Role of premixed insulin analogues in the treatment of patients with type 2 diabetes mellitus: A narrative review (预混胰岛素类似物在2型糖尿病治疗中的作用：叙述性综述)

Because of the progressive nature of type 2 diabetes mellitus (T2DM), insulin therapy will eventually become necessary in most patients. Recent evidence suggests that maintaining optimal glycemic control by early insulin therapy can reduce the risk of microvascular and macrovascular complications in patients with T2DM. The present review focuses on relevant clinical evidence supporting the use of premixed insulin analogues in T2DM when intensifying therapy, and as starter insulins in insulin‐naïve patients. Our aim is to provide relevant facts and clinical evidence useful in the decision‐making process of treatment selection and individualized treatment goal setting to obtain sustained blood glucose control.     

Basal-prandial insulin therapy: Scientific concept review and application

The majority of patients with type 2 diabetes mellitus (T2DM) eventually require the addition of basal insulin to existing oral therapy to achieve the glycemic goals set forth by the American Diabetes Association (A1C, <7.0%). In many patients with T2DM, insulin is the only option for achieving glycemic control and may be used successfully to attain glycemic targets in regimens that combine basal insulin with oral antidiabetic agents, or in regimens that combine basal insulin with mealtime (prandial) insulin. Basal-prandial insulin regimens that use a long-acting insulin analogue to control the fasting plasma glucose level and a short-acting insulin analogue for post-meal glucose excursions replace insulin in a manner that most closely approximates normal physiologic patterns. The current body of evidence demonstrates that such regimens will prove to be the optimal strategy for achieving glycemic control in patients with T2DM who require both basal and prandial insulin replacement. Here, we review current findings in the published literature on the efficacy of basal-prandial insulin, with a focus on practical information that might help to provide an evidence-based guide for progressing to basal-prandial insulin therapy in appropriate patients with T2DM.     

Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin

Transitioning safely to insulin therapy when oral antidiabetic agents fail to provide adequate glycemic control is a critical aspect of care for the patient with type 2 diabetes mellitus (T2DM). We evaluated the clinical effectiveness of starting patients on a relatively simple regimen of once-daily injections of either biphasic insulin aspart 70/30 (10 min before dinner), NPH insulin (at 10 p.m.), or biphasic human insulin 70/30 (30 min before dinner) in combination with metformin. Enrolled patients had T2DM and inadequate glycemic control (AlC≥7.5%) on a previous regimen of metformin as monotherapy or in combination with a sulphonylurea. One hundred and forty (140) patients received metformin monotherapy for 4 weeks followed by 12 weeks of combination treatment with metformin and once-daily insulin injections. AlC levels decreased from baseline by 1.1–1.3% for patients in each of the three treatment groups. Overall, FPG values decreased from baseline by 31% (biphasic insulin aspart), 37% (NPH insulin), and 28% (biphasic human insulin). Subjects whose final FPG level was <126 mg/dl experienced the largest decreases in AlC values (−2.3%, −1.9%, −1.8%, respectively). All three treatment regimens were well tolerated. The results indicate that patients with T2DM can safely and effectively begin insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin.     

Comparative Efficacy and Safety of Ultra-Long-Acting,Long-Acting,Intermediate-Acting,and Biosimilar Insulins for Type 1 Diabetes Mellitus: a Systematic Review and Network Meta-Analysis

BackgroundIncreasing availability of competing biosimilar alternatives makes it challenging to make treatment decisions. The purpose of this review is to evaluate the comparative efficacy and safety of ultra-long-/long-/intermediate-acting insulin products and biosimilar insulin compared to human/animal insulin in adults with type 1 diabetes mellitus (T1DM).MethodsMEDLINE, EMBASE, CENTRAL, and grey literature were searched from inception to March 27, 2019. Randomized controlled trials (RCTs), quasi-experimental studies, and cohort studies of adults with T1DM receiving ultra-long-/long-/intermediate-acting insulin, compared to each other, as well as biosimilar insulin compared to human/animal insulin were eligible for inclusion. Two reviewers independently screened studies, abstracted data, and appraised risk-of-bias. Pairwise meta-analyses and network meta-analyses (NMA) were conducted. Summary effect measures were mean differences (MD) and odds ratios (OR).ResultsWe included 65 unique studies examining 14,200 patients with T1DM. Both ultra-long-acting and long-acting insulin were superior to intermediate-acting insulin in reducing A1c, FPG, weight gain, and the incidence of major, serious, or nocturnal hypoglycemia. For fasting blood glucose, long-acting once a day (od) was superior to long-acting twice a day (bid) (MD - 0.44, 95% CI: - 0.81 to - 0.06) and ultra-long-acting od was superior to long-acting bid (MD - 0.73, 95% CI - 1.36 to - 0.11). For weight change, long-acting od was inferior to long-acting bid (MD 0.58, 95% CI: 0.05 to 1.10) and long-acting bid was superior to long-action biosimilar od (MD - 0.90, 95% CI: - 1.67 to - 0.12).ConclusionsOur results can be used to tailor insulin treatment according to the desired results of patients and clinicians and inform strategies to establish a competitive clinical market, address systemic barriers, expand the pool of potential suppliers, and favor insulin price reduction.PROSPERO RegistrationCRD42017077051Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-021-06642-7.KEY WORDS: network meta-analysis, systematic review, insulin, biosimilar insulin, basal-bolus, diabetes mellitus, type 1 diabetes, T1DM     

Insulin management in overweight or obese type 2 diabetes patients: the role of insulin glargine

Type 2 diabetes mellitus (T2DM) and obesity commonly co-exist. Improved clinical management of T2DM and improved glycaemic control with traditional therapies including insulin usually result in some weight gain – a frequently perceived barrier to the introduction of insulin by both patient and healthcare professionals. Weight gain of 2.5 kg per 1% change in haemoglobin A_1c (HbA_1c) is common in many studies. Strategies to minimize weight gain, particularly in obese patients, are essential to help patients better manage their diabetes and improve quality of life. Insulin analogues with lower risk of hypoglycaemia and better within-patient variability compared with human insulin may help facilitate reaching treatment goals. Moreover, weight gain can be minimized by earlier insulinization and the use of basal insulin, such as insulin glargine, instead of premixed insulin. Data specific to the obese patient with T2DM are presented; they are currently limited but do indicate that insulin glargine therapy is associated with improved glycaemic control as well as less weight gain than other insulins, such as premixed insulin and prandial insulin regimens. Retrospective subanalyses of earlier trials and ongoing studies would shed further light on the impact of insulin therapy in obese people with T2DM in addition to determination of optimal therapeutic strategies.     

Comparative efficacy and safety of basal insulins: A review

Background and aimTo provide an update on the usefulness of basal insulin in patients with type 2 diabetes mellitus.MethodsWe conducted a literature search using PubMed and MEDLINE, BIOSIS, Scopus, EMBASE, ClinicalTrials.gov, Google Scholar, and Springer Online Archives Collection until June 2021.ResultsAll basal insulins are similar in efficacy, with only small differences among them in terms of the risk of hypoglycemia.ConclusionsFor type 2 diabetes mellitus, all basal insulins have a similar efficacy, with some advantage of Glar-300 and Deg-100 in reducing the risk of hypoglycemia compared to Glar-100.     

Efficacy and safety of imeglimin in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized clinical trials

Background and aimImeglimin is a novel tetrahydrotriazine-containing drug suggested as a safe drug for glycemic management in patients with type 2 diabetes mellitus (T2DM). We aimed to 1) evaluate the efficacy of imeglimin on glycemic control and insulin resistance improvement measured by homeostatic model assessment of insulin resistance (HOMA-IR). 2) assess whether the novel drug improves lipid parameters in diabetic patients. 3) compare between different doses regarding safety.MethodsWe searched PubMed, Cochrane Library, Scopus, Web of Science, Google Scholar, and Wiley through April 25, 2021, for relevant randomized controlled trials comparing different doses of imeglimin supplied as a monotherapy or as add-on therapy versus placebo for adult patients with type 2 diabetes mellitus. Data on glycemic and lipid parameters and adverse events were extracted and pooled in random-effect models using Review Manager version 5.3.ResultsEight studies comprising 1555 patients with T2DM were included in this study. The overall effect estimate of the meta-analysis showed that the imeglimin group was superior to the control group concerning glycated hemoglobin and fasting plasma glucose (P < 0.00001). However, it did not affect HOMA-IR or lipid parameters, including triglyceride, LDL-C, and HDL-C (all p > 0.05). Regarding safety profile, imeglimin was safe and tolerable with no treatment-emergent or serious adverse events.ConclusionsImeglimin safely improved glycemic control by reducing HbA1c and FPG. However, no beneficial effects regarding insulin resistance measured by HOMA-IR or lipid parameters were observed. Further high-quality RCTs with high dose imeglimin are encouraged to ensure HOMA-IR and lipid parameters results.     

A longitudinal study of insulin antibodies and anti-insulin cytotoxicity in type I diabetes mellitus

Summary Insulin antibodies and T-cell lymphocyte cytotoxic reactivity against insulin and its related peptides were studied longitudinally in 3 groups of patients with type I diabetes mellitus (DM). Group 1 patients were those in whom the diagnosis was made within 1 week of the initiation diagnosis. They were subdivided into those receiving MC porcine (A) or MC bovine (B) insulin. Group 2 patients were those with a duration of DM for 2–6 years who were receiving either MC porcine (A) or MC bovine (B) insulins. Group 3 subjects were those who had been on conventional recrystallized insulin and then switched to MC porcine (A) or MC bovine (B) insulins for 2 weeks before the start of the study. The incidence of cytotoxic reactions and insulin antibodies were approximately 40–50% for group 1 (either 1A or 1B) at the initiation of the study. At 3-month follow up all patients in group 1B developed insulin antibodies (p<0.02) and a significant increase in the frequency of cytotoxic reactions (p<0.01). By contrast there was a decline in the frequency of cytotoxic reactions in group 1A (p<0.01 at 1 year) and the increase in insulin antibodies was non-significant. Group 2B had higher frequency in cytotoxic reactions (p<0.005) and of insulin antibodies (p<0.05) than group 2A. A significant decrease (p<0.01) in cytotoxic reactions was observed at 3 months following the switch of patients from conventional bovine insulin preparations to ‘A’ but not to ‘B’. However in both subgroups insulin antibodies persisted for at least 12 months. Cross-reactivity between antibodies to human, porcine and bovine insulins was evident in all groups. The early cellular and humoral immune phenomena were positively correlated in both group 1A and 1B suggesting their common involvement in the pathogenesis of DM.     

Use of herbal medicine for diabetes mellitus in adults from the central–western region of Mexico

ObjectiveThis study aims to assess the prevalence of herbal medicine (HM) use and factors influencing HM usage including the identification of the main plants consumed by patients with type 2 diabetes mellitus (T2DM) in central-western Mexico.DesignA total of 1862 patients with diabetes were surveyed in public and private hospitals in four states (Guanajuato, Jalisco, Michoacan, and San Luis Potosi) of the central-western region of Mexico. The chi-square test was used to assess associations between HM use and demographic characteristics, such as glucose levels, presence of complications and comorbidities, as well as the selected therapy to treat T2DM.ResultsThe prevalence of HM use (59.2%) in patients with T2DM was mainly associated with education level (p = 0.001), time of diagnosis of T2DM (p = 0.004), presence of complications (p < 0.001) and comorbidities (p = 0.018) and the use of insulin (p < 0.001). These patients report a higher consumption of herbal medicine compared to those on glycemic control (p < 0.001). The most frequently used medicinal plants to treat T2DM were nopal (54.9%), moringa (26.7%), and aloe (22.1%).ConclusionThe prevalence of HM use to treat T2DM in west-central Mexico is high (59.2%) and its consumption is mostly carried out without the recommendation of a health professional (91.9%). The use of HM increases mainly when the patient uses insulin, during complications of the disease or in patients with an inadequate glycemic control.     

The role of mosapride and levosulpiride in gut function and glycemic control in diabetic rats

Background and study aimsGastroparesis is a well-known consequence of long-standing diabetes that presents with gastric dysmotility in the absence of gastric outlet obstruction. This study aimed to evaluate the therapeutic effects of mosapride and levosulpiride on improving gastric emptying in type 2 diabetes mellitus (T2DM) while regulating glycemic levels.Material and methodsRats were divided into the normal control, untreated diabetic, metformin-treated (100 mg/kg/day), mosapride-treated (3 mg/kg/day), levosulpiride-treated (5 mg/kg/day), metformin (100 mg/kg/day) + mosapride (3 mg/kg/day)-treated, and metformin (100 mg/kg/day) + levosulpiride (5 mg/kg/day)-treated diabetic groups. T2DM was induced by a streptozotocin–nicotinamide model. Four weeks from diabetes onset, the treatment was started orally daily for 2 weeks. Serum glucose, insulin, and glucagon-like peptide 1 (GLP-1) levels were measured. Gastric motility study was performed using isolated rat fundus and pylorus strip preparations. Moreover, the intestinal transit rate was measured.ResultsMosapride and levosulpiride administration showed a significant decrease in serum glucose levels with improvement of gastric motility and intestinal transit rate. Mosapride showed a significant increase in serum insulin and GLP-1 levels. Metformin with mosapride and levosulpiride co-administration showed better glycemic control and gastric emptying than either drug administered alone.ConclusionMosapride and levosulpiride showed comparable prokinetic effects. Metformin administration with mosapride and levosulpiride showed better glycemic control and prokinetic effects. Mosapride provided better glycemic control than levosulpiride. Metformin + mosapride combination provided superior glycemic control and prokinetic effects.     

Prevalence and correlation of glycemic control achievement in patients with type 2 diabetes in Iraq: A retrospective analysis of a tertiary care database over a 9-year period

BackgroundThis study was designed to assess the achievement of a glycated hemoglobin (HbA1c) target in Iraqi type 2 diabetes mellitus (T2DM) patients via retrospective analysis of a tertiary care database over a 9-year period.MethodsA total of 12,869 patients with T2DM with mean (SEM) age: 51.4(0.1) years, and 54.4% were females registered into Faiha Specialized Diabetes, Endocrine and Metabolism Center(FDEMC) database between August 2008 and July 2017 were included in this retrospective study. Data were recorded for each patient during routine follow-up visits performed at the center every 3–12 months.ResultsPatients were under oral antidiabetic drugs (OAD; 45.8%) or insulin+ OAD (54.2%) therapy. Hypertension was evident in 42.0% of patients, while dyslipidemia was noted in 70.5%. Glycemic control (HbA1c <7%) was achieved by 13.8% of patients. Multivariate analysis revealed <55 years of age, female gender, >3 years duration of diabetes, HbA1c >10% at the first visit, presence of dyslipidemia, and insulin treatment as significant determinants of an increased risk of poor glycemic control. BMI <25 kg/m² and presence of hypertension were associated with a decreased risk of poor glycemic control.ConclusionUsing data from the largest cohort of T2DM patients from Iraq to date, this tertiary care database analysis over a 9-year period indicated poor glycemic control. Younger patient age, female gender, longer disease duration, initially high HbA1c levels, dyslipidemia, insulin treatment, overweight and obesity, and lack of hypertension were associated with an increased risk of poor glycemic control in Iraqi T2DM patients.     

Comparison of urinary amino acid excretory pattern in patients with type 2 diabetes mellitus and non-diabetic healthy controls at a tertiary referral hospital in India

AimSpecific amino acids have been linked to regulation of insulin secretion from pancreatic β-cells; on the contrary, increased concentration of certain amino acids is associated with insulin resistance (IR) and development of type 2 diabetes mellitus (T2DM). Nowadays, urine as a biological sample has attracted more attention for diagnosis of disease for its special superiority; insufficient research in the study of urinary amino acid (UAA) pattern in patients with T2DM has led to the present study with the aim to determine the levels of UAAs, their excretory patterns and the association of UAA to plasma glucose and IR in patients with T2DM.MethodsQuantification of total urinary amino acids was done spectrophotometrically and the patterns of amino acid excretion was elucidated by thin layer chromatography technique. Fasting blood samples were used for plasma glucose and insulin estimation by fully automated analyzer.ResultThe levels of UAA in patients with T2DM in comparison to healthy controls were higher (p < 0.0001). The frequency of urinary phenylalanine, arginine, tryptophan, tyrosine and cysteine were significantly higher in patients with T2DM than controls. There was also a strong positive correlation of UAA levels with blood glucose levels and HOMA–IR in patients with T2DM.ConclusionOur study has shown subtle abnormalities in UAA patterns in patients with T2DM. The measurement of UAA levels and excretory pattern can be used as an index of hyperglycemia and IR which could serve as an inexpensive and non-invasive marker for T2DM. More studies are required to confirm this association.     

Type-2 diabetes mellitus-associated cancer risk: In pursuit of understanding the possible link

Background and aimThe insulin resistance-mediated abnormal gluconeogenesis when exceeds a given threshold culminates in type 2 diabetes mellitus (T2DM). This induces severe cellular oxidative stress that may eventually facilitate typical neoplastic transformations. This narrative review aims to portray some of the plausible key mechanistic links bridging T2DM and specific cancers.MethodsA thorough literature search was conducted in the PubMedCentral database to retrieve information from various reputed biomedical reports/articles published from the year 2000. The information regarding the key biochemical signaling pathways mediating the carcinogenic transformation, especially in T2DM patients, was extensively excavated to systematically compile and present a narrative review.ResultsT2DM-associated insulin resistance is known to negatively influence certain crucial genetic and metabolic components (such as insulin/IGFs, PI-3K/Akt, AMPK, and AGEs/RAGE) that may eventually lead to neoplastic transformation. In particular, the risk of developing cancers like pancreatic, colorectal, breast, liver, endometrial, and bladder seems to be more significant in T2DM patients.ConclusionDespite the fact that several studies have suggested a possible correlation between T2DM and cancer mortality, a more detailed research at both pre-clinical and clinical levels is still required so as to fully understand the intricate relationship and make a precise conclusion.     

The past,present, and future of basal insulins

Insulin production by the pancreas follows a basic pattern where basal levels of insulin are secreted during fasting periods, with prandial increases in insulin associated with food ingestion. The aim of insulin therapy in patients with diabetes is to match the endogenous pattern of insulin secretion as closely as possible without causing hypoglycaemia. There are several optimal pharmacokinetic and pharmacodynamic properties of long‐acting basal insulins that can help to achieve this aim, namely, as follows: activity that is flat and as free of peaks as possible, a duration of action of ≥24‐h, and as little day‐to‐day variation as possible. The long‐acting basal insulins are a fundamental therapy for patients with type 1 and type 2 diabetes, and those that are currently available have many benefits; however, the development of even longer‐acting insulins and improved insulin delivery techniques may lead to better glycemic control for patients in the future. Established long‐acting basal insulins available in the United States and Europe include insulin glargine 100 units/mL and insulin detemir, both of which exhibit similar glycemic control to that of the intermediate‐acting neutral protamine Hagedorn insulin, but with a reduction in hypoglycaemia. Newer insulin products available include new insulin glargine 300 units/mL (United States and Europe) and the ultra‐long‐acting insulin degludec (Europe) with basal insulin peglispro currently in development. These new insulins demonstrate different pharmacokinetic/pharmacodynamic profiles and longer durations of action (>24 h) compared with insulin glargine 100 units/mL, which may lead to potential benefits. The introduction of biosimilar insulins may also broaden access to insulins by reducing treatment costs. Copyright © 2015 John Wiley & Sons, Ltd.     

Biosimilar Insulin and Costs: What Can We Expect?

The costs for insulin treatment are high, and the steady increase in the number of patients with diabetes on insulin presents a true challenge to health care systems. Therefore, all measures to lower these costs are welcomed by patients, physicians, and health care providers. The market introduction of biosimilar insulins presents an option to lower treatment costs as biosimilars are usually offered at a lower price than the originator product. However, the assumption that a drastic reduction in insulin prices will take place, as was observed with many generic drugs, is most probably not realistic. As the first biosimilar insulin has now been approved in the EU, this commentary discusses a number of aspects that are relevant when it comes to the potential cost reduction we will see with the use of biosimilar insulins.     

Increased insulin requirement may contribute to risk of obesity in children and young people with Type 1 Diabetes Mellitus

IntroductionType 1 diabetes mellitus (T1DM) is an autoimmune disorder that interferes with the function of the beta cells in the pancreas. Reports show that the incidence of T1DM is increasing throughout England and Wales, along with the Body Mass Index (BMI) of this patient group. The association between type 2 diabetes mellitus (T2DM) and obesity is recognised, but literature describing the association between T1DM and high BMI is more limited.The aim of this paper is to identify factors affecting BMI and the impact that this increasing trend has on children and young people with T1DM.MethodsInformation was obtained from the medical records of patients with T1DM at the local paediatric centre. BMI standard deviation scores (SDS) were calculated and compared to other factors, which include insulin requirement, HbA1c, pubertal status and age at diagnosis.ResultsThis study involved 102 patients (43 male and 59 female). The mean age at diagnosis was 7.79 years (range from 0.16 to 16.91 years). Our results showed a significant association between insulin requirement and BMI SDS (r = 0.23, p = 0.02) and a significant association between insulin requirement and mean HbA1c (r = 0.59, p=<0.01). A multivariable regression analysis of factors affecting BMI SDS showed that insulin requirement was an independent factor affecting BMI SDS.ConclusionThere were significant associations between increased insulin requirement, high BMI SDS and poorer glycaemic control. Further research is required to fully understand the risk factors that may contribute to obesity in T1DM.