Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

Bronsveld, Heleen K; ter Braak, Bas; Karlstad, Øystein; Vestergaard, Peter; Starup-Linde, Jakob; Bazelier, Marloes T; De Bruin, Marie L; de Boer, Anthonius; Siezen, Christine L E; van de Water, Bob; van der Laan, Jan Willem; Schmidt, Marjanka K

doi:10.1186/s13058-015-0611-2

Table 3 Relative risk estimations for breast cancer among insulin treatment groups and the evaluation of bias and power of the studies

From: Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

Author, year	Exposure of interest	Exposure comparison group	Cases/controls* or cases/person-years** in exposure group (number)	Cases/controls* or cases/person-years**in comparison group (number)	Risk Ratio**	95 % CI	Risk of bias	Power
Any insulin-no insulin: hazard ratio
Carstensen et al., 2012 [43]	Insulin users	No insulin users	248/102,500	2,118/627,100	0.96	0.84, 1.09	Moderate	Adequate
Ferrara et al., 2011 [48]	Insulin users	No insulin users	NR	NR	1.0	0.9, 1.2	Moderate	Adequate
Neumann et al., 2012 [60]	Insulin users	No insulin users	NR/NR*	NR/NR*	0.86	0.81, 0.91	High	Adequate
Onitilo et al., 2014 [61]	Insulin users	No insulin users	NR/NR*	NR/NR*	0.84	0.58, 1.23	High	Too low
Any insulin-no insulin: odds ratio
Bodmer et al., 2010a [41]	Insulin users	No insulin users	43/131	262/1,022	NE	NE	High	Too low
Cleveland et al., 2012 [45]	Insulin users	No insulin users	20/16	50/49	1.15	0.40, 3.40	High	Too low
Any insulin-NIAD: hazard ratio
Currie et al., 2009a [6]	Insulin users	Metformin only	NR/12,640*	NR/34,847*	1.07	0.79, 1.44	Moderate	Too low
Redaniel et al., 2012a [62]	Insulin and NIAD users	Sulfonylurea only users	33/8,233.8	93/27,308.2	1.23	0.63, 2.38	Low	Too low
Redaniel et al., 2012b [62]	Insulin only users	Sulfonylurea only users	8/2,247.3	93/27,308.2	1.67	0.70, 3.99	Low	Too low
Vallarino et al., 2013****** [67]	Pioglitzone users, not using insulin	Insulin users, not using pioglitazone	181/29,721	113/13,680	0.85	0.67, 1.08	High	Low
Any insulin-NIAD: odds ratio
Hsieh et al., 2012 [53]	Insulin only users	Metformin only users	5/NR	19/NR	1.63	0.60, 4.40	High	Too low
Koro et al., 2007a [54]	Insulin and NIAD users	TZD users	13/52	83/449	0.71	0.36, 1.37	High	Too low
Koro et al., 2007b [54]	Insulin only users	TZD users	9/62	83/449	1.27	0.61, 2.67	High	Too low
Glargine-no glargine: hazard ratio
Bordeleau et al., 2014***** [42]	Glargine users	Standard care, not using glargine	28/11,620*	28/12,845*	1.15	0.67, 1.97	Low	Too low
Home and Lagarenne, 2009***** [52]	Glargine users	Any anti-diabetic drug, NPH in 20 studies	4/4,711	6/4,524	0.62	0.17, 2.18	Moderate	Too low
Rosenstock et al., 2009 [63]	Glargine users	NPH users	3/2,144	5/2,096	0.90	0.64, 1.26	Low	Too low
Chang et al., 2011***** [44]	Glargine users, not using int-/long-acting HI	Non-glargine int/long-acting HI users	6/6,558.8*	65/47,724.6*	0.53	0.21, 1.31	Moderate	Too low
Colhoun et al., 2009a [5]	Glargine plus non-glargine insulin users	Non-glargine insulin users	0/NR	29/9,667*	NE	NE	High	Too low
Colhoun et al., 2009b***** [5]	Glargine only users	Non-glargine insulin users	6/1,200*	29/9,667*	1.47	0.59, 3.64	High	Too low
Currie et al., 2009b***** [6]	Glargine users	Non-glargine insulin users	10/2,245*	38/8,102*	0.86	0.42, 1.75	Moderate	Too low
Fagot et al., 2013a***** [47]	Glargine users	Other int-/long-acting insulin only users	114/42,129*	40/14,082*	1.08	0.72, 1.62	High	Too low
Habel et al., 2013a**** * [51]	Glargine users	NPH insulin users	52/10,614.8	217/60,868.1	1.3	1.0, 1.8	Moderate	Too low
Habel et al., 2013b [51]	Glargine only users	NPH insulin users	33/6,402.4	217/60,868.1	1.3	0.9, 2.0	Moderate	Too low
Habel et al., 2013c [51]	Glargine and NPH insulin users	NPH insulin users	19/4,212.5	217/60,868.1	1.3	0.8, 2.0	Moderate	Too low
Kostev et al., 2012a***** [55]	Glargine users	NPH insulin users	NR	NR	0.93	0.68, 1.27	High	Too low
Lind et al., 2012a***** [56]	Glargine users	Non-glargine users	19/7,019.4	96/48,889.6*	1.54	0.90, 2.67	Moderate	Too low
Morden et al., 2011a [59]	Glargine plus non-glargine insulin users	Non-glargine insulin users	102/18,889*	333/65,294*	1.08	0.86, 1.36	High	Low
Morden et al., 2011b***** [59]	Glargine only users	Non-glargine insulin users	118/21,071*	333/65,294*	1.03	0.83, 1.29	High	Low
Ruiter et al., 2012a***** [64]	Glargine only users	Human insulin only users	11/6,875*	NR; IR=2.28*	1.65	1.10, 2.47	Moderate	Too low
Sturmer et al., 2013a **** [65]	Glargine users	NPH users	103/26,277	19/5,885	1.07	0.65, 1.75	Moderate	Too low
Suissa et al., 2011a***** [66]	Glargine users	Non-glargine insulin users	18/6,094	60/12,262	0.8	0.3, 2.1	Moderate	Too low
Pooled hazard ratio	Glargine	No glargine			1.04	0.91, 1.17
Glargine-no glargine: incidence rate ratio
Ljung et al., 2011a [57]	Glargine plus non-glargine insulin users	Non-glargine insulin users	59/25,033	283/101,419	1.04	0.77, 1.41	High	Low
Ljung et al., 2011b [57]	Glargine only users	Non-glargine insulin users	31/7,302	283/101,419	1.58	1.09, 2.29	High	Too low
Glargine-no glargine: odds ratio
Grimaldi-Bensouda et al., 2013a [49]	Glargine users	Non-glargine users	78/287	697/2,763*	1.04	0.76, 1.44	Low	Borderline
Grimaldi-Bensouda et al., 2013b [49]	Glargine users	Non-glargine insulin users	74/203	70/207	0.96	0.61, 1.53	Low	Too low
Grimaldi-Bensouda et al., 2013c [49]	Glargine users	Human insulin users	NR	NR	1.29	0.78, 2.13	Low	NE
Grimaldi-Bensouda et al., 2013d [49]	Glargine users	Aspart users	NR	NR	1.10	0.64, 1.89	Low	NE
Grimaldi-Bensouda et al., 2013^e [49]	Glargine users	Lispro users	NR	NR	0.85	0.48, 1.50	Low	NE
Mannucci et al., 2010a [58]	Glargine users	Non-glargine insulin users	NR	NR	NE	NE	High	Too low
Determir-no determir: hazard ratio
Fagot et al., 2013b [47]	Determir users	Other int-/long-acting insulin only users	38/12,806*	116/43,131*	1.08	0.72, 1.62	High	Too low
Kostev et al., 2012b [55]	Detemir users	NPH insulin users	NR/789	NR/4,206	1.17	0.66, 2.06	High	Too low
Determir-no determir: incidence rate ratio
Dejgaard et al., 2009a [46]	Determir users	NPH users	1/2,252	0/1,420	NE	NE	Low	Too low
Dejgaard et al., 2009b [46]	Determir users	Glargine users	1/917	3/628	NR	NR	Low	Too low
Aspart-no aspart: odds ratio
Grimaldi-Bensouda et al., 2013f [55]	Aspart users	Non-aspart users	54/241	721/2,809*	0.95	0.64, 1.40	Low	Borderline
Lispro-no lispro: odds ratio
Grimaldi-Bensouda et al., 2013g [49]	Lispro users	Non-lispro users	46/133	729/2,917*	1.23	0.79, 1.92	Low	Borderline
Human insulin-no human insulin: hazard ratio
Fagot et al., 2013c [47]	Basal human insulin users	Other int-/long-acting insulin only users	15/5,813*	139/50,948*	1.03	0.56, 1.88	High	Too low
Gu et al., 2013 [50]	Human insulin users	No insulin users	4/6,188*	14/10,435*	0.33	0.10, 1.13	Moderate	Too low
Ruiter et al., 2012b [64]	Non-glargine insulin users	Human insulin only users	31/15,578*	NR; IR=2.28*	0.99	0.81, 1.20	Moderate	Too low
Human insulin-no human insulin: odds ratio
Grimaldi-Bensouda et al., 2013h [49]	Human insulin users	Non-human insulin users	59/260	716/2,790*	0.81	0.55, 1.20	Low	Borderline

Bold values are significantly different. *Calculated using data provided (if not indicated directly these were taken from the table in the paper). **Risk estimates are adjusted for covariates as stated in Additional file 1: Table S3. Covariates used in the various analyses are the same within one study. ***Case–control studies. ****Cohort studies or randomized clinical trials. *****Included in meta-analysis. ******The exposure of interest is the exposure comparison group in this analysis. Studies are first ordered by type of exposure and then by type of risk estimate. Note: Hiesh 2012 is a cohort study but provided odds ratio estimates in the paper. Names of exposure groups are defined by the authors of the study. Several papers showed multiple risk estimates for the same exposure with different analytical approaches. For each study and exposure, the results from the least biased or best performed analyses are shown; showing hazard ratios, incidence rate ratios or odds ratios as applicable. Different exposure comparisons within one study are indicated by a,b,c etc. We choose to include the risk estimate that gave (in order of importance): 1) estimates for incident users was preferred over estimates for prevalent users; 2) as-treated analysis (during study period/follow up) was preferred over intention-to-treat analysis (during fixed period/at baseline); 3) estimates with the longest latency period were preferred. Estimates from statistical models adjusted for covariates were preferred over crude estimate. NR not reported, NE not estimated, HI human insulin, TZD Thiazolidinedione, NIAD non-insulin anti-diabetic drug, NPH Neutral Protamine Hagedorn, Int intermediate.

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