The genetic architecture of type 2 diabetes

Christian Fuchsberger et al. Nature. Doi:10.1038/nature18642

Diabetes was famously referred to as the ‘geneticist’s nightmare’ in 1976. Although familial clustering of diabetes was well known, the pattern of inheritance did not conform to that of a dominant or recessive trait. The potential for genetic dissection had been boosted by the identification of HLA genes in type 1 diabetes, cementing the long recognised clinical description of at least two distinct forms of disease. Then, during the 1990’s genes for monogenic forms of diabetes (termed MODY) were identified. But where are we with the genetic predisposition for type 2 diabetes (T2DM)? This manuscript suggests not a good place. The authors conclude that their massive genotyping endeavor does not support the idea that lower-frequency variants have a major role in predisposition to T2DM. Numerous small gene effects have previously been reported to predispose to T2DM but none of them have led to new therapies nor can they be used as predictive markers. Given the well-known environmental factors which predispose to T2DM, perhaps R&D funds would be better directed to their reversal rather than pursuing the nightmare?

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature18642.html

 

Long-term excess mortality associated with diabetes following acute myocardial infarction

O A Alabas et al. Journal of Epidemiology & Community Health. Doi:10.1136/jech-2016-207402

It is well known that type 2 diabetes is associated with an increased risk of cardiovascular disease and acute myocardial infarction (AMI) is an important manifestation of this. Indeed, fatal and non-fatal AMI is included in the primary composite end-point for the cardiovascular outcome studies, now mandated for all new diabetes medicines. This publication examines the long-term excess risk of death associated with diabetes following AMI using data from the MINAP study, based in the UK. Between 2003-13, there were more than 1.94 million person-years follow-up including 120 568 (17.1%) patients with diabetes. All-cause mortality was higher among patients with diabetes (35.8% vs 25.3%). After adjustment for age, sex and year of acute myocardial infarction, diabetes was associated with a significant 72% excess risk of death following ST elevation AMI (and 67% for Non-STEMI). Diabetes remained significantly associated with substantial excess mortality despite cumulative adjustment for comorbidity and cardiovascular treatments. These results provide an updated, UK confirmation of the importance of AMI in patients with diabetes, highlighting the potential benefits of antidiabetic agents which reduce this end-point.

http://jech.bmj.com/content/early/2016/06/15/jech-2016-207402.short

 

Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus

Kenneth Cusi et al. Annals of Internal Medicine. Doi:10.7326/M15-1774

Nonalcoholic fatty liver disease (NAFLD) is said to be reaching epidemic proportions worldwide and most patients with type 2 diabetes (T2DM) are thought to have this condition. Indeed, many T2DM patients are at risk of the more severe nonalcoholic steatohepatitis (NASH) even if they have normal liver aminotransferase levels. The argument goes that therapies for T2DM should be prioritized if they have a beneficial impact on NAFLD. This study examined 101 subjects with prediabetes or T2DM and biopsy-proven NASH. All were prescribed a hypocaloric diet and then randomly assigned to pioglitazone (45mg OD), or placebo for 18 months, followed by 18-month open-label pioglitazone. The primary outcome of improvement in liver histology was achieved in 58% and 51% had resolution of NASH. One of the difficulties in interpreting these studies is how to tease out the impact of improved glycaemic control from that of the specific drug. Having said that, some recent data suggest that sitagliptin was no more effective at reducing NAFLD than placebo. So, a come-back for pioglitazone? Perhaps it will be led by the gastroenterologists….

http://annals.org/article.aspx?articleid=2529686

 

Trends in hospital admissions for hypoglycaemia in England: a retrospective, observational study

Francesco Zaccardi et al. The Lancet Diabetes & Endocrinology. Doi: http://dx.doi.org/10.1016/S2213-8587(16)30091-2

The recent National Diabetes In-patient audit continues to show that rates of hypoglycaemia remain an issue both for patients in hospital and also as a reason for admission. However, given the education provided to patients at diagnosis and during follow up around hypoglycaemia management, the expectation would be that self-treatment should reduce admissions. Using the hospital episode statistics database, this retrospective study showed that 72% of the 101475 admissions over a 10-year period for hypoglycaemia occurred in patients aged over 60 with 18% having multiple admissions. Furthermore, over the 10 years, admissions for hypoglycaemia increased by 39% although when the increase in the prevalence of diabetes was taken into consideration, there was a reduction in admission rates. Given the rise in diabetes prevalence, aging population and the need to reduce unnecessary admissions, the appreciation of hypoglycaemia awareness and prevention should be given more attention.

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(16)30091-2/abstract

 

Intensive treatment and severe hypoglycaemia among adults with type 2 diabetes

Rozalina G. McCoyet al. JAMA Internal Medicine. Doi:10.1001/jamainternmed.2016.2275

The UKPDS study demonstrated the benefit of glucose lowering in Type 2 Diabetes (T2DM), a fact reinforced by its legacy study. However, other evidence from ACCORD/ ADVANCE and VADT did raise concerns about intensive glucose lowering especially in patients at higher risk of cardiovascular disease. NICE guidance goes some way in acknowledging this with its messages of individualised glucose targets. This study seems to reinforce the potential problems associated with tight glycaemic control. Looking at >31000 patients who achieved and maintained an HbA1c <7.0% (53mmol/mol), it compared high complexity patients (aged >75years, dementia or end stage renal failure or 3 or more long term conditions) with low intensity patients. Complex patients requiring intensive (aiming for lower than recommended HbA1c targets) had double the frequency of severe hypoglycaemia. The authors calculated that more than 20% of patients with T2DM received unnecessarily intensive treatment. These results further highlight the risk and significance of hypoglycaemia in complex patients which at best is likely to outweigh any perceived benefit of improved control and at worse result in harm to patients.

http://archinte.jamanetwork.com/article.aspx?articleid=2526670