A Fixed Ratio Combination of Insulin Degludec and Liraglutide (IDegLira) Reduces Glycemic Fluctuation and Brings More Patients with Type 2 Diabetes Within Blood Glucose Target Ranges.

BACKGROUND: Reducing glycemic fluctuation is important for optimal diabetes management. This post hoc analysis examined glycemic fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone. METHODS: We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients with type 2 diabetes (T2D), and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess glycemic fluctuation and day-to-day variability. RESULTS: Compared with IDeg, IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (3.9-9.0 mmol/L) than IDeg for all pre- and postprandial values, and for the full nine-point profile (P < 0.05 for all). IDegLira also resulted in a greater reduction in the range of SMBG values over 24 h than IDeg (P ≤ 0.0001). CGM data showed that IDegLira provided greater reductions in interstitial glucose (IG) fluctuation (P = 0.0018) and postprandial IG increment (P = 0.0288) compared with IDeg. Compared with liraglutide, IDegLira brought a higher proportion of subjects within SMBG target ranges (all pre- and all postprandial values, and the full nine-point profile, P < 0.01 for all) and resulted in a greater reduction of time outside the IG target range (P = 0.0072). IDegLira also reduced mean IG more than liraglutide (P < 0.0001). CONCLUSIONS: Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than either IDeg or liraglutide alone.

A Review of Insulin-Dosing Formulas for Continuous Subcutaneous Insulin Infusion (CSII) for Adults with Type 1 Diabetes.

Dosing guidelines for patients with type 1 diabetes using continuous subcutaneous insulin infusion (CSII), which are historically based on clinical experience and retrospective studies of patients consuming an American diet, recommend that basal insulin should represent approximately 50 % of the total daily dose (TDD). Recent prospective studies in the USA and Japan conclude that the more appropriate proportion is closer to 30-40 % of TDD. In addition, currently used formulas for calculating the carbohydrate-to-insulin ratio (CIR) and correction factor (CF) may lead to underdosing of bolus insulin by as much as 12.8-50 % for a hypothetical patient. The discrepancies between traditional formulas and data from newer studies can be accounted for by the more rigorous design of the newer studies (e.g., prospective design, controlled diets, meal omission, and frequent glucose monitoring). International differences in diet composition may also be important to consider when developing dosing recommendations for CSII.

PATIENTS ACHIEVING GOOD GLYCEMIC CONTROL (HBA1c <7%) EXPERIENCE A LOWER RATE OF HYPOGLYCEMIA WITH INSULIN DEGLUDEC THAN WITH INSULIN GLARGINE: A META-ANALYSIS OF PHASE 3A TRIALS.

OBJECTIVE: Meta-analysis to compare hypoglycemia rates of basal insulin degludec (IDeg) with insulin glargine (IGlar) in patients with diabetes achieving good glycemic control (hemoglobin A1c [HbA1c] <7% at end of trial). METHODS: In a preplanned meta-analysis, patient data from 7 randomized, treat-to-target, 26- or 52-week trials in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) who administered IDeg (n = 2,899) or IGlar (n = 1,431) once daily were analyzed. Using a negative binomial regression model, this meta-analysis compared hypoglycemia rates in patients achieving HbA1c <7% at end of trial with IDeg (n = 1,347) and IGlar (n = 697). RESULTS: In all trials, IDeg was noninferior to IGlar in HbA1c reduction from baseline. At end of trial, 2,044 patients (T2DM, n = 1,661; T1DM, n = 383) achieved HbA1c <7%. The overall confirmed hypoglycemia rate, defined as plasma glucose <56 mg/dL or severe hypoglycemia if requiring assistance, was significantly lower with IDeg versus IGlar (estimated rate ratio [ERR] IDeg:IGlar, 0.86; 95% confidence interval [CI], 0.76 to 0.98). The nocturnal confirmed hypoglycemia rate, defined as occurring between midnight and 6:00 am, was significantly lower with IDeg (ERR, 0.63; 95% CI, 0.52 to 0.77). In the maintenance period (16 weeks onward when average insulin dose and glycemic levels stabilized), the overall confirmed hypoglycemia rate was significantly lower (ERR, 0.79; 95% CI, 0.68 to 0.92) and the nocturnal confirmed hypoglycemia rate was significantly lower (ERR, 0.57; 95% CI, 0.45 to 0.72) with IDeg versus IGlar. CONCLUSION: Patients with T1DM and T2DM achieved HbA1c <7% with significantly lower rates of overall and nocturnal confirmed hypoglycemia with IDeg versus IGlar. The lower hypoglycemia rate with IDeg was more pronounced in the maintenance period.

Misled by the Morning "Fasting" Plasma Glucose.

Because of its ease and simplicity of its measurement, the morning fasting plasma glucose (FPG), has been as used a surrogate marker for the entire basal day when titrating once-nightly basal insulin. Common in obese insulin-treated patients with type 2 diabetes, late and large evening meals elevate the FPG. This has led to dosing of basal insulin well beyond the basal requirements and contributes to hypoglycemia and weight gain seen with this therapy. It is recommended that during basal insulin titration, the evening meal be limited and hypoglycemia be monitored early in the morning, that bewitching time when the "peakless" basal insulin's action is peaking and the predawn phenomenon insulin sensitivity is higher.

Can a fixed-ratio combination of insulin degludec and liraglutide help Type 2 diabetes patients to optimize glycemic control across the day?

'IDegLira' combines insulin degludec (IDeg) with the glucagon-like peptide-1 analog liraglutide (Lira) at a ratio of 1 unit IDeg to 0.036 mg Lira. The two components have complementary therapeutic actions for the treatment of Type 2 diabetes. Studies have shown that combinations of basal insulin with glucagon-like peptide-1 receptor agonists can be clinically successful, lowering elevated blood glucose with a low risk of hypoglycemia and weight gain. IDegLira is being assessed in a series of studies (two already published), which provide insights into its clinical utility in previously insulin-naive patients and those failing to achieve good glycemic control on a basal-only insulin regimen. This article critically examines the available data to assess the product's likely clinical profile.

Omitting late-night eating may cause hypoglycemia in "well controlled" basal insulin-treated type 2 diabetes.

OBJECTIVE: To assess hypoglycemia caused by eating the last meal of the day earlier or its omission in "well controlled" type 2 diabetes mellitus patients treated with once-nightly basal insulin. METHODS: Previously basal insulin-titrated subjects (n = 20) (fasting plasma glucose, FPG, <110 mg/dL and no self-reported hypoglycemia) underwent continuous glucose monitoring (CGM) during 3 consecutive eating conditions of 3 days each; (1) usual eating, (2) the last meal restricted to 18:00, and (3) 1 sequential meal omitted/day thereby creating a fasting day after transposing the 4-hour period after a meal with that when the meal was omitted. One 24-hour (00:00 to 00:00) period within each eating condition was selected for comparison. RESULTS: The mean duration in all hypoglycemic ranges doubled (P = .0584 or greater) when the last meal was omitted or eaten at 18:09 ± 0:39 instead of 19:43 ± 1:01, the usual time for the subjects' undisturbed eating. The mean duration of hypoglycemia was greatest between 00:00 to 06:00 compared to the 3 other 6-hour periods of the day. CONCLUSIONS: Increased hypoglycemia occurs when the subject's last meal is eaten earlier or omitted and may not be recognized because it occurs predominately during sleep. When titrating basal insulin from the morning FPG, considerations should be given to the effect of the last meal of the day and possible hypoglycemia between 00:00 and 06:00 to avoid excessive basal insulin treatment.

Individualizing insulin therapy in the management of type 2 diabetes.

It is recognized that reducing hyperglycemia early on in disease progression has long-term benefits for patients with diabetes. Insulin therapy has greater potential to reduce hyperglycemia than other therapies; however, there is often a significant delay in insulin initiation and intensification. Insulin replacement therapy in type 2 diabetes should no longer be viewed as the treatment of last resort. With the development of modern insulin analogs, the field has evolved. Large clinical trials have improved our understanding of the potential benefits and risks associated with intensive glycemic control in different patient populations and highlighted the need for individualization of glycemic targets and treatment strategies. Current treatment guidelines recognize the important role of insulin therapy both early on and throughout the progression of type 2 diabetes.

Reassessment of insulin dosing guidelines in continuous subcutaneous insulin infusion treated type 1 diabetes.

It is a daunting task to initiate or evaluate continuous subcutaneous insulin infusion, pump, dosing in a patient with type 1 diabetes. Choosing a low dose may lead to hyperglycemia or, too high, hypoglycemia. Mathematical dosing guidelines were used with the first human insulin injection in 1922. Since that time, they have been enlarged and modified. The current widely published guidelines were developed from retrospective evaluations of pump-downloads in patients without specified diet conditions or timed glucose testing. When diet is controlled and glucose testing is timed to evaluate post-meal excursions and during sleep, recent prospective studies found that these current dosing recommendations for basal insulin were too high and for bolus insulin too low. Further, simple mathematical interrelationships were published that kept the right proportions between the bolus dosing factors and the basal dose.

Integrating advances in insulin into clinical practice: Advances In insulin formulations.

The central role of insulin in the management of patients with type 1 diabetes mellitus (T1DM) remains, nearly a century after its first use in humans. In patients with type 2 diabetes mellitus (T2DM), the role of insulin has evolved as other therapies have been introduced, with insulin now used across the spectrum of the disease. This article discusses the use of insulin in patients with T1DM or T2DM, including combined use with other agents in T2DM, with an emphasis on incretin-based therapies. In addition, new insulin products and concentrations are discussed along with their varied routes of administration.

Liraglutide achieves A1C targets more often than sitagliptin or exenatide when added to metformin in patients with type 2 diabetes and a baseline A1C <8.0%.

OBJECTIVE: Compare the safety and efficacy of liraglutide to that of sitagliptin or exenatide as add-on to metformin in patients with type 2 diabetes (T2D) and glycated hemoglobin (A1C) <8.0%. METHODS: Post hoc analysis of 26-week data from liraglutide 1.8 mg once daily (OD) versus exenatide 10 µg twice daily (LEAD-6) and liraglutide 1.8 mg OD versus sitagliptin 100 mg OD (LIRA-DPP-4); only patients treated as add-on to metformin with baseline A1C <8.0% were included. Efficacy analysis was performed on the intention-to-treat population with missing values imputed by last observation carried forward. RESULTS: More patients achieved A1C targets (<7.0% and ≤6.5%) with liraglutide versus exenatide or sitagliptin; the difference was greatest for A1C ≤6.5% (LEAD-6: 65% versus 35%; odds ratio [OR]=3.37, 95% confidence interval [CI]: 1.31-8.63; P = .01 or LIRA-DPP-4: 53% versus 19%; OR = 4.78, 95% CI 2.10 to 10.87; P = .0002). Significantly more patients achieved a composite endpoint of A1C <7.0% with no weight gain or hypoglycemia with liraglutide compared with exenatide (78% versus 42%; OR = 4.99, 95% CI: 1.77 to 14.04; P = .0023) or sitagliptin (61% versus 21%; OR = 5.95, 95% CI: 2.66 to 13.29; P<.0001). All treatments were well tolerated, there was no major hypoglycemia and few patients (8 to 10%) experienced minor hypoglycemia. CONCLUSION: When added to metformin in patients with an A1C <8.0%, more patients using liraglutide 1.8 mg reached A1C targets than with exenatide or sitagliptin. Sitagliptin had particularly low efficacy in this analysis. These data support the use of liraglutide 1.8 mg as a safe and effective alternative to sitagliptin or exenatide following metformin failure in patients with an A1C <8.0%.

The number of basal rates required to achieve near-normal basal glucose control in pump-treated type 2 diabetes.

BACKGROUND: It has been reported that most pump-treated patients with type 2 diabetes require only two or fewer basal rates. Using daily continuous glucose monitoring (CGM)-directed titration, this premise was re-evaluated at near-normal glycemic control. PATIENTS AND METHODS: Thirty subjects who were insulin-naive (n = 10), on basal insulin (n = 10), or on basal-bolus insulin therapy (n=10) ate a fixed diet. The basal rate was started as a single rate and then adjusted to a basal glucose goal of 70-130 mg/dL. The insulin-to-carbohydrate ratio (ICR) (in g/U) was adjusted to 2-4-h postmeal CGM glucose goal of 80-120% of premeal glucose. RESULTS: The mean (SE) CGM basal glucose was 99.9 (4.9) mg/dL, and 4.5% (1.4%) of the readings were <70 mg/dL. The mean 2-4-h postmeal glucose was 113.3% (4.8%) of the premeal glucose. Only six subjects (20%) required two basal rates, while the remainder needed only one. The mean (SE) dosing relationships were as follows: total basal dose (TBD) (in U/day) = 0.226(0.018) × weight (in kg); TBD (in U/day) = 0.339(0.012) × total daily dose (TDD) (in U/day); ICR (in g/U) = 126(8)/TBD (in U/day); and ICR (in g/U) = 365(14)/TDD (in U/day). CONCLUSIONS: This study confirms that one basal rate is adequate for the majority of subjects with type 2 diabetes. The mathematical proportionality between dosing factors closely agrees with those obtained in CGM-titrated pump-treated type 1 diabetes but differs from those derived from clinical studies in which insulin titration was based on infrequent self-monitored plasma glucose testing and while on an unstructured diet.

Insulin degludec/insulin aspart administered once daily at any meal, with insulin aspart at other meals versus a standard basal-bolus regimen in patients with type 1 diabetes: a 26-week, phase 3, randomized, open-label, treat-to-target trial.

OBJECTIVE: To evaluate efficacy and tolerability of a co-formulation of insulin degludec and insulin aspart (IDegAsp) with insulin aspart (IAsp) at other meals compared with basal-bolus therapy using insulin detemir (IDet) and IAsp. RESEARCH DESIGN AND METHODS: Adults (n = 548) with type 1 diabetes (A1C 7.0-10.0%; BMI ≤35.0 kg/m(2)) were randomized 2:1 in a 26-week, multinational, parallel-group, treat-to-target trial to IDegAsp or IDet. IDegAsp was given with a meal, and IDet was given in the evening, with a second (breakfast) dose added if needed. RESULTS: Non-inferiority for IDegAsp versus IDet was confirmed; A1C improved by 0.75% with IDegAsp and 0.70% with IDet to 7.6% in both groups (estimated treatment difference IDegAsp - IDet: -0.05% [95% CI -0.18 to 0.08]). There was no statistically significant difference between IDegAsp and IDet in the rates of severe hypoglycemia (0.33 and 0.42 episodes/patient-year, respectively) or overall confirmed (plasma glucose <3.1 mmol/L) hypoglycemia (39.17 and 44.34 episodes/patient-year, respectively). Nocturnal confirmed hypoglycemia rate was 37% lower with IDegAsp than IDet (3.71 vs. 5.72 episodes/patient-year, P < 0.05). Weight gain was 2.3 and 1.3 kg with IDegAsp and IDet, respectively (P < 0.05). Total insulin dose was 13% lower in the IDegAsp group (P < 0.0001). No treatment differences were detected in Health-Related Quality of Life, laboratory measurements, physical examination, vital signs, electrocardiograms, fundoscopy, or adverse events. CONCLUSIONS: IDegAsp in basal-bolus therapy with IAsp at additional mealtimes improves overall glycemic control and was non-inferior to IDet, with a reduced risk of nocturnal hypoglycemia and fewer injections in comparison with IDet + IAsp basal-bolus therapy.

Contribution of the dawn phenomenon to the fasting and postbreakfast hyperglycemia in type 1 diabetes treated with once-nightly insulin glargine.

OBJECTIVE: To observe the effect of the dawn phenomenon on basal glucose and postbreakfast hyperglycemia in patients with type 1 diabetes treated with once-nightly insulin glargine and premeal insulin lispro. METHODS: In 49 study subjects consuming a fixed isocaloric (50% carbohydrate) diet of usual food, the insulin glargine dose was titrated from daily continuous glucose monitoring downloads to achieve a basal glucose goal of <130 mg/dL 4 hours after meals and during serial meal omissions but with fewer than 10% of readings at <70 mg/dL during 24 hours. Patients also performed self-monitoring of plasma glucose 7 times a day (before and 2 hours after each meal or omitted meal and at bedtime). RESULTS: The target mean basal glucose level was achieved only during the non-dawn phenomenon period (1400 hours to 0400 hours). During the dawn phenomenon, the mean (standard deviation) basal glucose level increased from 118 (57) mg/dL at 0400 hours to 156 (67) mg/dL before the breakfast meal, a 32% increase (P = .00149). The mean self-monitored plasma glucose level with meal omission was 63.8% of that increase with a breakfast meal. CONCLUSION: The fasting morning glucose concentration is considerably elevated because of the dawn phenomenon. Targeting insulin titration to this glucose level may result in excessive basal insulin dosing for the non-dawn phenomenon periods of the day. The dawn phenomenon is a large component of the postbreakfast hyperglycemia. Rather than increasing the morning premeal insulin bolus, consideration should be given to pretreating the earlier dawn phenomenon with an insulin pump with use of a variable basal insulin rate.

Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.

BACKGROUND: Basal insulin therapy does not stop loss of ß-cell function, which is the hallmark of type 2 diabetes mellitus, and thus diabetes control inevitably deteriorates. Insulin degludec is a new, ultra-longacting basal insulin. We aimed to assess efficacy and safety of insulin degludec compared with insulin glargine in patients with type 2 diabetes mellitus. METHODS: In this 52 week, phase 3, open-label, treat-to-target, non-inferiority trial, undertaken at 123 sites in 12 countries, we enrolled adults (aged ≥18 years) with type 2 diabetes mellitus and a glycated haemoglobin (HbA(1c)) of 7·0-10·0% after 3 months or more of any insulin regimen (with or without oral antidiabetic drugs). We randomly allocated eligible participants in a 3:1 ratio to receive once-daily subcutaneous insulin degludec or glargine, stratified by previous insulin regimen, via a central interactive response system. Basal insulin was titrated to a target plasma glucose concentration of 3·9-<5·0 mmol/L self-measured before breakfast. The primary outcome was non-inferiority of degludec to glargine measured by change in HbA(1c) from baseline to week 52 (non-inferiority limit of 0·4%) by ANOVA in the full analysis set. We assessed rates of hypoglycaemia in all treated patients. This study is registered with ClinicalTrials.gov, number NCT00972283. FINDINGS: 744 (99%) of 755 participants randomly allocated degludec and 248 (99%) of 251 allocated glargine were included in the full analysis set (mean age 58·9 years [SD 9·3], diabetes duration 13·5 years [7·3], HbA(1c) 8·3% [0·8], and fasting plasma glucose 9·2 mmol/L [3·1]); 618 (82%) and 211 (84%) participants completed the trial. After 1 year, HbA(1c) decreased by 1·1% in the degludec group and 1·2% in the glargine group (estimated treatment difference [degludec-glargine] 0·08%, 95% CI -0·05 to 0·21), confirming non-inferiority. Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe episodes requiring assistance) were lower with degludec than glargine (11·1 vs 13·6 episodes per patient-year of exposure; estimated rate ratio 0·82, 95% CI 0·69 to 0·99; p=0·0359), as were rates of nocturnal confirmed hypoglycaemia (1·4 vs 1·8 episodes per patient-year of exposure; 0·75, 0·58 to 0·99; p=0·0399). Rates of severe hypoglycaemia seemed similar (0·06 vs 0·05 episodes per patient-year of exposure for degludec and glargine) but were too low for assessment of differences. Rates of other adverse events did not differ between groups. INTERPRETATION: A policy of suboptimum diabetes control to reduce the risk of hypoglycaemia and its consequences in advanced type 2 diabetes mellitus might be unwarranted with newer basal insulins such as degludec, which are associated with lower risks of hypoglycaemia than insulin glargine. FUNDING: Novo Nordisk.