Cambridge was a strange place. Take our physiology practicals- over the course of a year they made us collect our pee in the lab, stab ourselves and deliver electric shocks to our arms. And then document it all. For one experiment we had to drink one of three liquids (water, cranberry juice or a mystery alkaline cocktail of the departments making, eeeps) then titrate our pee. I kid you not. Can't for the life of me remember the point, or the results, but I'll never forget the boys competing to see who filled the biggest measuring cylinder, or the girl who spilled her pee across the desk . I never knew her name and forever after she was just the girl who pee'd on her practical book...But I digress. This week I've been reminded of a physiology blood glucose practical by an article in the New England Journal of Medicine. We skipped breakfast and took our own blood glucose, before and after a Mars bar. The chocolate was good, the repeated stabbing less so. Like us, the NEJM study was interested in fasting blood glucose- the blood glucose level after 8 hours of refraining from consuming anything other than water. Unlike us, they executed a pretty decent study on the topic which is worth discussing here.
The premise of the study is simple- elevated fasting plasma glucose is associated with an increase risk of cardiovascular disease. It's thought this is due to low background levels of insulin and therefore it has been hypothesised that correcting this deficiency would reduce cardiovascular disease. However, much of the evidence to date has been equivocal, with no clear reduction in cardiovascular disease and suggestions that treatment with insulin might carry an increased cancer risk. Recently, the balance shifted in favour of tight blood glucose with the publication of the UK Prospective Diabetes Study (UKPDS) which found that tighter blood glucose control in new diabetics was associated a 15% reduced risk of heart attack and a 13% lower mortality rate. So, perhaps tight blood glucose control is worthwhile?
Cue ORIGIN, the subject of our musings today. This study involved 12,537 people from 40 countries, who had elevated fasting glucose, impaired glucose tolerance (blood glucose is higher than normal 2hr after consuming glucose) or early Type 2 diabetes in addition to other cardiovascular risk factors. Participants were randomly allocated to receive either a) standard care or b) to inject insulin in addition to their normal glucose control regime aiming for a fasting blood glucose of 5.3 mmol/litre or less. They were then followed for 6 years.
So what did they find? Well, there was no difference between the two groups with regards cardiovascular outcomes (including stroke and heart attacks), cancer or overall mortality. However, they did find that the insulin group were less likely than the standard group to develop Type 2 diabetes (30% vs 35% at 100days after the end of the trial, p=0.05). So, aggressive blood glucose control in non-diabetics with raised fasting glucose or impaired glucose tolerance doesn't make a jot of difference to mortality at 6 years, but it might make you less likely to develop diabetes. Yay? Well, the downside was the insulin group were more likely to experience symptoms from low blood glucose (hypoglycaemia), which include shakiness, anxiety, headache and nausea. 57% of the insulin group experienced at least one episode of symptomatic hypolycaemia, compared to 25% of the standard group. The insulin group also experienced weight gain (median gain 1.6kg) which the standard group did not (median loss of 0.5kg).
Now, the study has its limitations- it's male dominated (65% of participants) and only includes the over 50s, making it hard to know how applicable it is to younger people and women. They only followed up for 6 years which isn't a very long time to catch relatively rare events. Plus only 44% of the eligible insulin group and 47% of the eligible standard group returned to be tested for diabetes at the 100 day point, which leaves a hefty chunk of unknown outcomes. 11% of the non-insulin group ended up taking insulin which further confuses the results. Also there's a depressingly epic list of investigators paid by pharmaceutical companies and the study itself was industry funded by the make of the insulin used. Nuff said.
But the overriding, screaming question for me is would you stab yourself every day, probably put on weight and suffer hypoglycaemia for the possibility that you might be one of the people who doesn't develop diabetes by doing all that? You have to be really motivated. The individuals selected for this trial were motivated and supported- they all said they were up for injecting insulin and they subsequently received regular contact from the trial organisers which can support people to stick with medications. Even in this environment 1 in 5 of those allocated to insulin had ditched it by the end of 5 years.
Diabetes comes with a host of awful complications- leg ulcers, kidney damage, eye damage. I know all this, but I'm still not sure I'd be up for daily insulin to moderately dial down my risk of getting diabetes. But then I paid tuition fees to collect my own pee and stab and electrocute myself, so perhaps sensible life choices are not my forte... What would you do?
Ref: Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia.The ORIGIN Trial Investigators. N Engl J Med 2012; 367:319-328 http://www.nejm.org/doi/full/10.1056/NEJMoa1203858