Long-acting insulin analogues for type 1 diabetes: An overview of systematic reviews and meta-analysis of randomized controlled trials.

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hypoglycemia 1691 LAIA glargine or detemir, compared to NPH insulin for T1D, assessing glycated hemoglobin (A1C) and hypoglycemia . Data sources included Pubmed, Cochrane Library, EMBASE and hand-searching. The methodological quality
hypoglycemia 2148 evidence that LAIA are efficacious compared to NPH, with estimates showing a reduction in nocturnal hypoglycemia episodes (RR 0.66; 95% CI 0.57; 0.76) and A1C (95% CI 0.23; 0.12). No significance was found related
hypoglycemia 2272 (RR 0.66; 95% CI 0.57; 0.76) and A1C (95% CI 0.23; 0.12). No significance was found related to severe hypoglycemia (RR 0.94; 95% CI 0.71; 1.24).ConclusionThis study design has allowed us to carry out the most comprehensive
hypoglycemia 5266 long-acting insulin analogues are effective and safe for T1D patients compared to NPH in reduction of hypoglycemia and maintenance or improvement of glycemic control.Materials and methodsWe performed an overview of
hypoglycemia 6331 included at least one of the primary outcomes related to efficacy (A1C, and general, severe and nocturnal hypoglycemia ).In cases of eligible systematic reviews that included RCTs and other study designs, we included these
hypoglycemia 7361 analyzed only rapid-acting insulin analogues as the intervention, or assessed outcomes other than A1C and hypoglycemia .To update the included systematic reviews, we performed a separate search for RCTs assessing long-acting
hypoglycemia 7716 the end of study and baseline or the measures of the baseline and the end of study independently) and hypoglycemia , considering the categories: general, severe and nocturnal (in terms of number of episodes or rate of
hypoglycemia 12903 in cases of no reply, we assumed SD = 0.05. For dichotomous variables (general, severe and nocturnal hypoglycemia ), we used the number of episodes per person-week, which is calculated by dividing the total number of
hypoglycemia 13109 number of episodes in each group by the number of persons in each group adjusted by the time until a hypoglycemia occurs. When studies reported only the rate of episodes per person-time (time other than a week), we
hypoglycemia 13377 episodes. For cross-over trials, we considered the A1C mean difference in the first period and the sum of hypoglycemia episodes in both periods of analysis. For trials that analyzed two intervention groups (i.e.: the same
hypoglycemia 13595 drug but different frequency or time of injection), we considered the best A1C results and summed the hypoglycemia episodes of both groups. This was different from Rossetti and colleagues [[19]], who yielded the hypoglycemia
hypoglycemia 13705 hypoglycemia episodes of both groups. This was different from Rossetti and colleagues [[19]], who yielded the hypoglycemia results as episodes per person-time, thus we considered the best results, as it was impossible to sum
hypoglycemia 15017 confidence intervals by DerSimonian & Laird method. For dichotomous data (general, severe and nocturnal hypoglycemia ) we calculated the relative risk as the effect measure. The measure for any type of hypoglycemia considered
hypoglycemia 15114 nocturnal hypoglycemia) we calculated the relative risk as the effect measure. The measure for any type of hypoglycemia considered in the analysis was number of episodes per person-week, so the relative risk should be interpreted
hypoglycemia 16863 insulin analogues; (f) if study design was cross-over or not; (g) follow-up period; (h) definition of hypoglycemia (just for general hypoglycemia); and if study had provided standard deviation for A1C measures.We assessed
hypoglycemia 16894 design was cross-over or not; (g) follow-up period; (h) definition of hypoglycemia (just for general hypoglycemia ); and if study had provided standard deviation for A1C measures.We assessed the potential for publication
hypoglycemia 23314 Concerning quantitative analysis, the outcomes that were most frequently analyzed were A1C and general hypoglycemia (25 trials).In relation to A1C, the long-acting insulin analogue yielded a statistically significant
hypoglycemia 23859 [[67]].10.1371/journal.pone.0194801.g002Fig 2Meta-analysis of outcomes assessed in this overview: A: glycated hemoglobin—A1C; B: general hypoglycemia ; C: severe hypoglycemia; D: nocturnal hypoglycemia.Regarding hypoglycemia, its definition varied among
hypoglycemia 23883 outcomes assessed in this overview: A: glycated hemoglobin—A1C; B: general hypoglycemia; C: severe hypoglycemia ; D: nocturnal hypoglycemia.Regarding hypoglycemia, its definition varied among the analyzed trials.
hypoglycemia 23910 overview: A: glycated hemoglobin—A1C; B: general hypoglycemia; C: severe hypoglycemia; D: nocturnal hypoglycemia .Regarding hypoglycemia, its definition varied among the analyzed trials. Furthermore, authors have classified
hypoglycemia 23933 hemoglobin—A1C; B: general hypoglycemia; C: severe hypoglycemia; D: nocturnal hypoglycemia.Regarding hypoglycemia , its definition varied among the analyzed trials. Furthermore, authors have classified hypoglycemia
hypoglycemia 24033 hypoglycemia, its definition varied among the analyzed trials. Furthermore, authors have classified hypoglycemia into many categories, such as general, overall, minor, severe, major, symptomatic, all-day, day and
hypoglycemia 24547 the general or severe class, depending on the applied definition in the studies.Considering general hypoglycemia , the meta-analysis showed a statistically significant difference between the insulin analogue and NPH
hypoglycemia 24831 effect was statistically significant, its magnitude and clinical significance were small.Data for severe hypoglycemia were usefully available from 16 studies (Fig 2C). Concerning this outcome, the pooled estimate of all
hypoglycemia 25158 significant results compared to NPH, revealing a RR = 0.94 (95% CI 0.71; 1.24; I2 94.7%).Concerning nocturnal hypoglycemia , it was available from 20 clinical trials, and the meta-analysis results favor insulin analogues (RR
hypoglycemia 25688 by duration of the study, but not statistically significant (p = 0.16). The heterogeneity in general hypoglycemia was explained in 26.13% by bolus insulin (p = 0.01), in 13.96% by hypoglycemia definition (p = 0.10),
hypoglycemia 25767 heterogeneity in general hypoglycemia was explained in 26.13% by bolus insulin (p = 0.01), in 13.96% by hypoglycemia definition (p = 0.10), and in 7.16% by duration of study (p = 0.10). For nocturnal hypoglycemia, it
hypoglycemia 25863 by hypoglycemia definition (p = 0.10), and in 7.16% by duration of study (p = 0.10). For nocturnal hypoglycemia , it was explained in 23.71% by crossover design (p = 0.08) and in 13.55% by intervention brand (p =
hypoglycemia 25994 in 23.71% by crossover design (p = 0.08) and in 13.55% by intervention brand (p = 0.08). For severe hypoglycemia , heterogeneity was marginally explained by age in 3.84% (p = 0.29).Analysis of publication biasVisual
hypoglycemia 26149 age in 3.84% (p = 0.29).Analysis of publication biasVisual inspection of Begg’s funnel plots for hypoglycemia endpoints (Fig 3A, 3B and 3C) showed a tendency of published trial results to have a small risk of publication
hypoglycemia 26383 the Egger’s test confirmed this direction for general (p = 0.75), severe (p = 0.68), and nocturnal hypoglycemia (p = 0.74). However, A1C studies were very dispersed (Fig 3D), suggesting that there is publication
hypoglycemia 26678 0.05).10.1371/journal.pone.0194801.g003Fig 3Publication bias analysis by Begg’s funnel plots.A. General hypoglycemia . B. Severe hypoglycemia. C. Nocturnal hypoglycemia. D A1C.DiscussionTo the best of our knowledge, this
hypoglycemia 26702 0.05).10.1371/journal.pone.0194801.g003Fig 3Publication bias analysis by Begg’s funnel plots.A. General hypoglycemia. B. Severe hypoglycemia . C. Nocturnal hypoglycemia. D A1C.DiscussionTo the best of our knowledge, this study is the first overview
hypoglycemia 26729 bias analysis by Begg’s funnel plots.A. General hypoglycemia. B. Severe hypoglycemia. C. Nocturnal hypoglycemia . D A1C.DiscussionTo the best of our knowledge, this study is the first overview of systematic reviews
hypoglycemia 27270 insulin analogues are efficacious compared to NPH, with estimates showing a reduction in nocturnal hypoglycemia episodes (RR 0.66) and general hypoglycemia episodes (RR = 0.95). Further results showed a non-clinically
hypoglycemia 27314 to NPH, with estimates showing a reduction in nocturnal hypoglycemia episodes (RR 0.66) and general hypoglycemia episodes (RR = 0.95). Further results showed a non-clinically significance reduction in A1C.Our study
hypoglycemia 27667 [[28],[30]]. Of the 11 reviews included in this overview, only three [[28],[30],[31]] reported the measure of hypoglycemia as episodes per person-time, as recommended by methodological guidelines [[15],[68]]. The other reviews
hypoglycemia 27827 methodological guidelines [[15],[68]]. The other reviews [[10],[11],[26],[29],[32]–[34]] reported hypoglycemia as the risk of having at least one event during the study (number of people who had hypoglycemia / number
hypoglycemia 27924 reported hypoglycemia as the risk of having at least one event during the study (number of people who had hypoglycemia / number of people in the study group). This is a misconception, given that each person could experience
hypoglycemia 28651 and collaborators [[30]], in a Cochrane review, yielded comparable results to our overview concerning hypoglycemia . Results showed the reduction was not statistically significant in general hypoglycemia (OR 0.93; 95%
hypoglycemia 28739 concerning hypoglycemia. Results showed the reduction was not statistically significant in general hypoglycemia (OR 0.93; 95% CI 0.8; 1.08) (30). For severe hypoglycemia, for which overview results were not statistically
hypoglycemia 28797 not statistically significant in general hypoglycemia (OR 0.93; 95% CI 0.8; 1.08) (30). For severe hypoglycemia , for which overview results were not statistically significant, Vardi and colleagues showed a reduction
hypoglycemia 28968 significant, Vardi and colleagues showed a reduction of 27% (OR 0.73; 95% CI 0.61; 0.87) and for nocturnal hypoglycemia , the results were in the same direction, with a significant reduction favouring insulin analogue (OR
hypoglycemia 29204 0.79) [[30]]. The results of Singh and colleagues’ review [[31]] are very similar to ours. Nocturnal hypoglycemia was reduced in insulin analogues in 35% (OR 0.65; 95% CI 0.55;0.77) [[31]].Regarding clinical trials,
hypoglycemia 29465 are usually misunderstood. Considering dose titration phases, the proportion of patients experiencing hypoglycemia episodes during the titration period was higher for insulin analogues than for NPH in the first trials
hypoglycemia 29835 analogues. Thus, a substantial number of hypos in the analogues group was noted. In conclusion, neither hypoglycemia episodes nor A1C in the titration period should be included in the results, according to Food and Drug
hypoglycemia 30276 studied” [[69]].Two other major challenges when analyzing RCTs in T1D are the different ways of measuring hypoglycemia and the short follow-up of studies. Regarding the definition of hypoglycemia, this varies across the
hypoglycemia 30353 different ways of measuring hypoglycemia and the short follow-up of studies. Regarding the definition of hypoglycemia , this varies across the studies (<2.0 mmol / L, <2.8 mmol / L, <3.1 mmol / L, <4.0 mmol / L), contributing
hypoglycemia 30509 / L, <2.8 mmol / L, <3.1 mmol / L, <4.0 mmol / L), contributing 14% to the heterogeneity of general hypoglycemia in our analysis. Recommendations from the American Diabetes Association Workgroup on Hypoglycemia [[72]]
hypoglycemia 30729 and the International Society for Pediatric and Adolescent Diabetes [[73]], which stratify and define hypoglycemia appropriately, have been published. However, many of the studies, published later than these recommendations,
hypoglycemia 32560 primary role in the algorithm for treating T1D is to improve glucose control and decrease the risk of hypoglycemia . Therefore, since A1C is an average of the glycaemia of the last three months, we can see the fact that
hypoglycemia 32719 glycaemia of the last three months, we can see the fact that these insulins decrease the occurrence of hypoglycemia (lower limit of the mean) as positive, providing maintenance or even little improvement of A1C [[74]],
hypoglycemia 33087 most explained the heterogeneity were bolus insulin (26%) and definition of hypo (14%) for general hypoglycemia , cross-over design (23%) and intervention brand (13%) for nocturnal hypoglycemia, and Jadad score (16%)
hypoglycemia 33168 (14%) for general hypoglycemia, cross-over design (23%) and intervention brand (13%) for nocturnal hypoglycemia , and Jadad score (16%) for A1C. Two other factors have influenced the inconsistency of the results,

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