the study protocol approved by Ethical Committee of University of Florence. During the study period of 20 days, all patients maintained their habitual diet and stable insulin therapy. Overnight fasting patients, alcohol and exercise free for 24 h, were admitted to the starting day only with capillary glycemia between 70 and 140 mg/dl. The food test, consumed with 250 ml of water in 50, consisted of 60 g of commercially available fresh wheat-refined bread (white bread: WB), whole-grain bread (dark bread: DB) and the same breads toasted for 2 min in an electric toaster. All patients consumed all four types of food test. The amount of total fibres for DB was 3.9 g for serving, whilst the amount of CHO was 40.2 and 29.4 g for WB and DB for serving, respectively. Four bread types were consumed for 5 days by each patient for total 20 days of collecting data. The patients were treated with preprandial insulin, with the own habitual doses of rapid insulin analogue. These doses were obtained during the pre-test period in order to achieve a post-breakfast glucose levels between 120 and 140 mg/dl. Figure 1 shows the glycemic responses to bread ingestion in the fasting (FPG) and PPG (2hPG) status (mean ± SD). FPG values were 104 ± 19, 105 ± 18, 106 ± 18 and 105 ± 19 mg/ dl for WB, toasted WB, DB and toasted DB, respectively. PPG levels were significantly higher than FPG, in all tests (P \ 0.05). PPG was higher with WB compared to DB with an incremental glucose response of 112.6 ± 4.2 versus 34.4 ± 20.3 mg/dl (P \ 0.001). In addition, the PPG incremental excursion between WB and toasted DB was not statistical different (112.6 ± 4.2 vs. 117 ± 13.4; P = 0.12) although a higher concentration of CHO was present in WB. Toasted WB showed the highest PPG levels (P \ 0.001), with an incremental of 168.7 ± 19.7 mg/dl, whilst the lower incremental was S. Giannini (&) G. Bardini E. Mannucci C. M. Rotella Section of Endocrinology, Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50134 Florence, Italy e-mail: s.giannini@dfc.unifi.it

Type 2 diabetes mellitus and risk of malignancy: is there a strategy to identify a subphenotype of patients with increased susceptibility to endogenous and exogenous hyperinsulinism?

To give an overview on the relationship between diabetes mellitus and increased cancer risk. We identified studies evaluating the association between diabetes mellitus, its treatment with insulin and insulin analogues and malignancies, paying special attention to studies on in vitro and in vivo effects of the long-acting analogue insulin glargine. Even although the pathophysiological mechanisms underlying the relationship between elevated cancer risk and Type 2 diabetes mellitus are not completely understood, hyperinsulinaemia in the presence of insulin resistance appears to be a key factor. Because of the mitogenic actions of insulin at high concentrations, hyperinsulinaemia may favour tumorigenesis. In line with this, an insulin-based therapy is associated with an increased cancer risk, whereas an insulin-sensitizing treatment results in a cancer risk reduction. Furthermore, alterations of the insulin receptor profile on tumour cells may contribute to an enhanced susceptibility towards insulin. Studies on the analogue insulin glargine have been controversial. In vitro data pointed to an elevated mitogenicity of insulin glargine, whereas in vivo data did not confirm cancerogenous effects. Moreover, recently published clinical studies on the association of insulin glargine (Lantus®) and cancer suggest that treatment with insulin glargine is not associated with increased cancer risk. The relationship between elevated cancer risk and Type 2 diabetes mellitus has been shown by numerous epidemiological studies, with endogenous and exogenous hyperinsulinaemia in the presence of insulin resistance as potential underlying pathophysiological mechanisms. Recent clinical studies do not support an increased cancer risk in patients treated with insulin glargine.

Controversies in the use of insulin analogues

Introduction: In recent years, insulin analogues have been developed in order to improve the pharmacological parameters of insulin and to better mimic endogenous insulin output. Given that some of the modifications introduced into insulin analogues are located in a domain involved in a potential interaction with the insulin-like growth factor-I receptor (IGF-IR), it has been postulated that certain analogues may display IGF-I-like activities.Areas covered: We review the recent literature investigating the risk of malignant neoplasms and mortality in diabetic patients treated either with human insulin or with one of three insulin analogues (lispro, aspart, and glargine). We examine how critical analyses are consistent with the notion that the use of insulin glargine is associated with a possible increased risk of tumors in humans.Expert opinion: The introduction of insulin analogues has had a major impact in diabetes care. However, the benefit of some of these new insulins for the patient has yet to be demonstrated. Furthermore, research is needed to clarify whether insulin glargine is more strongly associated with cancer risk compared with other insulins.

Development of AIDA v4.3b Diabetes Simulator: Technical Upgrade to Support Incorporation of Lispro, Aspart, and Glargine Insulin Analogues

Introduction. AIDA is an interactive educational diabetes simulator available on the Internet without charge since 1996 (accessible at: http://www.2aida.org/). Since the program’s original release, users have developed new requirements, with new operating systems coming into use and more complex insulin management regimens being adopted. The current work has aimed to design a comprehensive diabetes simulation system from both a clinical and information technology perspective.Methods. A collaborative development is taking place with a new generic model of subcutaneous insulin absorption, permitting the simulation of rapidly-acting and very long-acting insulin analogues, as well as insulin injections larger than 40 units. This novel, physiological insulin absorption model has been incorporated into AIDA v4. Technical work has also been undertaken to install and operate the AIDA software within a DOSBox emulator, to ensure compatibility with Windows XP, Vista and 7 operating systems as well as Apple Macintosh computers running Parallels PC emulation software.Results. Plasma insulin simulations are demonstrated following subcutaneous injections of a rapidly-acting insulin analogue, a short-acting insulin preparation, intermediate-acting insulin, and a very long-acting insulin analogue for injected insulin doses up to 60 units of insulin.Discussion.The current work extends the useful life of the existing AIDA v4 program.

Placental Transfer of the Insulin Analog Glargine in the Ex Vivo Perfused Placental Cotyledon Model

Objective. The aim was to characterize the transfer of the insulin analog glargine across the placenta using the placental perfusion model. Methods. Placentas were obtained and selected cotyledons were cannulated and dually perfused. Glargine, 50 mU/L (n = 2) and 200 mU/L (n = 1), and a reference marker, antipyrine (50 μg/mL), were added to the maternal circulation. Samples were taken from the maternal and fetal compartments. Results. Glargine was not detected in the fetal compartment. In the maternal compartment, the steady state concentration was 50% lower than the starting concentration. Conclusions. Glargine probably does not cross the human placenta. Reduced maternal steady state concentrations may suggest insulin uptake by the placenta.

Safety of Insulin Glargine Use in Pregnancy: A Systematic Review and Meta-Analysis

The prevalence of diabetes in women of childbearing age is increasing. As such, the number of pregnancies complicated by diabetes will inevitably increase. New insulin analogues such as the long-acting analogue insulin glargine may represent beneficial treatment options in pregnancy by ensuring that patients achieve excellent glycemic control without risk of maternal hypoglycemia. To determine the fetal safety of insulin glargine use in the treatment of diabetes in pregnancy compared with NPH insulin therapy. A systematic review and meta-analysis was performed of all original human studies that reported neonatal outcomes among women with pregestational or gestational diabetes who were managed with either insulin glargine or NPH insulin during pregnancy. A systematic literature search was conducted using MEDLINE, EMBASE, CINAHL, the Cochrane Central Register for Controlled Trials database, and Web of Science from 1980 to June 1, 2010. Outcomes included large size for gestational age, macrosomia, neonatal hypoglycemia, neonatal intensive care unit admissions, birth trauma, congenital anomalies, preterm delivery, perinatal mortality, respiratory distress, and hyperbilirubinemia. Relative risk ratios and weighted mean differences were computed with 95% confidence intervals. Eight studies reporting on a total of 702 women with pregestational or gestational diabetes in pregnancy treated with either insulin glargine (n = 331) or NPH insulin (n = 371) met the inclusion criteria. There were no statistically significant differences in the occurrence of fetal outcomes studied with the use of insulin glargine compared to NPH insulin. No evidence has been documented for increased adverse fetal outcomes with the use of insulin glargine in pregnancy compared to the use of NPH insulin. These results increase the choices for women requiring basal insulin therapy in pregnancy.

Health economic evaluations comparing insulin glargine with NPH insulin in patients with type 1 diabetes: a systematic review.

BackgroundCompared to conventional human basal insulin (neutral protamine Hagedorn; NPH) the long-acting analogue insulin glargine (GLA) is associated with a number of advantages regarding metabolic control, hypoglycaemic events and convenience. However, the unit costs of GLA exceed those of NPH. This study aims to systematically review the economic evidence comparing GLA with NPH in basal-bolus treatment (intensified conventional therapy; ICT) of type 1 diabetes in order to facilitate informed decision making in clinical practice and health policy.MethodsA systematic literature search was performed for the period of January 1st 2000 to December 1st 2009 via Embase, Medline, the Cochrane Library, the databases GMS (German Medical Science) and DAHTA (Deutsche Agentur für Health Technology Assessment), and the abstract books of relevant international scientific congresses. Retrieved studies were reviewed based on predefined inclusion criteria, methodological and quality aspects. In order to allow comparison between studies, currencies were converted using purchasing power parities (PPP).ResultsA total of 7 health economic evaluations from 4 different countries fulfilled the predefined criteria: 6 modelling studies, all of them cost-utility analyses, and one claims data analysis with a cost-minimisation design. One cost-utility analysis showed dominance of GLA over NPH. The other 5 cost-utility analyses resulted in additional costs per quality adjusted life year (QALY) gained for GLA, ranging from € 3,859 to € 57,002 (incremental cost effectiveness ratio; ICER). The cost-minimisation analysis revealed lower annual diabetes-specific costs in favour of NPH from the perspective of the German Statutory Health Insurance (SHI).ConclusionsThe incremental cost-utility-ratios (ICER) show favourable values for GLA with considerable variation. If a willingness-to-pay threshold of £ 30,000 (National Institute of Clinical Excellence, UK) is adopted, GLA is cost-effective in 4 of 6 cost utility analyses (CUA) included. Thus insulin glargine (GLA) seems to offer good value for money. Comparability between studies is limited because of methodological and country specific aspects. The results of this review underline that evaluation of insulin therapy should use evidence on efficacy of therapy from information synthesis. The concept of relating utility decrements to fear of hypoglycaemia is a plausible approach but needs further investigation. Also future evaluations of basal-bolus insulin therapy should include costs of consumables such as needles for insulin injection as well as test strips and lancets for blood glucose self monitoring.

Insulin glargine is more potent in activating the human IGF-I receptor than human insulin and insulin detemir

Objective To investigate whether human insulin (HI) and insulin analogues differ in their ability to activate the human IGF-I receptor (IGF-IR), the human insulin receptor A (IR-A) and the human insulin receptor B (IR-B) in vitro. Methods HI, short-acting insulin analogues (insulin aspart; insulin lispro) and long-acting insulin analogues (insulin glargine; insulin detemir) were compared by using kinase receptor activation (KIRA) bioassays specific for IGF-IR, IR-A or IR-B, respectively. These assays quantify ligand activity by measuring receptor auto-phosphorylation upon ligand binding. HI and insulin analogues were tested in a range from 0.1 to 100 nM. Results Short-acting analogues: Overall, short-acting insulin analogues did not differ substantially from HI, nor from each other. Insulin lispro was slightly more potent than HI and insulin aspart in activating the IGF-IR, only reaching statistical significance at 100 nM (p < 0.01). Long-acting analogues: At < 10 nM insulin glargine was as potent as HI in activating the IRs and IGF-IR. At 10–100 nM insulin glargine was significantly more potent than HI in activating the IR-B (p < 0.05) and IGF-IR (p < 0.001). Insulin glargine was more potent than insulin detemir in activating all three receptors (p < 0.001). Insulin detemir was less potent than HI in activating the IRs at 1–10 nM (p < 0.01) and IGF-IR at > 1 nM (p < 0.05). Conclusions Insulin glargine was more potent in activating the IGF-IR than HI and insulin detemir. Since KIRA bioassays do not mimic the exact in vivo situation, further research is needed to find out whether our data have implications for clinical use of insulin glargine.

Diabetes Mellitus and Increased Risk of Cancer: Focus on Metformin and the Insulin Analogs

Type 2 diabetes mellitus has been associated with an increased risk of hepatic, pancreatic, colon, endometrial, breast, and bladder cancer. Although a mechanism of action for the increased risk has been postulated, no definitive evidence has been completely elucidated in the medical literature. Results of recently released studies documented the use of specific antidiabetic drugs with increased rates of cancer. The insulin analog glargine was the focus of four observational studies published in 2009 that outlined an increase in the rates of cancer associated with its use. In contrast, the use of metformin has been shown to possibly decrease the rate of specific cancers when used in the treatment of type 2 diabetes. These data regarding cancer risk and antidiabetic drugs are contradictory and at this time are inconclusive. Until results of long-term randomized prospective studies are available to elucidate a correlation with cancer and insulin, we must continue treating diabetes in order to avert the long-term complications of the disease.