Efficacy and safety of basal insulins in people with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials.

Aim: The comparative effectiveness of basal insulins has been examined in several studies. However, current treatment algorithms provide a list of options with no clear differentiation between different basal insulins as the optimal choice for initiation. Methods: A comprehensive search of MEDLINE, Embase, Cochrane Library, ISI, and Scopus, and a reference list of retrieved studies and reviews were performed up to November 2023. We identified phase III randomized controlled trials (RCTs) comparing the efficacy and safety of basal insulin regimens. The primary outcomes evaluated were HbA1c reduction, weight change, and hypoglycemic events. The revised Cochrane ROB-2 tool was used to assess the methodological quality of the included studies. A random-effects frequentist network meta-analysis was used to estimate the pooled weighted mean difference (WMD) and odds ratio (OR) with 95% confidence intervals considering the critical assumptions in the networks. The certainty of the evidence and confidence in the rankings was assessed using the GRADE minimally contextualized approach. Results: Of 20,817 retrieved studies, 44 RCTs (23,699 participants) were eligible for inclusion in our network meta-analysis. We found no significant difference among various basal insulins (including Neutral Protamine Hagedorn (NPH), ILPS, insulin glargine, detemir, and degludec) in reducing HbA1c. Insulin glargine, 300 U/mL (IGlar-300) was significantly associated with less weight gain (mean difference ranged from 2.9 kg to 4.1 kg) compared to other basal insulins, namely thrice-weekly insulin degludec (IDeg-3TW), insulin degludec, 100 U/mL (IDeg-100), insulin degludec, 200 U/mL (IDeg-200), NPH, and insulin detemir (IDet), but with low to very low certainty regarding most comparisons. IDeg-100, IDeg-200, IDet, and IGlar-300 were associated with significantly lower odds of overall, nocturnal, and severe hypoglycemic events than NPH and insulin lispro protamine (ILPS) (moderate to high certainty evidence). NPH was associated with the highest odds of overall and nocturnal hypoglycemia compared to others. Network meta-analysis models were robust, and findings were consistent in sensitivity analyses. Conclusion: The efficacy of various basal insulin regimens is comparable. However, they have different safety profiles. IGlar-300 may be the best choice when weight gain is a concern. In contrast, IDeg-100, IDeg-200, IDet, and IGlar-300 may be preferred when hypoglycemia is the primary concern.

A prospective, multicentre, randomized, open-label comparison of a long-acting basal insulin analog glargine plus glulisine with premixed insulin in insulin naïve patients with Type 2 diabetes - A study from India.

AIMS: We aimed to compare the effectiveness of Glargine plus Glulisine to premixed insulin analogue, as measured by HbA1c ≤ 7.0% in insulin naive Type 2 Diabetes (T2D) patients with elevated fasting and/or postprandial plasma glucose. METHODS: Insulin-naive T2D patients (116 men, 84 women) on ≥ 2 oral hypoglycemic agents with inadequate glycemic control were randomized either to group 1 (insulin Glargine plus Glulisine, n = 101) or group 2 (Premixed Insulin analogue, n = 99). RESULTS: In the intention to treat analysis, at week 24, percentage of patients with good glycaemic control (HbA1c ≤ 7.0%) was similar between the two groups (16.8% in Group 1 vs. 13.1% in Group 2, χ2 - 0.535, p = 0.47). Significant reductions in fasting and postprandial levels were observed in groups 1 and 2 at both post-baseline time points (Week 12 and 24). In group 1, reduction in HbA1c from baseline to week 12 was 0.6 ± 0.1 and 0.7 ± 0.2 at week 24, p < 0.0001 for all. In group 2, no significant change in HbA1c was observed. In group 1, 83.2% required an additional dose of glulisine and in group 2, 88.9% required an additional dose of premixed insulin. Hypoglycemic events were similar in both groups (0.12 events per person-year in group 1 and 0.13 events per person-year in group 2). Weight gain was non-significant in both groups. CONCLUSIONS: Glargine plus Glulisine, though in higher dose was effective as premixed insulin in lowering HbA1c. Hypoglycemic events per person-year were similar in both groups.

Efficacy and safety of fixed-ratio combination insulin degludec/liraglutide in type 2 diabetes: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The efficacy and safety of fixed-ratio combination insulin degludec/liraglutide (IDegLira) for type 2 diabetes (T2DM) were extensively investigated by the global DUAL trials. However, the evidence on its efficacy and safety in T2DM has not been systematically reviewed. METHODS: Randomized controlled trials published in English that compared IDegLira with placebo or GLP-1 agonists or insulin in patients with T2DM were selected up to December 2022. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between "IDegLira versus Insulin," "IDegLira versus GLP-1RA," and "IDegLira versus Placebo". The risk of potential bias was assessed. RESULTS: In terms of glycaemic efficacy, IDegLira reduced levels of glycated haemoglobin (HbA1c; weighted mean differences (WMDs) 0.52%, 95% CI 0.33%-0.71%); fasting blood glucose (0.32 mg/dL, 0.14-0.50 mg/dL), and the nine-point self-measured plasma glucose (0.25 mmol/L, 0.25-0.36 mmol/L). Furthermore, IDegLira was generally better in the attainment of HbA1c < 7.0% or ≤6.5%, HbA1c < 7.0% or ≤6.5% without weight gain and/or without severe or blood glucose-confirmed hypoglycaemic episodes. In non-glycaemic efficacy aspects, IDegLira decreased systolic blood pressure but elevated heart rate. In terms of safety outcomes, IDegLira did not appear to be associated with a risk of hypoglycaemia (RR 1.23, 0.85-1.78) and nocturnal hypoglycaemia (0.89, 0.52-1.52) occurring when compared with other hypoglycaemic agents or placebo. CONCLUSIONS: IDegLira improves better glycaemic and non-glycaemic outcomes without weight gain and/or without severe or blood glucose-confirmed hypoglycaemic episodes in T2DM. Side effects of IDegLira are mild.

Real-World Analysis of Long-Acting and NPH-Containing Insulins on Glycemic Control.

Introduction Affordability of insulin products has become a concern in the past several years as the average price of various insulin products has increased. While awaiting legislation at the federal level that would address issues leading to high insulin costs, providers may have shifted prescribing practices to prescribe the lowest-priced insulin products to achieve patients' treatment goals. Objective To compare the prevalence of hypoglycemic events between patients receiving lower-cost neutral protamine Hagedorn (NPH)-containing human insulins and higher-cost long-acting insulin analogs in Medicare Part D enrollees within a management services organization, as well as assessing glycemic control and changes in body mass index. Methods This was a multicenter, retrospective study conducted at three primary care clinics. The co-primary outcomes were percent difference of documented mild and severe hypoglycemic events between individuals receiving NPH-containing human insulin and long-acting insulin. Results A total of 72 patients met inclusion criteria and were receiving NPH-containing human insulins or the long-acting insulin analogs, 15 and 57 patients, respectively. Severe hypoglycemic events occurred in 3.5% vs 0% of the long-acting insulin analog and NPH-containing human insulin group, respectively (P = 0.999). Mild hypoglycemic episodes were experienced by 31.6% versus 33.3% of long-acting insulin analog and NPH, respectively (P = 0.539). For secondary outcomes, no difference was observed in glycemic control outcomes across insulin groups. Conclusion Among Medicare Part D patients with type 2 diabetes mellitus, the use of NPH-containing human insulins was not associated with an increased risk of mild or severe hypoglycemia-related episodes or reduced glycemic control compared with long-acting insulin. Study findings suggest that lower-cost, NPH-containing human insulins may be an alternative to higher-cost, long-acting insulin analogs.

Comparison of treatment with insulin detemir and NPH in women with gestational diabetes mellitus: glycemic control and pregnancy outcomes. A retrospective study.

PURPOSE: The objective of this retrospective study was to compare glycemic control, pregnancy outcomes, and neonatal outcomes in women with gestational diabetes mellitus (GDM) treated with (a) insulin detemir and (b) insulin neutral protamine Hagedorn (NPH). METHODS: A total of 192 women with GDM were included in the analysis. Ninety-eight women received detemir, while 94 women received NPH. Data regarding medical history, glycemic control, and time and mode of delivery, as well as neonatal outcomes, were recorded. RESULTS: Baseline characteristics were comparable between the two groups. There were no differences with respect to the week of insulin initiation, total insulin dose, duration of insulin therapy, daily insulin dose/weight in early and late pregnancy, or the number of insulin injections per day. Maternal overall weight gain during pregnancy and weight gain per week did not differ either. The detemir group had slightly lower HbA1c levels at the end of gestation [median: det 5.2% (33 mmol/mol) vs NPH 5.4% (36 mmol/mol), p=0.035). There were no cases of hypoglycemia or allergic reactions in the two groups. There were also no differences regarding neonatal outcomes according to the available data, given that data in some cases were missing. CONCLUSION: The use of insulin detemir was found to be equally effective and safe compared to NPH in women with GDM.

In type 1 diabetes, weekly basal insulin Fc was noninferior to daily insulin degludec for HbA1c at 26 wk.

SOURCE CITATION: Kazda CM, Bue-Valleskey JM, Chien J, et al. Novel once-weekly basal insulin Fc achieved similar glycemic control with a safety profile comparable to insulin degludec in patients with type 1 diabetes. Diabetes Care. 2023;46:1052-1059. 36920867.

Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin.

BACKGROUND: Insulin icodec is an investigational once-weekly basal insulin analogue for diabetes management. METHODS: We conducted a 78-week randomized, open-label, treat-to-target phase 3a trial (including a 52-week main phase and a 26-week extension phase, plus a 5-week follow-up period) involving adults with type 2 diabetes (glycated hemoglobin level, 7 to 11%) who had not previously received insulin. Participants were randomly assigned in a 1:1 ratio to receive once-weekly insulin icodec or once-daily insulin glargine U100. The primary end point was the change in the glycated hemoglobin level from baseline to week 52; the confirmatory secondary end point was the percentage of time spent in the glycemic range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) in weeks 48 to 52. Hypoglycemic episodes (from baseline to weeks 52 and 83) were recorded. RESULTS: Each group included 492 participants. Baseline characteristics were similar in the two groups. The mean reduction in the glycated hemoglobin level at 52 weeks was greater with icodec than with glargine U100 (from 8.50% to 6.93% with icodec [mean change, -1.55 percentage points] and from 8.44% to 7.12% with glargine U100 [mean change, -1.35 percentage points]); the estimated between-group difference (-0.19 percentage points; 95% confidence interval [CI], -0.36 to -0.03) confirmed the noninferiority (P<0.001) and superiority (P = 0.02) of icodec. The percentage of time spent in the glycemic range of 70 to 180 mg per deciliter was significantly higher with icodec than with glargine U100 (71.9% vs. 66.9%; estimated between-group difference, 4.27 percentage points [95% CI, 1.92 to 6.62]; P<0.001), which confirmed superiority. Rates of combined clinically significant or severe hypoglycemia were 0.30 events per person-year of exposure with icodec and 0.16 events per person-year of exposure with glargine U100 at week 52 (estimated rate ratio, 1.64; 95% CI, 0.98 to 2.75) and 0.30 and 0.16 events per person-year of exposure, respectively, at week 83 (estimated rate ratio, 1.63; 95% CI, 1.02 to 2.61). No new safety signals were identified, and incidences of adverse events were similar in the two groups. CONCLUSIONS: Glycemic control was significantly better with once-weekly insulin icodec than with once-daily insulin glargine U100. (Funded by Novo Nordisk; ONWARDS 1 ClinicalTrials.gov number, NCT04460885.).

Hypoglycemia with insulin in post-transplant diabetes mellitus.

INTRODUCTION: To prevent hypoglycemic episodes, the management of insulin therapy against post-transplant diabetes mellitus (PTDM) is important. We compared glargine (long-acting insulin) versus NPH isophane (intermediate-acting insulin) as an armamentarium against PTDM. Indeed, the study evaluated PTDM patients with hypoglycemic episodes treated with isophane or glargine. MATERIAL AND METHODS: We evaluated a total number of 231 living-donor renal transplant recipients with PTDM of age ≥ 18 years admitted to the hospital between January 2017 and September 2021. However, patients taking hypoglycemic agents before transplantation were excluded from this study. Out of 231 patients, 52 (22.15%) suffered from PTDM out of whom 26 were treated with glargine or isophane. RESULTS: After applying exclusion criteria, out of 52 PTDM patients 23 were included in the study: 13 PTDM patients were treated with glargine, whereas 10 PTDM patients with isophane. Our analysis revealed 12 episodes of hypoglycemia in glargine-treated PTDM patients compared to 3 in isophane-treated PTDM patients (p = 0.056). Clinically, 9 out of 15 hypoglycemic episodes were nocturnal (60%). Furthermore, no other risk factors were observed in our study population. Detailed analysis showed that both groups had equivalent doses of immunosuppressants and oral hypoglycemic agents. The odds ratio for hypoglycemia in the group treated with isophane compared to that treated with glargine was 0.224 (95% CI, 0.032-1.559). Glargine users recorded significantly lower blood sugar levels before lunch, dinner and at bedtime with p-values of 0.001, 0.009 and 0.001 respectively. A better hemoglobin A1c (HbA1c) level was seen in the glargine vs. isophane group (6.98 ± 0.52 vs. 7.45 ± 0.49, p-value 0.03). CONCLUSION: The study shows better blood sugar control with long-acting insulin analog, glargine, than with intermediate-actin analog, isophane. Overall, a higher number of hypoglycemic episodes was nocturnal. Long term safety of long-acting insulin analogs needs to be further studied.

One-year safety and efficacy results of insulin treatment simplification with IDegLira in type 2 diabetes.

INTRODUCTION: This study aimed to investigate the sustained safety and efficacy of insulin treatment simplification with IDegLira in patients with type 2 diabetes and an HbA1c ≤ 7.5% (58 mmol/mol) during a 12-month follow-up. METHODS: Seventy-two adults with type 2 diabetes and an HbA1c ≤ 7.5% (58 mmol/mol) treated with multiple daily insulin injections (MDI) participated in the trial (age 63.8 ± 9.5 years, HbA1c 6.4 ± 0.7%, [46 ± 8 mmol/mol] body weight 92.95 ± 18.83 kg, total daily insulin dose: 43.21 ± 10.80 units; mean ± SD). Previous insulins were stopped, and once daily IDegLira was started. IDegLira was titrated by the patients to achieve a self-measured prebreakfast plasma glucose concentration of ≥5 mmol/L to ≤6 mmol/L. RESULTS: After 12 months, good glycaemic control was maintained, while body weight decreased significantly. Mean HbA1c changed to 6.2 ± 0.8% (44 ± 9 mmol/mol) (p = .109) and body weight changed by -3.89 kg to 89.06 ± 18.61 kg (p < .0001). The simplified treatment was safe and well-tolerated. Percentage of patients experiencing at least one episode of hypoglycaemia was 49% during the month before simplification and 17% during the last 3 months of the follow-up. CONCLUSIONS: Insulin treatment simplification with IDegLira in selected patients with type 2 diabetes is safe, maintains adequate glycaemic control and is associated with weight loss over 12 months.

Assessment of the Effect of Timing of Insulin Glargine Administration (Bedtime versus Morning) on Glycemic Control in Children with Type 1 Diabetes in Cairo, Egypt: A Single Centre Experience.

BACKGROUND: Diabetes control without developing hypoglycemia is challenging in Type 1 diabetes (T1D) management, with few studies evaluating the effect of insulin glargine timing on glucoregulation. OBJECTIVES: The aim is to compare glycemic control using continuous glucose monitoring (CGM) in children with T1D receiving bedtime versus morning glargine and to assess CGM effect on glycemia. METHODS: This cross-sectional observational study was conducted on 30 pediatric patients with T1D receiving glargine (19 at bedtime and 11 in the morning). CGM sensor was applied for 3-5 days using the I-Pro2 blood glucose sensor. RESULTS: Total daily dose of glargine showed a significant correlation with HbA1C (p=0.006) and percentage of glucose readings within average (p=0.039). HbA1C correlated significantly with time in range (TIR) (p=0.049). Nocturnal hypoglycemia was significantly higher in the bedtime glargine group than in the morning one (p=0.016). The morning glargine group showed better control in terms of lower HbA1C and higher TIR, but these did not reach statistical significance. Follow- up after 3 months revealed significant improvement in the percentage of hyperglycemia, BG readings within average, as well as HbA1c (p:0.001). CONCLUSIONS: Bedtime glargine administration was associated with a higher frequency of occurrence of nocturnal hypoglycemia. No statistically significant difference in glycemic control between both groups was found. CGM use improved glycemic control.

Rate of Inpatient Hypoglycemia Following a 1:1 Dose Interchange Between Concentrated Insulin Glargine to Insulin Detemir.

BACKGROUND: Insulin remains a mainstay of treating hyperglycemia in an acute setting. Insulin glargine 300 units/mL (Toujeo, iGlar300) has a different pharmacokinetic profile than 100 units/mL basal insulins, such as insulin detemir (iDet100) and iGlar100. While conversion from iGlar300 to iGlar100 requires a 20% dose decrease, there is currently no recommended interchange from iGlar300 to iDet100. OBJECTIVE: Compare the incidence of hypoglycemia in patients who received a 1:1 unit interchange from home iGlar300 or iGlar100 to iDet100 while admitted. METHODS: A retrospective study was conducted to evaluate adults within a multi-site network admitted between May and December 2019. Patients were included if they received at least one dose of iDet100 following interchange from home iGlar300 or iGlar100. The primary endpoint was the incidence of hypoglycemic events following a 1:1 interchange of iGlar300 vs. iGlar100 to inpatient iDet100. Secondary outcomes include overall hypoglycemic events, time to hypoglycemia, and doses given before hypoglycemia. RESULTS: Of 615 patients, 394 received a 1:1 unit interchange to iDet100 (52 from iGlar300 and 342 from iGlar100). Incidence of hypoglycemic events was significantly higher in those with a 1:1 interchange from iGlar300 versus iGlar100 (36.5% vs. 18.7%, p = 0.007). Significant differences were observed in overall hypoglycemic events, time to hypoglycemia, and number of doses given before hypoglycemic event. CONCLUSION AND RELEVANCE: A 1:1 unit interchange from iGlar300 to iDet100 led to a higher incidence of hypoglycemic events compared to those interchanged from iGlar100. Dose reduction should be considered when transitioning from home iGlar300 to iDet100 in the inpatient setting.

Efficacy and safety of insulin glargine 300 units/mL vs insulin degludec in patients with type 1 and type 2 diabetes: a systematic review and meta-analysis.

Background: Ultra-long-acting insulin analogs [insulin degludec (IDeg) and insulin glargine 300 units/mL (IGla-300)] offer a longer duration of action with less risk of hypoglycemia compared to other long-acting insulins. However, data about the comparative efficacy and safety are inconsistent. Methods: We searched CENTRAL, PubMed, Embase, ICTRP Search Portal, and ClinicalTrials.gov on 7 October 2022. Randomized controlled trials (RCTs) comparing the safety and efficacy of IDeg (100 or 200 units/mL) and IGla-300 in patients with type 1 or type 2 diabetes were included. Three review authors independently selected trials, assessed the risk of bias, extracted data, and evaluated the overall certainty of the evidence using GRADE. The primary outcomes were the change in glycated hemoglobin (HbA1c) and any hypoglycemia; the secondary outcomes were the change in fasting plasma glucose (FPG) and severe and nocturnal hypoglycemia. Results: Four open-label RCTs were included (2727 participants), 3 parallel and 1 cross-over. Overall, the risk of bias assessment yielded some concern or high risk. There was a comparable change in HbA1c from baseline to the end of treatment, a mean difference of 0.07% (95% confidence interval (CI) 0.06 - 0.19; p = 0.29; 3 trials; 2652 patients; very low-certainty evidence), and a comparable rate of any hypoglycemia, rate ratio 1.02 (95% CI 0.8 - 1.3; p = 0.87; 3 trials; 2881 patients; very low-certainty evidence). IDeg resulted in more reduction in FPG compared to IGla-300, mean difference of 10.27 mg/dL (95% CI 7.25 - 13.29; p < 0.001; 3 trials; 2668 patients; low-certainty evidence). Similar rates of nocturnal and severe hypoglycemia were observed, rate ratio of 1.13 (95% CI 0.72 - 1.78; p = 0.54; 3 trials; 2668 patients; very low-certainty evidence) and 1.4 (95% CI 0.41 - 4.73; p = 0.59; 2 trials; 1952 patients; very low-certainty evidence), respectively. Conclusion: There is no evidence of a difference between IDeg and IGla-300 in the mean change in HbA1c and the risk of anytime, nocturnal, and severe hypoglycemia. IDeg appeared to cause a higher reduction in FPG compared to IGla-300. However, this finding should be interpreted with caution due to the small number of trials included and their high risk of bias. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022364891, identifier CRD42022364891.

Insulin: evolution of insulin formulations and their application in clinical practice over 100 years.

The first preparation of insulin extracted from a pancreas and made suitable for use in humans after purification was achieved 100 years ago in Toronto, an epoch-making achievement, which has ultimately provided a life-giving treatment for millions of people worldwide. The earliest animal-derived formulations were short-acting and contained many impurities that caused adverse reactions, thereby limiting their therapeutic potential. However, since then, insulin production and purification improved with enhanced technologies, along with a full understanding of the insulin molecule structure. The availability of radio-immunoassays contributed to the unravelling of the physiology of glucose homeostasis, ultimately leading to the adoption of rational models of insulin replacement. The introduction of recombinant DNA technologies has since resulted in the era of both rapid- and long-acting human insulin analogues administered via the subcutaneous route which better mimic the physiology of insulin secretion, leading to the modern basal-bolus regimen. These advances, in combination with improved education and technologies for glucose monitoring, enable people with diabetes to better meet individual glycaemic goals with a lower risk of hypoglycaemia. While the prevalence of diabetes continues to rise globally, it is important to recognise the scientific endeavour that has led to insulin remaining the cornerstone of diabetes management, on the centenary of its first successful use in humans.

Efficacy and safety of insulin detemir versus glargine in patients with diabetes: a systematic review and meta-analysis.

OBJECTIVES: Performing an updated meta-analysis to compare the safety and efficacy of insulin glargine and insulin detemir in adults with type 1 and type 2 diabetes. METHODS: Electronic databases were searched up to 18 August 2021. A random-effects model was applied to pool data from included studies to calculate the standardized mean differences (SMDs) for the continuous variables and relative risks (RRs) for the dichotomous variable. RESULTS: Nine studies compared insulin detemir and insulin glargine in type 2 diabetes and three studies in patients with type 1 diabetes. The pooled SMD of weight gain was -0.59 (95% CI -1.05 to -0.14; P=0.01; I2=98%) in patients with type 2 diabetes. The pooled RR of severe hypoglycemia was 0.28 (95% CI 0.12 to 0.63; P=0.002; I2=0%) in patients with type 1 diabetes. The effects of detemir and glargine on HbA1c, fasting plasma glucose, nocturnal hypoglycemia, and overall hypoglycemia were not statistically different (P>0.05). CONCLUSIONS: It was found that there is no clinically considerable difference between the impacts of insulin detemir and insulin glargine in diabetic patients. The only statistically significant differences were less weight gain in type 2 diabetes and fewer episodes of severe hypoglycemia in type 1 diabetes with insulin detemir.