The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma

Abstract

Background: Insulin/insulin-like growth factor-1 signalling may underlie the promoting effect of type 2 diabetes on cancer. This study examined the association of diabetes, including steroid-induced diabetes (SID), and the impact of anti-diabetic medication on clinical outcomes of multiple myeloma (MM).

Methods: A retrospective review was conducted of 1240 MM patients. Overall survival (OS) and MM disease status prior to death were analysed.

Results: Diabetic patients had a significantly shorter OS than non-diabetic patients (median: 65.4 vs 98.7 months). In multivariate analysis, SID was a significant predictor of decreased OS, along with age, comorbidity, MM stage, and cytogenetic abnormalities. Analyzing only the diabetic MM patients, Cox regression showed that metformin predicted an increased OS, whereas use of insulin/analogues predicted a decreased OS. Competing risk analysis showed that DM was associated with increased cumulative incidence of death with progressive MM. Among the diabetics, multivariate regression showed that insulin/analogues were associated with increased, but metformin with decreased death with progressive MM. Potential immortal time bias was evaluated by landmark analyses.

Conclusions: DM, SID in particular, is associated with poor clinical outcomes in MM. Insulin/analogues are associated with poor outcomes, whereas metformin is associated with improved outcomes. No conclusion about causal relationships can be made at this time. Managing hyperglycaemia with non-insulin regimens should be investigated in randomised trials.

Figures

Figure 1

Univariate Kaplan–Meier analyses of prognostic factors for myeloma patients. Kaplan–Meier curves of overall survival are shown for age of diagnosis (A), race (B), sex (C), obesity (D), Charlson Comorbidity Score (CCI) >5 (E), ISS Stage (F), chromosome 14 translocation (G), Stem cell transplant (H), Mean glucose values <120 mg dl−1 (I), maximum glucose values <200 mg dl−1 (J), diabetes status (HxD type 2 and SID groups combined) (K), and diabetes status as three groups (no diabetes, pre-existing diabetes, and SID) (L).

Figure 2

Univariate Kaplan–Meier analyses of glycemic control and anti-diabetic pharmacotherapies as prognostic factors for diabetic myeloma patients. The associations of anti-diabetic medications with overall survival were evaluated in diabetic myeloma patients (pre-existing and SID groups combined). Kaplan–Meier survival curves are shown for maximum glucose values <200 mg dl−1 (A), mean glucose values <120 mg dl−1 (B), insulin and analogues (C), insulin secretagogues (D), metformin (E), thiazolidinediones (F), other anti-diabetic drugs (G).

Figure 3

Univariate competing risk analyses of diabetes and anti-diabetic pharmacotherapies as prognostic factors for death in the presence of progressive myeloma. Based on Fine & Gray competing risk analysis, death with progressive myeloma and death without progressive myeloma were analysed as competing events. Cumulative incidence curves are shown as labelled for diabetic patients vs non-diabetic patients (A). Diabetes was associated with significantly (P<0.001) increased incidence of deaths with progressive myeloma (red vs black) but not deaths without progressive myeloma (blue vs green). Analyzing the diabetes status as three groups (no diabetes vs pre-existing diabetes vs SID), cumulative incidence curves and significant P-values are shown as labelled in (B). Analyzing only the diabetic patients, cumulative incidence curves of deaths with progressive myeloma comparing users (red line) and non-users (black line) and those of deaths without progressive myeloma comparing users (blue line) with non-users (green line) are shown for insulin/analogues (C), insulin secretagogues (D), metformin (E), thiazolidinediones (F), other anti-diabetic medications (G). Insulin and analogues usage was significantly (P=0.007) associated with death with progressive myeloma (C).