TITLE: Efficacy of injection technique education in diabetes with lipohypertrophy: a systematic review and meta-analysis protocol
AUTHORS: Masahiro Ichikawa, Tomoaki  Akiyama, Yasushi Tsujimoto, Keisuke  Anan, Tadashi Yamakawa, Yasuo Terauchi

[DESCRIPTION]
<div class = "text-blocks"><div class = "text-block">1.Introduction</div><div class = "text-block"><div class = "justify" style = "text-align:left">Many diabetic patients who use insulin develop changes in the subcutaneous adipose tissue at the injection site. These lesions are called lipohypertrophy (LH). The prevalence of LH was reported to be 30-50% or more (1). In a randomized crossover study, injections into sites of LH showed blunted insulin absorption and increased variability compared to injections into normal adipose tissues (2).</div></div><div class = "text-block"><div class = "justify" style = "text-align:left">Since sites of LH reduce the absorption of insulin, patients with LH often use higher total daily doses (TDD) of insulin and have worsened glycemic control and higher hyperglycemic hemoglobin (HbA1c) levels (3-5). LH may increase the risk of adverse clinical outcomes and the cost of healthcare.</div></div><div class = "text-block"><div class = "justify" style = "text-align:left">Recently, the effect of injection technique (IT) education to avoid the injection into LH and improve glycemic control on patients with LH has been reported (1, 6).IT education includes stopping injections into LH, stopping needle reuse, rotating injection site, and switching to 4 mm needles. However, no meta-analysis has been performed. Thus, to assess the impact of IT education on clinical and metabolic parameters in adults with LH, we will summarize current evidence.</div></div><div class = "text-block">2.Research question</div><div class = "text-block">P: Patients with type 1 diabetes or type 2 diabetes who are injecting insulin and have LH.</div><div class = "text-block">I: Injection technique education</div><div class = "text-block">C: standard care</div><div class = "text-block">O: change in TDD</div><div class = "text-block">3.Method</div><div class = "text-block">3.1 Protocol</div><div class = "text-block"><span>We used a systematic review protocol template(</span><a href="https://dx.doi.org/10.17504/protocols.io.biqrkdv6" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">dx.doi.org/10.17504/protocols.io.biqrkdv6</span></a><span>). We followed the Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 for preparing this protocol(7). We will publish this protocol in protocols.io (</span><a href="https://www.protocols.io" style = "text-decoration:underline;color:blue;cursor:pointer;"><span style = ":;">https://www.protocols.io/</span></a><span>).</span></div><div class = "text-block">3.2 Inclusion criteria of the articles for the review</div><div class = "text-block">3.2.1 Type of studies</div><div class = "text-block">We will include individual, cluster, and cross-over randomized trials that assess the injection technique education in patients with type 1 or type 2 diabetes who are injecting insulin and have LH. We will not apply language or country restrictions. We will include all papers including published, unpublished articles, abstract of conference and letter.</div><div class = "text-block">We will exclude observational studies and non randomized controlled trials. We will not exclude studies based on the observation period or publication year.</div><div class = "text-block">3.2.2 Study participants</div><div class = "text-block">We will includepatients with type 1 or type 2 diabetes who have been on insulin injections for at least 1 year, with LH, 18 years of age or older, any gender, no HbA1c restriction, and no education about LH within the past 6 months. The diagnosis of LH were made by a physician, nurse or investigators when it is clinically visible, palpable, or visible on ultrasound (8). We will accept any number of insulin injections per day, or size of needle for insulin injections.</div><div class = "text-block">We will exclude pregnant women, patients who wish to become pregnant, lactating women and patients taking medications that may cause LH (anti-retroviral or corticosteroid therapy).</div><div class = "text-block">3.2.3 Intervention</div><div class = "text-block">IT education: Stop injecting into the LH site, stop reusing needles, rotate injection sites, and switch to 4 mm needles. We will also include other education that aimed to improve lipohypertrophy and accept other definitions of IT education. Any education period is acceptable.</div><div class = "text-block">3.2.4 Control</div><div class = "text-block">Standard care (no intervention, usual care).</div><div class = "text-block">3.3 Type of outcomes</div><div class = "text-block">3.3.1 Primary outcomes</div><div class = "text-block">1.Change in total daily doses of insulin</div><div class = "text-block">Definition: Change in total daily doses of insulin from baseline</div><div class = "text-block">Period: Time frame is the longest follow-up period after 3 months</div><div class = "text-block">2. Change in HbA1c</div><div class = "text-block">Definition: Change in HbA1c from baseline</div><div class = "text-block">Period: Time frame is the longest follow-up period after 3 months</div><div class = "text-block">3. Hypoglycemia</div><div class = "text-block">Definition: Hypoglycaemia was defined as the occurrence of one or more symptoms of hypoglycaemia (such as palpitations, tiredness, sweating, strong hunger, dizziness and tremor) and a confirmed blood glucose meter reading of ≤ 60 mg/dL (4). We will also accept hypoglycemia as the original investigators defined.</div><div class = "text-block">Period: during follow up period</div><div class = "text-block">3.3.2 Secondary outcomes</div><div class = "text-block">1. Change in proportion of patients with cured LH</div><div class = "text-block">Definition: as original investigators defined</div><div class = "text-block">Period: Time frame is the longest follow-up period after 3 months</div><div class = "text-block">2. All adverse events</div><div class = "text-block">Definition: definition of adverse events are set by original authors.</div><div class = "text-block">Period: during follow up period</div><div class = "text-block">3.4 Search method</div><div class = "text-block">3.4.1 Electronic search</div><div class = "text-block">We will search the following databases:</div><div class = "text-block">1. the Cochrane Central Register of Controlled Trials (CENTRAL);</div><div class = "text-block">2. MEDLINE via PubMed;</div><div class = "text-block">3. EMBASE via ProQuest Dialog;</div><div class = "text-block">See Appendix 1, 2, and 3 for the search strategies.</div><div class = "text-block">3.4.2 Other resources</div><div class = "text-block">We will also search the following databases for ongoing or unpublished trials:</div><div class = "text-block">1. the World Health Organization International Clinical Trials Platform Search Portal (ICTRP);</div><div class = "text-block">2. ClinicalTrials.gov;</div><div class = "text-block">See Appendix 4, 5 for the search strategies.</div><div class = "text-block">We will check the reference lists of studies, including international guidelines as well as the reference lists of eligible studies and articles citing eligible studies. We will ask the authors of original studies for unpublished or additional data.</div><div class = "text-block">3.5 Data collection and analysis</div><div class = "text-block">3.5.1 Selection of the studies</div><div class = "text-block">Two independent reviewers will screen titles and abstracts, followed by the assessment of the eligibility based on the full texts. We will contact original authors if relevant data is missing. Disagreements between the two reviewers will be resolved by discussion, and if this fails, a third reviewer will act as an arbiter.</div><div class = "text-block">3.5.2 Data extraction and management</div><div class = "text-block">Two reviewers will perform independent data extraction of the included studies using standardized data collection form. </div><div class = "text-block">The form will include the information on the first author’s name, year of study publication, country, sample size, proportion of male participants, mean age of participants, the number of participants with type 1 diabetes mellitus/type 2 diabetes mellitus, estimated diabetic duration, mean duration of insulin treatment, intervention details, detection methods of LH and the outcome measures above. Any disagreements will be resolved by discussion, and if this fails, a third reviewer will act as an arbiter. </div><div class = "text-block">3.6 Assessment of risk of bias in included studies</div><div class = "text-block">Two reviewers will evaluate the risk of bias independently using the Risk of Bias 2 tool(9). The effect of interest is the intention-to-treat effect; the effect of assignment to the interventions at baseline, regardless of whether the interventions are received as intended. Disagreements between the two reviewers will be discussed, and if this fails, a third reviewer will be acting as an arbiter, if necessary.</div><div class = "text-block">3.7 Measures of treatment effects</div><div class = "text-block">We will pool the relative risk ratios and the 95% confidence intervals (CIs) for the following binary variables: Hypoglycemia, proportion of patients with cured LH and all adverse events</div><div class = "text-block">We will pool the mean differences and the 95% CIs for the following continuous variables: HbA1c, total daily doses of insulin</div><div class = "text-block">We will summarize adverse events based on the definition by the original article, but we will not perform meta-analysis..</div><div class = "text-block">3.8 Unit of analysis issues</div><div class = "text-block">Clustering at the level of the enrolled units in cluster randomised studies </div><div class = "text-block">In dealing with cluster-RCTs, for dichotomous data, we will apply the design effect and calculate effective sample size and number of events using the intracluster correlation coefficient (ICC) among each unit and the average cluster size, as described in Chapter 16.3.5 of the Cochrane Handbook (10). If the ICC has not been reported, we will use the ICC of a similar study as a substitute. For continuous data, only the sample size will be reduced; means and standard deviation will remain unchanged (10).</div><div class = "text-block">Randomised cross-over studies</div><div class = "text-block">We will consider only data from the first period.</div><div class = "text-block">Multiple comparisons</div><div class = "text-block">All intervention groups that are relevant to this review will be included.</div><div class = "text-block">3.9 Handling of missing data</div><div class = "text-block">We will ask not-presented data to the original authors.</div><div class = "text-block">3.9.1 Missing outcomes</div><div class = "text-block">We will perform the intention-to-treat (ITT) analysis for all dichotomous data as much as possible.</div><div class = "text-block">For continuous data, we will not impute missing data based on the recommendation by Cochrane handbook (10). We will perform meta-analysis about the available data in the original study.</div><div class = "text-block">3.9.2 Missing statistics</div><div class = "text-block">When original studies only report standard error or p-value, we will calculate the standard deviation based on the method by Altman (11). If we could not obtain these values by contacting authors, standard deviation will be calculated by confidence interval and t-value based on the method by Cochrane handbook (10), or validated method (11). Validity of these methods will be analyzed by sensitivity analysis.</div><div class = "text-block">3.10 Assessment of heterogeneity</div><div class = "text-block"><span>We will evaluate the statistical heterogeneity by visual inspection of the forest plots and calculating the I</span><span style = "vertical-align:super;">2</span><span>statistic (I</span><span style = "vertical-align:super;">2</span><span> values of 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity). When there is substantial heterogeneity (I</span><span style = "vertical-align:super;">2</span><span>> 50%), we will assess the reason of the heterogeneity. Cochrane Chi</span><span style = "vertical-align:super;">2 </span><span>test (Q-test) will be performed for I</span><span style = "vertical-align:super;">2</span><span> statistic, and P value less than 0.10 will be defined as statistically significant.</span></div><div class = "text-block">3.11 Assessment of reporting bias</div><div class = "text-block">We will search the clinical trial registry system (ClinicalTrials.gov and ICTRP) and will perform extensive literature search for unpublished trials. We will assess the potential publication bias by visual inspection of the funnel plot. Egger’s test will be performed as well. We will not conduct the test when we find less than 10 trials or trials which have similar sample size. We will assess the potential publication bias by visual inspection of the funnel plot</div><div class = "text-block">3.12 Meta-analysis</div><div class = "text-block">Meta-analysis will be performed using Review Manager software (RevMan 5.4). We will use a random-effects model.</div><div class = "text-block">3.13 Subgroup analysis</div><div class = "text-block">To elucidate the influence of effect modifiers on results, we will evaluate the subgroup analyses of the primary outcomes on the following factors when sufficient data are available.</div><div class = "text-block">1. age (<65 vs ≥65 years old)</div><div class = "text-block">2. baseline HbA1c <8% vs ≧8% (12)</div><div class = "text-block">3. gender</div><div class = "text-block">4. IT education protocols with versus without initial insulin reduction</div><div class = "text-block">3.14 Sensitivity analysis</div><div class = "text-block">We will undertake the following sensitivity analyses for the primary outcomes to assess whether the results of the review are robust to the decisions made during the review process. </div><div class = "text-block">1. Exclusion of studies using imputed statistics.</div><div class = "text-block">2. Exclusion of studies with high overall risk of bias</div><div class = "text-block">4. Summary of findings table</div><div class = "text-block">Summary of findings table will be made for the following outcome based on the Cochrane handbook (10).</div><div class = "text-block">We will include grading to evaluate the quality of evidence based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for each Summary of findings table (13).</div><div class = "text-block">1. Change in total daily doses of insulin</div><div class = "text-block">2. Change in HbA1c</div><div class = "text-block">3. Hypoglycemia</div><div class = "text-block">5. Conflict of Interest</div><div class = "text-block">The authors declare no conflicts of interests.</div><div class = "text-block">Appendix 1: CENTRAL search strategy</div><div class = "text-block">#1[mh Amyloidosis]</div><div class = "text-block">#2 lipohypertrophy:ti,ab</div><div class = "text-block">#3 "insulin-derived amyloidosis":ti,ab </div><div class = "text-block">#4lipos:ti,ab</div><div class = "text-block">#5 "subcutaneous induration":ti,ab</div><div class = "text-block">#6"subcutaneous nodules":ti,ab</div><div class = "text-block">#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6</div><div class = "text-block">#8 [mh "Injections, Subcutaneous"]</div><div class = "text-block">#9 [mh "Patient Education as Topic"]</div><div class = "text-block">#10injection*:ti,ab</div><div class = "text-block">#11 education*:ti,ab</div><div class = "text-block">#12 (reus*:ti,ab AND needle*:ti,ab)</div><div class = "text-block">#13 #8 OR #9 OR #10 OR #11 OR #12</div><div class = "text-block">#14 #7 AND #13</div><div class = "text-block">Appendix 2: MEDLINE (via PubMed) search strategy</div><div class = "text-block">#1 "Amyloidosis"[Mesh]</div><div class = "text-block">#2 "lipohypertrophy"[tiab]</div><div class = "text-block">#3 "insulin-derived amyloidosis"[tiab]</div><div class = "text-block">#4 "lipos"[tiab]</div><div class = "text-block">#5 "subcutaneous induration"[tiab]</div><div class = "text-block">#6 "subcutaneous nodules"[tiab]</div><div class = "text-block">#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6</div><div class = "text-block">#8 "Injections, Subcutaneous"[Mesh]</div><div class = "text-block">#9 "Patient Education as Topic"[Mesh]</div><div class = "text-block">#10 injection*[tiab] </div><div class = "text-block">#11 education*[tiab] </div><div class = "text-block">#12 reus*[tiab] AND needle*[tiab]</div><div class = "text-block">#13 #8 OR #9 OR #10 OR #11 OR #12</div><div class = "text-block">#14 #7 AND #13</div><div class = "text-block">#15 randomized controlled trial[pt]</div><div class = "text-block">#16 controlled clinical trial[pt]</div><div class = "text-block">#17 randomized[tiab]</div><div class = "text-block">#18 placebo[tiab]</div><div class = "text-block">#19 drug therapy[sh]</div><div class = "text-block">#20 randomly[tiab]</div><div class = "text-block">#21 trial[tiab]</div><div class = "text-block">#22 groups[tiab]</div><div class = "text-block">#23 #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22</div><div class = "text-block">#24 animals[mh] NOT humans[mh]</div><div class = "text-block">#25 #23 NOT #24</div><div class = "text-block">#26 #14 AND #25</div><div class = "text-block">Appendix 3: EMBASE (via ProQuest Dialog) search strategy</div><div class = "text-block">#1 emb(amyloidosis) OR ti(lipohypertrophy) OR ab(lipohypertrophy) OR ti(insulin-derived amyloidosis) OR ab(insulin-derived amyloidosis) OR ti(lipos) OR ab(lipos) OR ti(subcutaneous induration) OR ab(subcutaneous induration) OR ti(subcutaneous nodules) OR ab(subcutaneous nodules) </div><div class = "text-block">#2 exact(subcutaneous drug administration) OR exact(patient education) OR ti(injection*) OR ab(injection*) OR ti(education*) OR ab(education*) OR (ti(reus*) OR ab(reus*)) AND (ti(needle*) OR ab(needle*)) </div><div class = "text-block">#3 (ab(random*) OR ti(random*)) OR (ab(clinical NEAR/1 trial*) OR ti(clinical NEAR/1 trial*)) OR (EMB.EXACT("health care quality"))</div><div class = "text-block">#4 #1 AND #2 AND #3</div><div class = "text-block">Appendix 4: ICTRP search strategy</div><div class = "text-block">Participant: lipohypertrophy OR insulin-derived amyloidosis OR subcutaneous induration OR subcutaneous nodules</div><div class = "text-block">Intervention: injection OR education OR (reus AND needle)</div><div class = "text-block">Appendix 5: ClinicalTrials.gov search strategy</div><div class = "text-block">Condition or disease: lipohypertrophy OR insulin-derived amyloidosis OR subcutaneous induration OR subcutaneous nodules</div><div class = "text-block">Intervention: injection OR education OR (reus AND needle)</div><div class = "text-block">References</div><div class = "text-block">1.Chen L, Xing Q, Li J, Zhou J, Yuan Y, Wan Y, et al. Injection Technique Education in Patients with Diabetes Injecting Insulin into Areas of Lipohypertrophy: A Randomized Controlled Trial. Diabetes Ther. 2021.</div><div class = "text-block">2.Famulla S, Hövelmann U, Fischer A, Coester H-V, Hermanski L, Kaltheuner M, et al. Insulin Injection Into Lipohypertrophic Tissue: Blunted and More Variable Insulin Absorption and Action and Impaired Postprandial Glucose Control. Diabetes Care. 2016;39(9):1486-92.</div><div class = "text-block">3.Frid AH, Hirsch LJ, Menchior AR, Morel DR, Strauss KW. Worldwide Injection Technique Questionnaire Study: Injecting Complications and the Role of the Professional. Mayo Clinic proceedings. 2016;91(9):1224-30.</div><div class = "text-block">4.Blanco M, Hernández MT, Strauss KW, Amaya M. Prevalence and risk factors of lipohypertrophy in insulin-injecting patients with diabetes. Diabetes Metab. 2013;39(5):445-53.</div><div class = "text-block">5.Ji L, Sun Z, Li Q, Qin G, Wei Z, Liu J, et al. Lipohypertrophy in China: Prevalence, Risk Factors, Insulin Consumption, and Clinical Impact. Diabetes Technol Ther. 2017;19(1):61-7.</div><div class = "text-block">6.Campinos C, Le Floch JP, Petit C, Penfornis A, Winiszewski P, Bordier L, et al. An Effective Intervention for Diabetic Lipohypertrophy: Results of a Randomized, Controlled, Prospective Multicenter Study in France. Diabetes Technol Ther. 2017;19(11):623-32.</div><div class = "text-block"><div class = "justify" style = "text-align:left"><span>7. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. </span><span style = "font-style:italic;">BMJ</span><span>. 2015;349(jan02 1):g7647-g7647. doi:10.1136/bmj.g7647</span></div></div><div class = "text-block"><div class = "justify" style = "text-align:left">8.Deg N,Zhang X, Zhao F, Wang Y, He H. Prevalence of lipohypertrophy in insulin-treated diabetes patients: A systematic review and meta-analysis. 2018;9(3):536-43.</div></div><div class = "text-block"><div class = "justify" style = "text-align:left"><span>9. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. </span><span style = "font-style:italic;">BMJ</span><span>. August 2019:l4898. doi:10.1136/bmj.l4898</span></div></div><div class = "text-block"><div class = "justify" style = "text-align:left">10. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019.</div></div><div class = "text-block"><div class = "justify" style = "text-align:left"><span>11. Furukawa T a, Barbui C, Cipriani A, Brambilla P, Watanabe N. 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