The role of rapid-acting insulin analogues and inhaled insulin in type 2 diabetes mellitus

sBackground:The availability of rapid-acting insulin analogues and inhaled insulin gives clinicians additional treatmentoptions in the management of patients with diabetes mellitus (DM). Combining rapid-acting insulin analogues with basal insulin can more closely mimic physiologic insulin release to maximize glycemic control.Objective:The objective of this article was to discuss the role of rapid-acting insulin analogues and inhaled insulin inthe treatment of patients with type 2 DM.Methods:Materials for this article were obtained through an online search of MEDLINE/PubMed and Google(1996-2006) using the search terms bolus insulin, postprandial, rapid-acting insulin analogues, titration, hypoglycemia, glycemic control, inhaled insulin, and insulins lispro, aspart, and glulisine.Results:Glycosylated hemoglobin (A1C) levels and number of all hypoglycemic episodes were similar in patients withtype 2 DM taking either mealtime rapid-acting insulin analogues or regular human insulin (RHI). Rapid-acting insulins have been successfully used in basal-bolus regimens with a variety of long- and intermediate-acting insulins, as well as with oral hypoglycemic agents. Injectable rapid-acting insulin analogues markedly decreased postprandial glucose (PPG) levels compared with RHI. Better reduction in PPG levels may be key to achieving target A1C levels in some patients, but long-term outcome studies are needed to assess whether lowering PPG levels decreases cardiovascular risk in patients with type 2 DM. Inhaled insulin may be an option for patients who cannot inject insulin, but route of administration and dosing issues limit its use in many patients. The effect of inhaled insulin on PPG is unclear at this time.Conclusions:Although rapid-acting insulin analogues are effective in the management of patients with type 2 DM, the limited numbers of studies have yet to demonstrate that these agents have any significant long-term advantage compared with RHI. In addition, they cost more than RHI. Further studies are needed to compare the efficacy of the rapid-acting insulin analogues, to compare the different dosing regimens used with mealtime insulin administration, and to ascertain if the decrease in PPG levels seen with the use of rapid-acting insulin analogues translates into improved glycemic control and perhaps even a reduction in cardiovascular risk in patients with type 2 DM. (Insulin. 2007;2:61-67) Copyright 2007 Excerpta Medica, Inc.     

Insulin Injections in Relation to Meals in the Hospital Medicine Ward: Comparison of 2 Protocols

ObjectiveTo investigate whether changing the prandial regular insulin to rapid-acting insulin analogue in hospital medicine wards improves the timing of insulin delivery in relation to meals and improves patient safety and glucose control.MethodsThis open-label randomized controlled trial in type 2 diabetic patients compared insulin lispro with meals and basal insulin glargine (intervention) vs regular insulin before meals and basal neutral protamine Hagedorn insulin twice daily (control). The primary endpoint was the rate of targeted timing of insulin to meals (target time). In the intervention group, target time was defined as insulin administered from 15 minutes before to 15 minutes after the patient started a meal. For the control group, target time was defined as insulin administered from 30 minutes before to 30 minutes after the patient started a meal. Hypoglycemic, hyperglycemic, and severe hyperglycemic patient-days were compared between groups.ResultsTwenty-seven patients in the intervention group and thirty-three patients in the control group were studied. The percentage of times that the insulin was given within target time was significantly higher in the intervention group as a whole (88.9% vs 70.1%, P < .001) and was higher for lunch and the evening meal (90% vs 66.7% and 94.7% vs 70.1%, P < .001). The rate of hypoglycemia was lower in the intervention group (1.85% vs 15%, P < .001). The rate of hyperglycemia was similar in both groups (68.2% vs 59.8%, P = .224), but the intervention group had a higher rate of severe hyperglycemia (28.9% vs 12.9%, P = .003).ConclusionsThe use of prandial insulin analogues in medicine wards allows better timing with meals than regular insulin and results in better hypoglycemic outcomes. Higher rates of hyperglycemia with prandial analogues may need adjustment in insulin doses. (Endocr Pract. 2011:17:737-746)     

Comparison of pharmacokinetic properties,physicochemical stability,and pump compatibility of 3 rapid-acting insulin analogues— aspart,lispro, and glulisine

ObjectiveTo compare how the rapid-acting insulin analogues (RAIAs) aspart, lispro, and glulisine perform in continuous subcutaneous insulin infusion (CSII) therapy regarding (1) pharmacokinetic properties, (2) chemical and physical stability, and (3) pump compatibility.MethodsPubMed was searched for articles pertaining to the use of RAIAs in CSII, without a restriction on the time period.ResultsThese RAIAs have pharmacokinetic profiles that more closely mimic endogenous insulin in comparison with regular human insulin and tend to produce less hypoglycemia. Among these RAIAs, the rates of absorption and clinical efficacy in terms of glycemic control were similar. Although glulisine showed a faster onset of action in some studies with aspart and lispro, this advantage lasted only for a maximum of 1 hour, after which results were similar for glulisine and aspart or lispro. Each RAIA is created by making minor amino acid substitutions to the regular human insulin molecule and adding a stabilizer to help prevent fibrillation. A series of chemical and covalent changes affecting the primary structure of an insulin preparation, however, may cause decomposition during storage, handling, and use, diminishing the potency of the insulin molecule while contained in an insulin pump. Precipitation, fibrillation, and occlusion may ensue, undermining compatibility for CSII pump use. Aspart has demonstrated the greatest chemical and physical stability in the insulin pump, with the lowest rates of overall occlusion in comparison with lispro and glulisine (aspart 9.2%, lispro 15.7%, and glulisine 40.9%; P < .01).ConclusionAspart is the most compatible of the 3 RAIAs for pump use. (Endocr Pract. 2011;17:271-280)     

Rapid-Acting Insulin Analogues in Basal-Bolus Regimens in Type 1 Diabetes Mellitus

ObjectiveTo compare rapid-acting insulin analogues with regular human insulin in terms of hemoglobin A_1c, hypoglycemia, and insulin dose when used in a basal-bolus regimen in patients with type 1 diabetes mellitus.MethodsMEDLINE and congress proceedings were searched for randomized controlled trials comparing pran- dial insulins in a basal-bolus regimen in adults or children/ adolescents with type 1 diabetes. Studies in pregnancy, ob- servational studies, studies that compared premixed insulin or continuous subcutaneous insulin infusion/insulin pumps, and studies where the basal insulin was also changed were excluded. Only studies reporting baseline-endpoint change in insulin dose, or baseline and/or endpoint values, were included.ResultsTwenty-eight studies were identified (insulin glulisine, 4; insulin aspart, 7; insulin lispro, 17). Twenty- five studies compared a rapid-acting insulin analogue with regular human insulin, and 3 trials compared 2 rapid-acting insulin analogues. Overall, rapid-acting insulin analogues in a basal-bolus regimen provided similar or greater im- provements in glycemic control than regular human insulin at similar insulin doses, as well as a lower incidence of hypoglycemia.ConclusionsResults of the studies identified in this literature review indicate that a basal-bolus regimen with prandial rapid-acting insulin analogue provides advan- tages over basal-bolus regimens using prandial regular hu- man insulin, providing improvements in glycemic control comparable to those obtained with regular human insulin, as well as a lower incidence of hypoglycemia. (Endocr Pract. 2010;16:486-505)     

Impact of Prandial Plus Basal vs Basal Insulin on Glycemic Variability in Type 2 Diabetic Patients

ObjectiveTo determine whether metformin-treated patients with type 2 diabetes given an analogue mixture of basal and rapid-acting insulins (insulin lispro protamine suspension plus insulin lispro) would have less glycemic variability than patients given basal insulin glargine.MethodsTwo post hoc analyses were used to compare 7-point blood glucose profiles from 3 published studies comparing basal plus prandial premixed insulin lispro mixtures with insulin glargine in metformin-treated patients with type 2 diabetes. Glycemic variability indices used included standard deviation of mean daily blood glucose, coefficient of variation, M-value, mean amplitude of glycemic excursion, and J-index.ResultsPatients on the twice-daily insulin lispro mix 75/25 (75% insulin lispro protamine suspension/25% insulin lispro) plus metformin regimen had significantly lower standard deviation, M-value, and J-index than patients on the insulin glargine plus metformin regimen, but not lower coefficient of variation or mean amplitude of glycemic excursion. Patients on the 3 times daily insulin lispro mix 50/50 (50% insulin lispro protamine suspension/50% insulin lispro) plus metformin regimen had significantly lower values for all 5 indices than patients on the insulin glargine plus metformin regimen.ConclusionUse of basal plus prandial insulin lispro mixtures at 2 or 3 meals was associated with lower glycemic variability in metformin-treated patients with type 2 diabetes. (Endocr Pract. 2009;15:343-348)     

Insulin Stacking Versus Therapeutic Accumulation: Understanding the Differences

ObjectiveThe build-up in insulin levels following repeated injection of prandial insulin at close intervals— referred to as insulin stacking—can increase the risk of hypoglycemia. With the development of basal insulins with a half-life > 24 hours and a duration of action > 40 hours, clinicians may be concerned about stacking when these long-acting formulations are administered once daily. The objective of this review is to clarify the difference between inappropriate insulin stacking when shorter-acting insulin formulations are repeatedly used to correct hyperglycemia and the appropriate accumulation of long-acting insulin formulations dosed to steady-state pharmacokinetic (PK) profiles.MethodsRelevant literature on insulin stacking, glucose-clamp studies, and clinical studies of insulin, in conjunction with the clinical experience of the authors, were used to present an overview of insulin PK properties and the effects of appropriate and inappropriate dosing intervals on steady-state conditions and likely clinical outcomes.ResultsClinical studies confirm theoretical PK principles showing that unwanted insulin stacking (excessive concentrations) for basal insulin can be avoided by following recommended dosing and titration algorithms. Long-acting basal insulins need more time to reach steady state than shorter-acting basal insulins but then show reduced peak-trough fluctuations, translating into more consistent biologic action over a 24-hour period.ConclusionThe unwanted stacking and consequent hypoglycemia that can occur when correctional doses of rapid-acting insulin are administered at close intervals does not occur when long-acting basal insulins are dosed in appropriate amounts and adjusted at appropriate time intervals (e.g., insulin stacking, insulin administration, diabetes, ultralong duration of action, hypoglycemia every three or more days), allowing for pharmacologic steady-state accumulation. (Endocr Pract. 2014;20:75-83)     

Optimized Basal-Bolus Insulin Regimens in Type 1 Diabetes: Insulin Glulisine Versus Regular Human Insulin in Combination with Basal Insulin Glargine

ObjectiveTo compare the efficacy and safety of insulin glulisine (GLU), a new rapid-acting insulin analogue, injected 0 to 15 minutes before or immediately after meals, with regular human insulin (RHI), injected 30 to 45 minutes before meals.MethodsPatients with type 1 diabetes (N = 860) received once-daily insulin glargine and subcutaneous injections of either GLU (premeal or postmeal) or premeal RHI in this open-label, randomized, controlled, multicenter, parallel-group, 12-week study.ResultsBaseline to endpoint changes in mean glycated hemoglobin (as A1c equivalents) (A1c) occurred in the premeal GLU, postmeal GLU, and premeal RHI groups (-0.26%, -0.11%, and -0.13%, respectively). The reduction in A1c was greater for the premeal GLU group in comparison with the RHI group (P = 0.02) and the post-meal GLU group (P = 0.006); no significant between-treatment difference was found for postmeal GLU versus RHI. Overall, blood glucose profiles were similar in all 3 treatment groups but were significantly lower for premeal GLU 2-hour postbreakfast measurements (premeal versus postmeal GLU, P = 0.0017; premeal GLU versus RHI, P = 0.0001) and 2-hour postdinner measurements (premeal GLU versus RHI, P = 0.0001; premeal versus postmeal GLU, P = 0.0137). Severe hypoglycemic episodes were comparable for premeal GLU, postmeal GLU, and pre-meal RHI groups (8.4%, 8.4%, and 10.1%, respectively). Body weight increased (+ 0.3 kg) in the RHI and premeal GLU groups; however, weight decreased in the postmeal GLU group (-0.3 kg; between-treatment difference, P = 0.03).ConclusionBetter A1c reductions were obtained with premeal GLU, but postmeal administration of GLU was as safe and effective as premeal GLU or RHI in combination with insulin glargine and was not associated with weight gain. (Endocr Pract. 2005;11:11-17)     

The Rationale for Prandial Glycemic Control in Diabetes Mellitus

Background:Diabetes mellitus (DM) is of epidemic proportions worldwide, and its microvascular and macrovascular complications have been well described. Achieving glycemic control has been demonstrated to reduce patients' risk of developing these complications.Objective:The objective of this article was to examine how prandial hyperglycemia-especially postprandial hyperglycemia (PPHG)-affects overall glycemic control and the complications of DM and to discuss the pharmacologic agents available to reduce PPHG.Methods:Materials used for this article were identified through a MEDLINE search of the literature (1975–2006). English-language randomized, controlled, prospective, cohort, and observational studies were chosen using the search terms postprandial hyperglycemia, oxidative stress, cardiovascular disease, macrovascular disease, microvascular disease, lipidemia, and coagulation.Results:Data show that controlling prandial hyperglycemia reduces the risk of cardiovascular disease (CVD) andmicrovascular complications, lowers glycosylated hemoglobin levels, causes less oxidative stress, and leads to a more favorable coagulation and postprandial lipidemia profile. Guidelines for targeting PPHG are becoming standard, and various pharmacologic agents (eg, a-glucosidase inhibitors, amylin analogues, incretin mimetics, rapid-acting insulins and insulin analogues, meglitinide analogues) that target PPHG may also improve overall glycemic control and reduce CVD risk.Conclusions:Although the level of hyperglycemia that leads to microvascular and macrovascular complications inpatients with DM remains to be elucidated, it appears prudent to address prandial hyperglycemia, especially PPHG, rather than focus solely on fasting glucose levels. Clinicians should consider incorporating agents that lower PPHG in their treatment of patients with DM.     

A Bridge to Insulin Pump Therapy: Twice-Daily Regimen with NPH and Detemir Insulins During Initial Treatment of Youth with Type 1 Diabetes Mellitus

ObjectiveTo describe clinical outcomes in youth with new-onset type 1 diabetes mellitus (TlDM) treated with a modified, twice-daily regimen of a mixture of NPH insulin and rapid-acting insulin analogue at breakfast and separate injections of rapid-acting insulin analogue and insulin detemir at dinner.MethodsOur clinic database was used to describe changes in insulin doses, hemoglobin A_1c (A1C) levels, and frequency of severe hypoglycemia during the first year of therapy in young patients with T1DM diagnosed between September 2006 and April 2009. Data are presented as median values (25%, 75%).ResultsOverall, 108 patients (62 girls; mean age, 10.0 ± 0.4 years) were eligible for inclusion. Total daily insulin doses at 3, 6, and 12 months were 0.6 (0.4, 0.8), 0.7 (0.4, 0.9), and 0.8 (0.6, 0.9) U/kg, respectively. A1C levels were 9.8% (8.5%, 10.8%) at 2 weeks (baseline). Of the 108 patients, 19 had switched to insulin pump therapy by 3 months and 49 had switched by 12 months after initial diagnosis of T1DM. The 49 pump-treated patients had an A1C of 6.9% (6.6%, 7.3%), whereas the 59 injection- treated patients had an A1C of 7.2% (6.7%, 7.7%) by 12 months. There were only 6 severe hypoglycemic events in 5 patients; none occurred during the first 3 months, none occurred during the night, and all occurred in patients receiving insulin injection treatment.ConclusionA twice-daily insulin regimen that uses insulin detemir for overnight basal replacement and morning NPH insulin to avoid lunch and afternoon snack doses is an effective initial treatment for young patients with new-onset T1DM that can provide a smooth transition to intensive basal/bolus insulin pump therapy. (Endocr Pract. 2011;17:862-866)     

Lower Rate of Cardiovascular Complications in Patients on Bolus Insulin Analogues: A Retrospective Population-Based Cohort Study

Background

Few studies are available evaluating the impact of rapid-acting insulin analogues on long-term diabetes outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients through the analysis of administrative databases.

Methods

A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. The incidence of diabetic complications was ascertained by hospital discharge claims. Hazard ratios (HRs) and 95% CIs of any diabetic complication and macrovascular, microvascular and metabolic complications were estimated separately using Cox proportional hazard models adjusted for patients’ characteristics and anti-diabetic drug use. Propensity score matching was also used to adjust for significant difference in the baseline characteristics between the two treatment groups.

Results

A total of 2,286 patients were included: 914 receiving human regular insulin and 1,372 rapid-acting insulin analogues. During the follow-up, 286 (31.3%) incident events occurred in the human regular insulin group and 235 (17.1%) in the rapid-acting insulin analogue group. After propensity score-based matched-pair analyses, rapid-acting insulin analogues users had a HR of 0.73 (0.58–0.92) for any diabetes-related complication and HRs of 0.73 (0.55–0.93) and 0.55 (0.32–0.96) for macrovascular and metabolic complications respectively, as compared with human regular insulin users. No difference between the two groups was found for microvascular complications.

Conclusions

Our findings suggest that the use of rapid-acting insulin analogues is associated with a lower risk of cardiovascular and metabolic complications compared with human regular insulin use.     

Analogues et dosages d’insuline : le cas général et le cas particulier de la glargine

Since 1996, genetic engineering has allowed modifications of insulin yielding to multiple modified insulins with different pharmacokinetic and/or pharmacodynamic properties. Molecules with maintained pharmacodynamic and modified pharmacokinetic profiles have been selected. Currently available rapid-acting analogues (lispro, aspart and glulisine) achieve plasma peak concentrations about twice as high and within approximately half the time compared with regular human insulin thus closely mimicking the physiological insulin response to a meal. Long-acting analogues (glargine and detemir) ensure the steady supplement of basal insulin plasma levels, with a plateau type of profile. Main analytical pitfalls of commercially human insulin immunoassays include crossreactivity with analogues and their metabolites. These crossreactivities are of great concern for interpreting insulin levels in patients treated with analogues. The development of more specific analytical methods to quantify separately the concentrations of endogenous insulin, rapid-acting and long-acting analogues and metabolites would be of utmost importance: (1) to further understand long-acting analogue variability in terms of efficiency; (2) to perform analogue kinetic studies; (3) to measure analogues in routine toxicology (forensic medicine) and (4) to assess intact glargine or glargine metabolite in vivo toxicity: recent debates about glargine safety have highlighted the lack of data about metabolite status (proportion of metabolized glargine and bioactivity of its metabolite). This goal could be achieved by specific immunoassay development or/and mass spectrometry analysis.     

A Stepwise Approach to Insulin Therapy in Patients with Type 2 Diabetes Mellitus and Basal Insulin Treatment Failure

ObjectiveTo determine whether 1 or 2 preprandial injections before the meals of greatest glycemic impact can be as effective as 3 preprandial injections in patients with type 2 diabetes mellitus and basal insulin treatment failure.MethodsThis was an open-label, parallel-group, 1:1:1 randomized study of adults with type 2 diabetes mellitus on oral antidiabetic drugs with glycated hemoglobin (A1C) levels of 8.0% or greater. After a 14week run-in with insulin glargine, patients with an A1C level greater than 7.0% were randomly assigned to 1, 2, or 3 time(s) daily insulin glulisine for 24 weeks. Changes in A1C from randomization to study end; percentage of patients achieving an A1C level less than 7.0%; changes in A1C, fasting glucose concentrations, and weight at individual study points; and safety (adverse events and hypoglycemia) were assessed throughout the study.ResultsThree hundred forty-three of 631 patients (54%) completing the run-in phase with insulin glargine were randomly assigned to treatment arms. During the randomization phase, A1C reductions with insulin glulisine once or twice daily were noninferior to insulin glulisine 3 times daily (confidence intervals: -0.39 to 0.36 and -0.30 to 0.43; P > .5 for both). However, more patients met the target A1C with 3 preprandial injections (46 [46%]) than with 2 injections (34 [33%]) or 1 injection (30 [30%]). Severe hypoglycemia occurred in twice as many patients receiving 3 preprandial injections (16%) compared with those receiving 2 injections (8%) and 1 injection (7%), but these differences did not reach significance.ConclusionThis study provides evidence that initiation of prandial insulin in a simplified stepwise approach is an effective alternative to the current routine 3 preprandial injection basal-bolus approach. (Endocr Pract. 2011;17:395-403)     

The Use of Premixed Insulin Analogues in the Treatment of Patients with Type 2 Diabetes Mellitus: Advantages and Limitations

Background:Intensive, target-oriented therapy is the standard of care in the management of patients with type 2 diabetesmellitus (DM). Early and aggressive use of insulin that is as close as possible to the physiologic pattern of insulin secretion from healthy pancreatic β-cells is advocated to achieve glycemic goals and reduce complications of DM.Objective:The objective of this article was to review the characteristics, advantages, and drawbacks of premixedinsulin analogues and to evaluate their role in the treatment of patients with type 2 DM.Methods:A PubMed search of articles from 1990 to 2006 was undertaken using the search terms type 2 diabetes, basalbolus therapy, premixed insulins, biphasic insulins, and insulin analogues. Pertinent content from relevant articles was extracted and combined with the authors' knowledge, experience, and clinical expertise.Results:The advent of insulin analogues has streamlined the treatment of patients with DM. When to initiate insulin during the course of treatment is the subject of much debate. Insulin therapy targeting both fasting and postprandial hyperglycemia is important in achieving optimal blood glucose (BG) control in patients with type 2 DM. A practical and feasible option is the use of >1 injection of premixed insulin analogues. Premixed insulin preparations provide both basal and prandial coverage because of their biphasic pharmacokinetic properties. Clinical trials have shown that these agents improve glycemic control, are associated with an acceptably low rate of severe hypoglycemia, and have a high degree of patient acceptance. Limitations include the inability to adjust the long- and short-acting components separately, to use a flexible regimen of self-titration and premeal bolus-insulin calculations, and to adequately treat postlunch and earlymorning BG elevations.Conclusion:Clinicians should be aware of premixed insulin analogues' advantages and limitations so that these agentscan be used appropriately in the treatment of patients with type 2 DM.     

Comparison of the Effect of Insulin Glulisine to Insulin Aspart on Breakfast Postprandial Blood Glucose Levels in Children with Type 1 Diabetes Mellitus on Multiple Daily Injections

ObjectiveRapid-acting insulins, including insulin aspart (NovoLog) and lispro (Humalog), do not seem to effectively control postprandial glycemic excursions in children with type 1 diabetes mellitus (T1DM). The objective of this study was to determine if insulin glulisine (Apidra), another rapid-acting insulin analog, would be superior in controlling postprandial hyperglycemia in children with T1DM.MethodsThirteen prepubertal children ages 4 to 11 years completed this study. Inclusion criteria included T1DM ≥6 months, glycosylated hemoglobin (HbAlC) 6.9 to 10%, blood glucose (BG) levels in adequate control for 1 week prior to study start, multiple daily injections (MDI) with insulin glargine or determir once daily and aspart or lispro premeal. If fasting BG was 70 to 180 mg/dL, subjects received insulin glulisine alternating with aspart prior to a prescribed breakfast with a fixed amount of carbohydrate (45, 60, or 75 g) for 20 days. Postprandial BG values were obtained at 2 and 4 hours.ResultsMean baseline BG values for insulin glulisine (136.4 ± 15.7 mg/dL; mean ± SD) and aspart (133.4 ± 14.7 mg/dL) were similar (P = .34). Mean increase in 2-hour postprandial BG was higher in glulisine (+113.5 ± 65.2 mg/dL) than aspart (+98.6 ± 66.9 mg/dL), (P = .01). BG remained higher at 4 hours (glulisine: 141.9 ± 36.5 mg/ dL, aspart: 129.0 ± 37.0 mg/dL) (P = .04). Although statistically insignificant, more hypoglycemic events occurred at 2-and 4-hours postprandial with insulin aspart.ConclusionInsulin aspart appears to be more effective than insulin glulisine in controlling 2-and 4-hour postprandial BG excursions in prepubertal children with T1DM. (Endocr Pract. 2013;19:614-619)     

Superiority of insulin analogues versus human insulin in the treatment of diabetes mellitus

The modern goals of insulin replacement in Type 1 and Type 2 diabetes mellitus (T1, T2DM) are A1C <6.5% long-term, and prevention of hypoglycaemia (blood glucose, BG <70 mg/dl). In addition to appropriate education and motivation of diabetic subjects, the use of rapid- and long-acting insulin analogues, is critical to achieve these goals. The benefits of rapid-acting analogues (lispro, aspart and glulisine have similar pharmacodynamic effects) compared with non-modified human regular insulin, are: (a) lower 1- and 2-h post-prandial blood glucose; (b) lower risk of late post-prandial hypoglycaemia (and therefore lower BG variability); (c) better quality of life (greater flexibility in timing and dosing of insulin). In T1DM, rapid-acting analogues improve A1C only by the extent to which replacement of basal insulin is optimized at the same time, either by multiple daily NPH administrations, or continuous subcutaneous insulin infusion (CSII), or use of the long-acting insulin analogues glargine or detemir. In T2DM, rapid-acting analogues reduce post-prandial hyperglycaemia more than human regular insulin, but systematic studies are needed to examine the effects on A1C. The benefits of long-acting insulin analogues glargine and detemir vs. NPH, are: (1) lower fasting BG combined with lower risk of hypoglycaemia in the interprandial state (night); (2) lower variability of BG. Glargine and detemir differ in terms of potency and duration of action. Detemir should be given twice daily in the large majority of people with T1DM, and in a large percentage of subjects with T2DM as well, usually at doses greater vs those of the once daily glargine. However, when used appropriately for individual pharmacokinetics and pharmacodynamics, glargine and detemir result into similar effects on BG, risk of hypoglycaemia and A1C. Rapid- and long-acting insulin analogues should always be combined in the treatment of T1 and T2DM.     

Variability of Insulin Action: Does It Matter?

Background: Repeat SC injection of identical insulin doses does not induce an identical metabolic effect in patients with diabetes. This concept hampers practical insulin therapy tremendously.Objective: The aim of this article is to briefly and critically review the available literature on the variability of insulin action.Methods: There are only limited numbers of clinical-experimental and clinical studies focusing on the variability of insulin action; therefore, no formal literature search was performed. However, the available studies, along with their references, provided the basis for our findings.Results: Insulin absorption from the SC depot is mainly determined by local blood flow, and many factors affect blood flow. The metabolic effect of absorbed insulin depends on a patient's insulin sensitivity, which is highly variable both intraindividually and interindividually. SC injection of prandial insulin shows an intraindividual coefficient of variation (CV) of insulin action of 15% to 25% and an interindividual CV of 20% to 45% under experimental conditions. The intraindividual variability of insulin action for intermediate-acting/basal insulin is not much higher at 25% to 35% than that of prandial insulin. The variability of the currently available soluble long-acting insulin analogues is reduced compared with neutral protamine Hagedorn insulin in most but not all studies. Although other routes of insulin application (eg, inhalation) might provide an opportunity to reduce the variability of insulin action, the intraindividual variability of metabolic effect observed after inhalation of insulin (15%–30%) was comparable to that seen after SC administration of prandial insulin (15%–25%).Conclusions: The variability of insulin action is clinically highly relevant; however, an intensive scientific investigation of this topic is lacking. Nonetheless, this research might well enable the development of insulin formulations or insulin application techniques that would help reduce this disturbing aspect of insulin therapy.     

Property based optimization of δ-lactam HDAC inhibitors for metabolic stability

The novel δ-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and δ-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability.     

Basal-Bolus Regimen With Insulin Analogues Versus Human Insulin in Medical Patients with type 2 Diabetes: A Randomized Controlled Trial in Latin America

Objective: Few randomized studies have focused on the optimal management of non–intensive care unit patients with type 2 diabetes in Latin America. We compared the safety and efficacy of a basal-bolus regimen with analogues and human insulins in general medicine patients admitted to a University Hospital in Asunción, Paraguay.Methods: In a prospective, open-label trial, we randomized 134 nonsurgical patients with blood glucose (BG) between 140 and 400 mg/dL to a basal-bolus regimen with glargine once daily and glulisine before meals (n = 66) or Neutral Protamine Hagedorn (NPH) twice daily and regular insulin before meals (n = 68). Major outcomes included differences in daily BG levels and frequency of hypoglycemic events between treatment groups.Results: There were no differences in the mean daily BG (157 ± 37 mg/dL versus 158 ± 44 mg/dL; P = .90) or in the number of BG readings within target <140 mg/dL before meals (76% versus 74%) between the glargine/glulisine and NPH/regular regimens. The mean insulin dose in the glargine/glulisine group was 0.76 ± 0.3 units/kg/day (glargine, 22 ± 9 units/day; glulisine, 31 ± 12 units/day) and was not different compared with NPH/regular group (0.75 ± 0.3 units/kg/day [NPH, 28 ± 12 units/day; regular, 23 ± 9 units/day]). The overall prevalence of hypoglycemia (<70 mg/dL) was similar between patients treated with NPH/regular and glargine/glulisine (38% versus 35%; P = .68), but more patients treated with human insulin had severe (<40 mg/dL) hypoglycemia (7.6% versus 25%; P = .08). There were no differences in length of hospital stay or mortality between groups.Conclusion: The basal-bolus regimen with insulin analogues resulted in equivalent glycemic control and frequency of hypoglycemia compared to treatment with human insulin in hospitalized patients with diabetes.Abbreviations: BG = blood glucose BMI = body mass index HbA_1c = glycated hemoglobin NPH = Neutral Protamine Hagedorn T2D = type 2 diabetes     

Management of Type 2 Diabetes Mellitus with Basal-Prandial Insulin Therapy: A Case-Based Review

Background: Diabetes mellitus (DM) is a growing epidemic in the United States—20.8 million people are affected and 90% to 95% of all diagnosed cases are type 2 DM. Nevertheless, implementation of insulin therapy is often delayed in patients with type 2 DM. This delay can increase the risk of DM-related complications, including microvascular neuropathy, nephropathy, retinopathy, and cardiovascular disease.Objective: This article provides a case-based review outlining a novel strategy for advancing therapy with a modified basal and prandial insulin regimen to achieve recommended glycemic targets in type 2 DM as quickly as possible. Evidence-based treatment strategies are also discussed.Methods: Materials used for this article were identified through an English-language literature search of MEDLINE (1967-2007) using the following terms: insulin, postprandial glucose control, and type 2 diabetes.Results: As shown with this male 46-year-old case study patient, type 2 DM is treated initially with diet and exercise, followed by oral antidiabetic drugs (OADs). However, oral therapy typically reduces glycosylated hemoglobin values only by -1.5% to 2.0%. Intensive therapy with once-daily basal insulin in combination with a previously prescribed OAD regimen can achieve normoglycemia and reduce the long-term complications of DM. In patients with postprandial glucose excursions, prandial insulin can be added using a rapid-acting insulin analogue (aspart, lispro, or glulisine).Conclusions: A key factor in this case patient's ability to reach glycemic targets within I year of diagnosis of type 2 DM was the accelerated implementation of insulin therapy. Such a therapeutic approach obviates the risk for uncontrolled hyperglycemia, which is associated with the standard practice of beginning treatment with diet and exercise alone and slowly advancing by i OAD at a time, ending with insulin therapy as a last resort. (Insulin. 2007;2:118-126)     

High-dose Insulin Therapy: is it Time for U-500 Insulin?

ObjectiveTo provide an overview of U-500 regular insulin action, review published clinical studies with U- 500 regular insulin, and offer guidance to practicing endocrinologists for identifying patients for whom U-500 regular insulin may be appropriate.MethodsThis review has been produced through a synthesis of relevant published literature compiled via a literature search (MEDLINE search of the English-language literature published between January 1969, and July 2008, related to U-500, insulin resistance, concentrated insulin, high-dose insulin, insulin pharmacokinetics, and diabetes management) and the authors’ collective clinical experience.ResultsThe obesity epidemic is contributing to an increase in the prevalence of type 2 diabetes, as well as to increasing insulin requirements in insulin-treated patients. Many of these patients exhibit severe insulin resistance, manifested by daily insulin requirements of 200 units or greater or more than 2 units/kg. Delivering an appropriate insulin volume to these patients can be difficult and inconvenient and may be best accomplished with U-500 regular insulin by multiple daily injections or with continuous subcutaneous insulin infusion, rather than with standard U-100 insulin. Implementation of U-500 regular insulin in patients previously on other insulin formulations is described with a treatment algorithm covering dosage requirements ranging from 150 to more than 600 units per day on the basis of the authors’ experience.ConclusionRegimen conversion of appropriately selected patients from high-dose, U-100 insulin to U-500 regular insulin therapy on the basis of the recommendations presented in this article may potentially result in improved glycemic control and lower cost. (Endocr Pract. 2009;15:71-79)