Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity: An analysis of the PROactive study population

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Abstract

Context

Although weight reduction is a recommended goal in type 2 diabetes mellitus (T2DM), weight loss is linked to impaired survival in patients with some chronic cardiovascular diseases.

Objective

To assess the association of weight and weight change with mortality and non-fatal cardiovascular outcomes (hospitalisation, myocardial infarction and stroke) in T2DM patients with cardiovascular co-morbidity and the effect of pioglitazone-induced weight change on mortality.

Setting and participants

We assessed in a post hoc analysis body weight and weight change in relation to outcome in 5202 patients from the PROactive trial population who had T2DM and evidence of pre-existing cardiovascular disease. Patients were randomized to treatment with pioglitazone or placebo in addition to their concomitant glucose-lowering and cardiovascular medication. Mean follow up was 34.5 months.

Main outcome measure

The impact of body weight and body weight change on all-cause mortality, cardiovascular mortality, on non-fatal cardiovascular events and on hospitalisation.

Results

The lowest mortality was seen in patients with BMI 30–35 kg/m2 at baseline. In comparison to this (reference group), patients in the placebo group with BMI < 22 kg/m2 (Hazard Ratio (95% confidence intervals) 2.96 [1.27 to 6.86]; P = 0.012) and BMI 22 to 25 kg/m2 (HR 1.88 [1.11 to 3.21]; P = 0.019) had a higher all-cause mortality. Weight loss was associated with increased total mortality (HR per 1% body weight: 1.13 [1.11 to 1.16]; P < 0.0001), with increased cardiovascular mortality, all-cause hospitalisation and the composite of death, myocardial infarction and stroke. Weight loss of ≥ 7.5% body weight (seen in 18.3% of patients) was the strongest cut-point to predict impaired survival (multivariable adjusted HR 4.42 [3.30 to 5.94]. Weight gain was not associated with increased mortality. Weight gain in patients treated with pioglitazone (mean + 4.0 ± 6.1 kg) predicted a better prognosis (HR per 1% weight gain: 0.96 [0.92 to 1.00] P = 0.037) compared to patients without weight gain.

Conclusion

Among patients with T2DM and cardiovascular co-morbidity, overweight and obese patients had a lower mortality compared to patients with normal weight. Weight loss but not weight gain was associated with increased mortality and morbidity. There may be an “obesity paradox” in patients with type 2 diabetes and cardiovascular risk.

The original PROactive trial is registered as an International Standard Randomized Controlled Trial (Number ISRCTN NCT00174993).

Introduction

Overweight is an established risk factor for increased cardiovascular morbidity and mortality [[1], [2], [3], [4], [5]]. Overweight is closely associated with other metabolic risk factors such as impaired glucose metabolism and type 2 diabetes mellitus (T2DM). Weight control and, if possible, weight reduction are therefore recommended treatment goals in T2DM patients [6]: any weight gain associated with anti-diabetic therapy such as glitazones might be regarded as an unwanted effect.

However, obesity is not associated with a worse outcome in all patient populations. There is a survival benefit in being overweight or moderately obese for patients with overt chronic cardiovascular disease. In patients with chronic heart failure (CHF), overweight is associated with decreased mortality [[7], [8], [9], [10]]. In patients with acute heart failure, a higher BMI is associated with lower in-hospital mortality [11]. Further, despite the known role of obesity as a risk factor for ischemic cardiovascular events [[12], [13], [14]], mortality following acute myocardial infarction is not higher in overweight and obese patients compared with normal weight patients [15]: indeed, in a systematic review of 40 studies including a total of more than 250,000 patients with coronary artery disease, there was a better outcome in the overweight and mildly obese patients compared with normal weight patients [16].

In addition to single time point assessment of body weight, weight loss during the course of the disease is strongly related to worse prognosis. In heart failure patients [17], [18] as well as in patients with coronary artery disease [19] weight loss is an independent marker of reduced survival.

The significance of weight change on patients with T2DM and cardiovascular co-morbidity in association with outcome has not been studied in detail. In the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events), pioglitazone reduced the combined endpoint of all-cause mortality, non-fatal infarction and stroke [20]. This effect was observed despite significant weight gain due to pioglitazone therapy. The aim of the present analysis was to assess the effects of body weight, weight loss and weight gain on mortality and non-fatal cardiovascular outcomes (hospitalisation, myocardial infarction and stroke) in the patients with Diabetes and cardiovascular co-morbidity. We hypothesised that in patients with T2DM and cardiovascular co-morbidity overweight is associated with better outcome and weight loss but not weight gain is associated with worse outcome.

Section snippets

Methods

We assessed in a post hoc analysis the association of body weight and weight change with mortality and non-fatal outcome in the patient cohort of the PROactive study.

Baseline characteristics

From the original PROactive study population, 5202 patients (99.3%) had sufficient weight measurements to be included in the analysis. The mean age was 62 ± 8 years and the mean follow-up was 34.5 months. 2592 of the included patients were randomly allocated to pioglitazone and 2610 patients to placebo. Treatment groups were well matched for baseline characteristics (Table 1). Co-morbidity, clinical characteristics, and drug regimen were similar between groups and not different from the main

Discussion

We have found that in patients with type 2 diabetes mellitus and cardiovascular co-morbidity, all-cause mortality and hospitalization are lower in overweight and mildly obese patients and are significantly increased in patients with BMI < 25 kg/m2. Weight loss was an independent predictor of increased all-cause mortality. Further, weight loss was associated with an increased risk of cardiovascular mortality and morbidity as indicated by increased hospitalization, myocardial infarction and stroke.

Conclusions

In a large cohort of patients with diabetes and with cardiovascular co-morbidity, overweight and mild obesity were associated with improved survival compared to patients with normal weight. Weight loss predicted impaired outcome on all-cause mortality, cardiovascular mortality and hospitalisation. Weight loss of ≥ 7.5% body weight occurred in 18% of the patients and was the best cut-point to predict impaired prognosis. Weight gain, in contrast, did not confer increased mortality risk. Weight

Contributors

All authors participated significantly to the work presented in this manuscript. W Doehner and SD Anker designed the analysis plan and are responsible for data interpretation, drafting and final approval of the manuscript. W Doehner takes responsibility for the integrity of the work as a whole, from inception to published article. JA Dormandy, E Ferrannini, and E Erdmann are members of the PROative Steering Committee, granted access to the database and contributed to the analysis plan, data

Conflict of interest

The PROacvite study was funded by Takeda Pharmaceutical Company and Eli Lilly and Company. JA Dormandy and E Erdmann are members of the international steering committee of the PROactive study. Both served as consultants and received travel expenses and payments for speaking at meetings from Takeda. R Cairns worked at the Nottingham Clinical Research Group, which was contracted by Takeda for the PROactive study. The sponsors of the PROactive study had no rule in design or mode of this analysis,

Acknowledgments

W Doehner is supported by the German Research Foundation (DO 718/5-1), by the Bundesministerium für Bildung und Forschung (No.01EO 0801) and by the European Commission (FP7, grant No 241558; SICA-HF).

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