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Whittington Health NHSUCL

Important papers

Listing a paper does not mean that we necessarily agree with the views of its author.

There is so much research into type 2 diabetes that it can be very difficult to keep on top of the evidence.

Below are some of the important papers to have come out over the last few decades. It is by no means an exhaustive list.

The evidence is divided into subject headings and we start off with Cochrane reviews wherever possible. Hyperlinks for specific papers link to the pubmed listing. 

The UK Prospective Diabetes study (UKPDS)

The UKPDS trial was one of the first trials to show that treating type 2 diabetes really is worthwhile.

UKPDS was a randomised control trial set up in 1977. The original trial ran for 20 years.
Its aims were to establish whether reducing blood glucose levels and maintaining good blood pressure control actually protects people with type 2 diabetes from having complications.

Over 5,000 patients were enrolled across 23 UK sites.

The initial trial showed that improving blood glucose levels reduced the microvascular complication rate. This means that people with lower blood glucose levels had a lower risk of eye and kidney problems for example.
Reducing blood pressure levels helped reduce the risk of microvascular but also macrovascular complications such as stroke.

UKPDS stands for: the UK Prospective Diabetes Study. 

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Original paper published in the Lancet. 1998 Sep 12;352(9131):837-53.

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.
Adler et al. BMJ. 2000 Aug 12;321(7258):412-9.

10-year follow-up of intensive glucose control in type 2 diabetes.
Holman et al. N Engl J Med. 2008 Oct 9;359(15):1577-89. Epub 2008 Sep 10.

Long-term follow-up after tight control of blood pressure in type 2 diabetes.
Holman et al. N Engl J Med. 2008 Oct 9;359(15):1565-76. Epub 2008 Sep 10.

Tight control of blood glucose level

Tight control of blood glucose in long standing type 2 diabetes
BMJ 2009; 338
 UK study, Lehman R, Krumholz HM


Cholesterol, diet, weight and exercise

Completed Cochrane reviews

Medicines for weight loss in diabetes: 'Pharmacotherapy for weight loss in adults with type 2 diabetes.' 2009

Dietary advice for treatment of type 2 diabetes mellitus in adults' 2007

'Exercise for type 2 diabetes mellitus' 2006

Sedentary time, breaks in sedentary time and metabolic variables in people with newly diagnosed type 2 diabetes.
Diabetologia. 2012 Mar;55(3):589-99. Epub 2011 Dec 14.
 UK study, Cooper AR
‘Higher sedentary time is associated with a poorer metabolic profile in people with type 2 diabetes’. 

Fasting Successfully Treats Early Diabetes Type 2. Forschende Komplementaermedizin 2011, 18(6), 359-360. UK study, Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R.

Effect of changing the amount and type of fat and carbohydrate on insulin sensitivity and cardiovascular risk: the RISCK (Reading, Imperial, Surrey, Cambridge, and Kings) trial. 
Am J Clin Nutr. 2010 Oct;92(4):748-58. Epub 2010 Aug 25.RISCK trial, Cambridge
Jebb et al.
‘This study did not support the hypothesis that isoenergetic replacement of SFAs with MUFAs or carbohydrates has a favorable effect on insulin sensitivity.’

Diet or diet plus physical activity versus usual care in patients with newly diagnosed type 2 diabetes: the Early ACTID randomised controlled trial.
Lancet. 2011 Jul 9;378(9786):129-39. Epub 2011 Jun 24. Early ACTIC trial, Bristol, Andrews RC et al
‘An intensive diet intervention soon after diagnosis can improve glycaemic control. The addition of an activity intervention conferred no additional benefit.’

n-3 fatty acids and cardiovascular events after myocardial infarction.
N Engl J Med. 2010 Nov 18;363(21):2015-26. Epub 2010 Aug 28. Netherlands study, Kromhout et al. Alpha omega trial (not specific to diabetes).

‘Low dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state of the art …therapy’

Egg consumption as part of an energy-restricted high-protein diet improves blood lipid and blood glucose profiles in individuals with type 2 diabetes.Br J Nutr. 2011 Feb;105(4):584-92. Epub 2010 Dec 7. Australia study, Pearce et al.
‘These results suggest that a high-protein energy-restricted diet high in cholesterol from eggs improved glycaemic and lipid profiles, blood pressure and apo-B in individuals with type 2 diabetes.

Egg consumption in relation to cardiovascular disease and mortality: the Physicians' Health Study. Am J Clin Nutr. 2008 Apr;87(4):964-9. US study, Djousse L, Gaziano JM
‘Infrequent egg consumption does not seem to influence the risk of CVD in male physicians. In addition, egg consumption was positively related to mortality, more strongly so in diabetic subjects, in the study population.’

Bariatric surgery

Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis.Am J Med. 2009 Mar;122(3):248-256.e5. US study, Buchwald et al.
‘The clinical and laboratory manifestations of type 2 diabetes are resolved or improved in the greater majority of patients after bariatric surtery; these responses are more pronounced in procedures associated with a greater percentage of excess body weight loss and is maintained for 2 years of more.’

Diabetes and testosterone

Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. 2011 Aug;96(8):2341-53.Epub 2011 Jun 6. Australian study, Grossman M.
The key response to the aging, overweight man with type 2 diabetes and subnormal testosterone levels should be implementation of lifestyle measures such as weight loss and exercise, which, if successful, raise testosterone and provide multiple health benefits. Although approved therapy for diabetes should be used, testosterone therapy should not be given to such men until benefits and risks are clarified by adequately powered clinical trials.

Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011 Apr;34(4):828-37. Epub 2011 Mar 8 TIMES2 study, UK, Jones et al.
‘Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS.’

Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004 May;27(5):1036-41. Finnish study, Laaksonen et al.
‘Low total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged med. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.’

Eye care

Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010 Jul 15;363(3):233-44. Epub 2010 Jun 29. ACCORD eye study, America, Chew et al.
‘Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy.’

Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomized controlled trial. Lancet. 2007 Nov 17;370(9600):1687-97.
Epub 2007 Nov 7
 The FIELD study, Australian study, Keech et al.
‘Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.’

Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991 May;98(5 Suppl):766-85. ETDRS study. This helped clinicians to determine referral criteria for diabetic eye disease.

Incretins and pancreatitis risk

Risk of pancreatitis with incretins

At the beginning of May 2014 the BMJ published an editorial and 2 research papers which investigated the possible increased risk of acute pancreatitis related to the use of incretin based drugs in patients with type 2 diabetes.

Initial concerns were raised in a paper in Diabetes Care in 2013. Since then, the European Medicines Agency and the Food and Drug Administration in the United States have been reviewing evidence around the drug. Both agencies decided to keep the drugs available while the review was ongoing, with the potential for pancreatitis described on labels.

NICE published a Medicine Evidence Commentary on this in August 2013

This Commentary recommended that Healthcare professionals should continue to prescribe these agents in line with the Summary of Product Characteristics and NICE guidance.

In brief, this is that sitagliptin, vildagliptin, exenatide and liraglutide 1.2 mg daily may be considered in specific circumstances as part of dual therapy and triple therapy for type 2 diabetes. This advice is laid out as part of the NICE pathway on blood glucose lowering therapy.

The editorial in the BMJ essentially supports the recent recommendations, stating that the available evidence suggests "there is no significant increase in the risk of acute pancreatitis with these drugs".

It goes on to recommend that clinicians share current information about the risk of acute pancreatitis with their patients as part of shared decision making. Estimates of risk are around 15 cases out of 10,000 patients with type 2 diabetes, which is almost identical to the risk from sulfonylureas. In other words, it is rare. Targeting the drug to low risk groups might decrease the risk even more.

The 2 studies that support the conclusions of the editorial are:

Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies – this looks at results from 55 randomised trials of incretin based drugs (mostly industry-funded) and 5 observational studies (cohort studies and case control studies). The authors conclude that their study suggests "the incidence of pancreatitis in patients with type 2 diabetes taking incretins is low and that incretins are not associated with an increased pancreatitis risk".

Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study – this study drew on data from the UK Clinical Practice Research Datalink. It compared 20,748 new users of incretin based drugs with 51,712 users of sulfonylureas. Incidence of acute pancreatitis was almost identical (1.45 per 1,000 patients with incretin based drugs; 1.47 per 1,000 patients with sulfonylureas). Secondary analysis suggested that risk did not vary by either gender or duration of use.