Comparative cardiovascular morbidity and mortality in patients taking different insulin regimes for type 2 diabetes: A systematic review Search Question: What is the impact of insulin type, does and regime on the incidence of cardiovascular disease in adult type 2 diabetes patients taking insulin? Information Sources Searches were conducted in the following databases: The Cochrane Library (Trials and Technology Assessments), PubMed/MEDLINE, EMBASE, and International Pharmaceutical Abstracts (IPA) to identify randomized controlled trails, cohort studies, or case-control studies relevant to the search question. The reference lists of all relevant studies were hand searched for relevant articles. Search A combination of MeSH, EMTREE, and free text search terms were employed based on the database being searched. Search filters including Humans, Age 18, and English language were used where appropriate and applicable. There were no restrictions on publication date or publication status. In the Embase database, lines of free text words in the search strategy were searched within the Advanced Search window with the Map to preferred terminology (with spell check) and Also search as free text boxes selected, and the Include sub-terms/derivatives (explosion search) box deselected. In The Cochrane Library only results within the Trials and the Technology Assessments databases were retrieved. In the IPA database, lines of free text words in the search strategy were searched with the TX All Text option in the dropdown menu selected. No filters were applied due to limited filter options. PubMed/MEDLINE: 1) "Insulins"[Mesh] 2) "Cardiovascular Diseases/adverse effects"[mesh] OR "Cardiovascular Diseases/chemically induced"[mesh] OR "Cardiovascular Diseases/complications"[Mesh] OR "Cardiovascular Diseases/drug effects"[mesh] OR "Cardiovascular Diseases/drug therapy"[mesh] OR "Cardiovascular Diseases/mortality"[Mesh] OR "Cardiovascular Diseases/pharmacology"[Mesh] OR "Cardiovascular Diseases/therapy"[Mesh] 1
3) "Diabetes Mellitus, Type 2/complications"[Mesh] OR "Diabetes Mellitus, Type 2/drug therapy"[mesh] OR "Diabetes Mellitus, Type 2/epidemiology"[Mesh] OR "Diabetes Mellitus, Type 2/mortality"[Mesh] OR "Diabetes Mellitus, Type 2/prevention and control"[mesh] OR "Diabetes Mellitus, Type 2/therapy"[Mesh] 5) insulin regime[tw] OR insulin schedule[tw] OR insulin tim*[tw] OR insulin us*[tw] OR insulin dos*[tw] OR insulin administration[tw] OR insulin quantit*[tw] OR insulin shot*[tw] OR insulin measure*[tw] 6) bolus[tw] OR prandial[tw] OR rapid acting[tw] OR analogue*[tw] OR aspart[tw] OR novorapid[tw] OR glulisine[tw] OR apidra[tw] OR lispro[tw] OR humalog[tw] OR short acting[tw] OR regular[tw] OR humulin[tw] OR novolin[tw] 7) basal[tw] OR intermediate acting[tw] OR NPH[tw] OR neutral protamine hagedorn [tw] OR long acting[tw] OR detemir[tw] OR levemir[tw] OR glargine[tw] OR lantus[tw] 8) premixed[tw] OR regular[tw] OR humulin 30/70 [tw] OR novolin ge 30/70 [tw] OR novolin ge 40/60 [tw] OR novolin ge 50/50 [tw] OR biphasic[tw] OR biphasic insulin aspart [tw] OR aspart[tw] OR novomix[tw] OR novomix 30 [tw] OR insulin lispro[tw] OR lispro[tw] OR lispro protamine suspension[tw] OR lispro protamine suspension [tw] OR Humalog mix25[tw] OR Humalog mix50[tw] 11) diabetes[tw] 12) Type 2[tw] OR type ii[tw] OR NIDDM[tw] OR noninsulin dependent[tw] OR matur* onset[tw] OR adult onset[tw] OR late onset[tw] OR T2DM[tw] 14) cardiovascular disease[tw] OR heart disease[tw] OR macrovascular[tw] OR cardio*[tw] OR myocardial infarction[tw] OR MI[tw] OR stroke[tw] OR cerebrovascular[tw] OR cerebro*[tw] OR major adverse cardiovascular event [tw] OR major adverse coronary event [tw] OR MACE[tw] OR all cause mortality[tw] 15) fatal[tw] OR non fatal[tw] OR dea*[tw] OR mortalit*[tw] OR event[tw] OR inciden*[tw] OR accident[tw] OR adverse outcome*[tw] OR complication*[tw] OR adverse event*[tw] OR disorder*[tw] OR ill*[tw] 16) #14 AND #15 17) #10 AND #13 AND #16 18) #4 OR #17 19) #18 Filters: Humans; English; Adult: 19+ years 2
EMBASE: 1) 'insulin'/exp 2) 'cardiovascular disease'/exp/dm_dt,dm_th,dm_co,dm_si,dm_dm 3) 'non insulin dependent diabetes mellitus'/exp/dm_dt,dm_th,dm_co,dm_ep,dm_pc 5) 'insulin'/exp OR 'insulin' AND regime OR 'insulin'/exp OR 'insulin' AND schedule OR 'insulin'/exp OR 'insulin' AND tim* OR 'insulin'/exp OR 'insulin' AND itinerary OR 'insulin'/exp OR 'insulin' AND us* OR 'insulin'/exp OR 'insulin' AND dos* OR 'insulin'/exp OR 'insulin' AND administration OR 'insulin'/exp OR 'insulin' AND quantit* OR 'insulin'/exp OR 'insulin' AND shot* OR 'insulin'/exp OR 'insulin' AND measure* 6) bolus OR prandial OR rapid AND acting OR analogue* OR aspart OR 'novorapid'/de OR novorapid OR 'glulisine'/de OR glulisine OR 'apidra'/de OR apidra OR 'lispro'/de OR lispro OR 'humalog'/de OR humalog OR short AND acting OR regular OR 'humulin'/de OR humulin OR 'novolin'/de OR novolin 7) basal OR intermediate AND acting OR 'nph'/de OR nph OR 'neutral protamine hagedorn' OR long AND acting OR 'long acting basal analogues' OR 'long-acting basal analogues' OR detemir OR 'levemir'/de OR levemir OR glargine OR 'lantus'/de OR lantus 8) premixed OR regular OR 'premixed regular nph' OR 'humulin 30/70'/de OR 'humulin 30/70' OR 'novolin ge 30/70'/de OR 'novolin ge 30/70' OR 'novolin ge 40/60' OR 'novolin ge 50/50' OR biphasic OR 'biphasic insulin aspart' OR aspart OR 'novomix'/de OR novomix OR 'novomix 30'/de OR 'novomix 30' OR 'insulin'/de OR insulin AND ('lispro'/de OR lispro) OR 'lispro'/de OR lispro AND ('protamine'/de OR protamine) AND ('suspension'/de OR suspension) OR 'lispro protamine suspension' OR 'humalog'/de OR humalog AND mix25 OR 'humalog'/de OR humalog AND mix50 11) 'diabetes'/de OR diabetes 12) type AND 2 OR type AND ii OR 'niddm'/de OR niddm OR noninsulin AND dependent OR matur* AND onset OR 'adult'/de OR adult AND onset OR late AND onset OR t2dm OR 'glucose'/de OR glucose AND intolerance OR hyperglyc?emi* 14) cardiovascular AND ('disease'/de OR disease) OR 'heart'/de OR heart AND ('disease'/de OR disease) OR macrovascular OR cardio* OR myocardial AND ('infarction'/de OR infarction) OR mi OR 'stroke'/de OR stroke OR cerebrovascular OR cerebro* OR 'major adverse cardiovascular event'/de OR 'major adverse cardiovascular event' OR 'major adverse coronary event' OR 'mace'/de OR mace OR all AND cause AND ('mortality'/de OR mortality) 15) fatal OR non AND fatal OR dea* OR mortalit* OR event OR inciden* OR 'accident'/de OR accident OR adverse AND outcome* OR complication* OR adverse AND event* OR disorder* OR ill* 3
16) #14 AND #15 17) #10 AND #13 AND #16 18) #4 OR #17 19) #18 AND [english]/lim AND ([adult]/lim OR [aged]/lim) The Cochrane Library: 1) insulin 2) cardiovascular disease 3) type 2 diabetes 5) insulin regime OR insulin schedule OR insulin tim* OR insulin itinerary OR insulin us* OR insulin dose OR insulin administration OR insulin quantit* OR insulin shot OR insulin measure 6) bolus OR prandial OR rapid acting OR analogue* OR aspart OR novorapid OR glulisine OR apidra OR lispro OR humalog OR short acting OR regular OR humulin OR novolin 7) basal OR intermediate acting OR NPH OR neutral protamine hagedorn OR long acting OR long acting basal analogues OR detemir OR levemir OR glargine OR lantus 8) premixed OR regular OR premixed regular NPH OR humulin 30/70 OR novolin ge 30/70 OR novolin OR novolin ge 40/60 OR novolin ge 50/50 OR biphasic OR biphasic insulin aspart OR aspart OR novomix OR novomix 30 OR insulin lispro OR lispro OR lispro protamine suspension OR Humalog 11) diabetes 12) Type 2 OR type ii OR NIDDM OR noninsulin dependent OR mature onset OR adult onset OR late onset OR T2DM OR glucose intolerance OR hyperglyc?emi* 14) cardiovascular disease OR heart disease OR macrovascular OR cardio* OR myocardial infarction OR MI OR stroke OR cerebrovascular OR cerebro* OR major adverse cardiovascular event OR major adverse coronary event OR MACE OR all cause mortality 15) fatal OR non fatal OR dea* OR mortalit* OR event OR inciden* OR accident OR adverse outcome OR complication* OR adverse event OR disorder* OR ill* 16) #14 AND #15 4
17) #10 AND #13 AND #16 18) #4 OR #17[in Trials, and Technology Assessments] International Pharmaceutical Abstracts 1) insulin 2) cardiovascular disease 3) non-insulin dependent diabetes 4) S1 AND S2 AND S3 5) insulin regime OR insulin schedule OR insulin tim* OR insulin itinerary OR insulin us* OR insulin dos* OR insulin administration OR insulin quantit* OR insulin shot* OR insulin measure* 6) bolus OR prandial OR rapid acting OR analogue* OR aspart OR novorapid OR glulisine OR apidra OR lispro OR humalog OR short acting OR regular OR humulin OR novolin 7) basal OR intermediate acting OR NPH OR neutral protamine hagedorn OR long acting OR long acting basal analogues OR long-acting basal analogues OR detemir OR levemir OR glargine OR lantus 8) premixed OR regular OR premixed regular NPH OR humulin 30/70 OR novolin ge 30/70 OR novolin ge 40/60 OR novolin ge 50/50 OR biphasic OR biphasic insulin aspart OR aspart OR novomix OR novomix 30 OR insulin lispro OR lispro OR lispro protamine suspension OR lispro protamine suspension OR Humalog mix25 OR Humalog mix50 9) S6 OR S7 OR S8 10) S5 OR S9 11) diabetes 12) Type 2 OR type ii OR NIDDM OR noninsulin dependent OR matur* onset OR adult onset OR late onset OR T2DM OR glucose intolerance OR hyperglyc?emi* 13) S11 AND S12 14) cardiovascular disease OR heart disease OR macrovascular OR cardio* OR myocardial infarction OR MI OR stroke OR cerebrovascular OR cerebro* OR major adverse cardiovascular event OR major adverse coronary event OR MACE OR all cause mortality 15) fatal OR non fatal OR dea* OR mortalit* OR event OR inciden* OR accident OR adverse outcome* OR complication* OR adverse event* OR disorder* OR ill* 16) S16 AND S17 17) S10 AND S13 AND S16 18) S4 OR S17 5