Some 15,600 people from 134 countries attended the 51st European Diabetes Conference in Stockholm (Annual Meeting of the European Association for the Study of Diabetes). The results of the EMPA-REG study with empagliflozin, which for the first time showed a positive effect of an antidiabetic drug on cardiovascular mortality, caused a sensation. We also report studies on frailty in diabetics, the relationship between nephro- and retinopathy, and vitamin B12 deficiency as a consequence of metformin treatment.
The EMPA-REG outcome study of empagliflozin (Jardiance®), an SGLT-2 inhibitor, aimed to demonstrate the cardiovascular effects of the drug in type 2 diabetic patients at high risk of cardiovascular disease [1]. A total of 7020 patients were randomized into three groups: Group 1 received empagliflozin 10 mg in addition to standard treatment (antidiabetic drugs and drugs to reduce cardiovascular risk, including antihypertensives and statins), Group 2 received empagliflozin 25 mg in addition to standard treatment, and Group 3 received placebo in addition to standard treatment. The primary end point consisted of death from cardiovascular disease, nonfatal myocardial infarction, and nonfatal stroke.
The end point was reduced in the pooled data of the two verum groups, relatively by 14% compared with placebo (10.5% vs. 12.1%). Cardiovascular mortality was significantly reduced by 38% (3.7% vs. 5%) in the group of patients treated with the SGLT-2 inhibitor, as was all-cause mortality by 32% (5.7% vs. 8%). EMPA-REG-Outcome is thus the first study to show a positive effect of an antidiabetic drug on mortality.
Mortality risk in frail type 2 diabetic patients.
In a Dutch study, the authors investigated the association between the degree of frailty, HbA1c, and mortality [2]. The prospective observational study involved 858 type 2 diabetic patients aged 60 years and older who were treated by primary care providers in their offices. Frailty was defined as a score below 80 on the “physical abilities” scale of the RAND-36 questionnaire. The median follow-up was 14 years. Factors such as age, gender, BMI, duration of diabetes, and cardiovascular risk factors were included in the analysis.
The average age of the study population was 72 years. 73% of patients were classified as frail; among them, high HbA1c levels increased cardiovascular mortality and all-cause mortality (hazard ratios 1.19 and 1.11, respectively). No such association was observed in the non-frail study participants. However, the majority of these differences disappeared when only data from patients who had had type 2 diabetes for more than five years were analyzed. The authors conclude that in frail patients, high HbA1c increases all-cause mortality and cardiovascular mortality, but that the impact is very small – compared with non-frail individuals. More important than frailty seems to be the duration of diabetes.
Protection against retinopathy, but not against nephropathy.
Type 1 diabetics with nephropathy (DN) often also develop retinopathy (DR), but diabetics with retinopathy often do not have nephropathy. This fact suggests that there are different causes – and different protective factors – for the two diseases. In a US study from Boston, the corresponding correlations were investigated [3]. In the cohort, type 1 diabetics were divided into four groups:
- With DN and DR (+DN/+DR, n=63)
- With DN but without DR (+DN/-DR, n=30)
- Without DN, but with DR (-DN/+DR, n=345)
- Without DN and without DR (-DN/-DR, n=326).
In the +DN/-DR group, the rate of cardiovascular disease was surprisingly lower than expected (34.5%) when compared with the rates of the other groups (+DN/+DR: 71.0%, -DN/+PDR: 43.8%, -DN/-DR: 29.3%). The rate of patients in whom C-peptide was detected was also highest in the +DN/-DR group (56.7%, and 30-35% in the other groups).
The release of vascular endothelial growth factor (VEGF) by fibroblasts as a result of stimulation with insulin and hypoxia was twice as high in the +DN/-DR group as in the +DN/+DR group, and the VEGF response was strongest in the -DN/-DR group (the VEGF response to stimulation was inversely proportional to the prevalence of cardiovascular disease in all four groups).
Authors’ conclusion: In this cohort, patients with diabetic nephropathy but no retinopathy had lower prevalence of cardiovascular disease, better beta-cell function, and higher VEGF response than those with nephropathy and retinopathy. This indicates that there are probably factors that simultaneously protect against cardiovascular disease and diabetic retinopathy.
Metformin treatment, vitamin B12 deficiency and neuropathy.
Metformin lowers serum vitamin B12 levels and increases levels of methylmalonic acid (MMA), a biomarker of vitamin B12 deficiency. However, the clinical relevance of metformin-associated vitamin B12 deficiency is controversial because clinical outcome data are lacking to date. Current guidelines mention vitamin B12 deficiency as a drawback of metformin therapy, but there are no recommendations for diagnosis and prevention of such deficiency. A Dutch study therefore investigated whether an increase in MMA was associated with the onset or worsening of neuropathy [4]. 390 type 2 diabetics treated with insulin also received 850 mg metformin or placebo up to three times daily for 52 months. The associations between the changes in HBA1c, MMA score, and Valk score (score used to diagnose neuropathy) were analyzed.
Metformin increased MMA levels compared with placebo. At the end of 52 months, there was no difference in neuropathy score between the metformin and placebo groups. However, this was attributed to the greater reduction in HbA1c in the metformin group, because neuropathy also worsened in the MMA-increased group. For the authors, these results indicate that vitamin B12 deficiency induced by metformin treatment may be clinically relevant. Control of vitamin B12 and, if possible, MMA levels should be considered in patients treated with metformin.
Source: 51st Annual Meeting of the European Association for the Study of Diabetes (EASD), September 14-18, 2015, Stockholm.
Literature:
- Zinman B, et al: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; DOI: 10.1056/NEJMoa1504720.
- Hartog LC, et al: Frailty and the relationship between HbA1c and mortality in elderly patients with type 2 diabetes. EASD 2015, para 225.
- Hillary KA, et al: Protection from diabetic retinopathy, but not nephropathy. EASD 2015, para 228.
- Out M, et al: Metformin, methylmalonic acid and the risk of neuropathy: a randomised placebo-controlled trial. EASD 2015, para 220.
CARDIOVASC 2015; 14(6): 30-31
