Research Editorial

Prevention of type 1 diabetes: the time has come
This month sees a review published in Nature Clinical Practice: Endocrinology and Metabolism discussing prevention of type 1 diabetes. The key points as summarized by the authors are: 1. Screening of relatives with type 1 diabetes to identify individuals with an extraordinarily high risk of developing overt type 1 diabetes mellitus within 5-6 years. 2. Diagnostic criteria for diabetes not associated with the disease process, but rather with glycaemic levels associated with the development of complications. 3. Prevention trials to target individuals with greater functional beta-cell mass, who have not yet demonstrated overt hyperglycaemia but who are at high risk of disease development. 4. Future prevention trials, including therapies that are antigen specific or antigen non-specific or used in combination (1).

Cost-effectiveness of multifactorial intervention in type 2 diabetes
New interventions that improve patient outcomes are often associated with increased costs. The Steno-2 study demonstrated important effects of multifactorial intervention on cardiovascular morbidity and mortality, as well as effects on diabetic microangiopathy. In a further analysis of the study it was shown that intensive multifactorial intervention as applied in the Steno-2 study is likely to be highly cost-effective from a third-party healthcare payer perspective in patients with type 2 diabetes with microalbuminuria (2).

Continuous glucose monitoring
A randomized multicentre clinical trial evaluating the efficacy and safety of continuous glucose monitoring (CGM) in adults and children with type 1 diabetes was published in the New England Journal of Medicine. In the group of adult patients using CGM, glycated haemoglobin levels improved and the management of type 1 diabetes was enhanced (3). In a different setting the effect of sensor-augmented insulin pump therapy was studied. This study is the first randomized treat-to-target study with the aim to assess the safety and clinical efficacy of a sensor-augmented insulin pump in adolescent and adult subjects. Levels of HbA_1c did not differ between the two groups at the end of the study, but the same level of glycaemia was achieved with fewer hypoglycaemic episodes in the CGM group. Future studies should also take into account patient willingness and ability to use this technology appropriately (4). The last paper selected for this section is a review of current minimally invasive and non-invasive CGM sensors discussing indications, advantages, and limitations as well as clinical and technical aspects of their use. The authors suggest that if a CGM system proves to be accurate, reliable under different conditions, and has sufficient longevity under daily life conditions, then it could be used in the future to construct a (semi-) closed loop system, a step towards the artificial pancreas. This would represent a major breakthrough in diabetes care (5).

HbA_1c and average glucose values
The vast majority of assays have been standardized worldwide, through the National Glycohemoglobin Standardization Program (10). They have been standardized to the assay used in the Diabetes Control and Complications Trial (DCCT), which established the relationship between HbA_1c levels and risk of long-term diabetes complications. In a study of 507 subjects including 268 patients with type 1 diabetes, 169 with type 2 diabetes, and 80 non-diabetic subjects it was shown that HbA_1c levels can indeed be expressed as an estimated average glucose value for most patients with type 1 and type 2 diabetes (6).

Direct renin inhibition with aliskiren
The outlook for patients with diabetes who have microalbuminuria or macroalbuminuria has improved, probably owing to early aggressive lowering of blood pressure and blocking of the renin-angiotensin-aldosterone system. However, there is still a largely unmet need to develop strategies for the prevention of diabetic nephropathy and its progression to end-stage renal disease. The next study investigated the potential renoprotective capacity of direct renin inhibition with aliskiren in patients with hypertension, type 2 diabetes, and proteinuria. It appears that aliskiren has a renoprotective effect that is independent of its blood pressure-lowering effect, in patients with type 2 diabetes who are already receiving the maximal recommended renoprotective treatment including an optimal antihypertensive therapy (7).

Is there a role for blood pressure in the development of retinopathy
In addition to hyperglycaemia, hypertension has emerged as a risk factor for diabetic retinopathy and its progression in adults. Adolescents with diabetes are an ideal group in which to study the effect of blood pressure on the very early development of retinopathy. It was hypothesized that blood pressure as a continuous variable should be a predictor of early development of retinopathy, and that this relation is present even in the absence of incipient nephropathy. It was shown that a continuous relation exists between blood pressure and risk of retinopathy. Interventional trials are needed to test the risks and benefits of lowering blood pressure in children and adolescents with type 1 diabetes (8).

Secular decline in mortality from coronary heart disease in adults with diabetes mellitus
Compared with the general population, people with diabetes have a 2-4 fold higher mortality from coronary heart disease (CHD). More recently many studies have, however, demonstrated a secular decline in mortality from CHD in patients with diabetes. Thus, in the next study it was confirmed that during follow up of mortality over 2 consecutive 9-year periods, the risk of death from CHD was still more than 2-fold higher in patients with diabetes. The good news is that the mortality rates from CHD decreased substantially in all age groups irrespective of sex and diabetes status. This indicates that patients with diabetes have also benefited from the overall decline in mortality from CHD (9).

Diabetes and cardiovascular disease
The aim of the next study was to evaluate potential prothrombotic alterations in patients with acute myocardial infarction (MI) in relation to hyperglycaemia. Two groups of patients were studied, one with and one without diabetes prior to acute MI. It was demonstrated that acute hyperglycaemia in patients with acute MI, without a previous history of diabetes, is associated with increased thrombin generation and platelet activation at the site of vascular injury. An association with a greater resistance to fibrinolysis was also seen. The study provides further insight into the relationship between hyperglycaemia and thrombosis in patients with acute MI (10). In another study of 816 hypertensive patients with type 2 diabetes, the data support the beneficial effects of early ACE inhibitor therapy for effective prevention of left-ventricular hypertrophy and, conceivably, cardiovascular morbidity and mortality in a population with microalbuminuria and arterial hypertension (11). The last paper selected for this section addressed drug-eluting stents in patients with and without diabetes. It was shown that with a duration of dual antiplatelet therapy of 6 months or longer, drug-eluting stents were safe and effective in patients with and without diabetes (12).

Liraglutide: treatment of type 2 diabetes with incretin-based therapies
A report on the “LEAD-3 Mono” randomized trial of liraglutide in the treatment of type 2 diabetes was published in the Lancet in September. Liraglutide is an analogue of human GLP-1 with 97% homology to the endogenous protein and a half-life of 13 hours, which gives it a pharmacokinetic profile suitable for once-daily treatment. The safety and efficacy of two doses of liraglutide versus glimepiride over 52 weeks for treatment of type 2 diabetes mellitus was investigated. It was shown that liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and has advantages over other drugs used in monotherapy, including greater reductions in weight, number of hypoglycaemic events, and systolic blood pressure (13).

Exenatide
Two new classes of antidiabetic agents based on potentiation of incretin action have been approved for the treatment of diabetes: glucagon-like peptide-1 receptor (GLP-1R) agonists or incretin mimetics and dipeptidyl peptidase-4 (DPP-4) inhibitors or incretin enhancers. Exenatide is an incretin mimetic. It was studied in a 30-week, randomized, non-inferiority study comparing a long-acting release formulation of exenatide 2 mg administered once weekly to 10 microg exenatide administered twice daily. The primary end-point was changes in levels of HbA_1c. Exenatide both once daily and twice daily resulted in significant reductions in HbA_1c and body weight from baseline after 30 weeks of treatment. Exenatide once weekly produced better glycaemic control than exenatide twice daily. The authors state that in view of the complexity of current diabetes treatment options requiring once or twice daily administration of therapeutic agents, the significant improvement in HbA_1c in association with weight loss observed with a once-weekly formulation of exenatide suggest that continuous GLP-1R activation offers a promising treatment option for the management of type 2 diabetes (14). In the next study it was shown that exenatide slows gastric emptying of solid and liquid components of a meal in subjects with type 2 diabetes. The effect was particularly evident in subjects with relatively rapid gastric emptying and was not attenuated in subjects with cardiac autonomic neuropathy. The reduction in postprandial glucose excursions during exenatide treatment was significantly related to the slowing of gastric emptying (15).

HbA_1c and preterm delivery in type 1 diabetes
HbA_1c predicts preterm delivery in type 1 diabetes. It is, therefore, recommended that the target HbA_1c in diabetic pregnancy in the third trimester should be kept close to the upper limit for normal late pregnancy (16).

Continuous subcutaneous insulin infusion in children at onset of type 1 diabetes
Continuous subcutaneous insulin infusion (CSII) was compared to multiple daily injections in 72 children/adolescents at the onset of type 1 diabetes. In this particular study there was no difference in metabolic control between the groups. However, treatment satisfaction was improved in the CSII group. The authors speculate whether this improved treatment satisfaction will compensate for the increase in costs. So far there is no answer to this question (17).

Weight gain, obesity, and type 2 diabetes
The next three papers all address obesity, weight gain, and weight history of patients with type 2 diabetes. In the first paper it is shown that there is strong association between abdominal obesity and the development of type 2 diabetes (18). The results in the second paper indicate that it is important to advise young patients, and especially women, who gain and sustain considerable weight to curb this upward weight trend in order to prevent the development of diabetes (19). The third paper was a report from the predictive study showing that there was less weight gain and hypoglycaemia with once-daily insulin detemir than NPH insulin during intensification of insulin therapy in overweight patients with type 2 diabetes (20).

Hemipancreatectomized (HPx) donors
During 2004 more than 1,400 pancreatic transplants were performed in the USA. The vast majority of these transplants were done using deceased-donor organs. However, some centres have considered using living donors in situations in which improved outcomes over the use of deceased-donor organ might be expected. Unfortunately the development of abnormal glucose tolerance now seems to be a risk inherent to hemipancreatectomized donors (HPx). Despite the use of stringent criteria to exclude those at risk for developing abnormalities in glucose metabolism, 43% of healthy humans who underwent HPx had impaired fasting glucose, impaired glucose tolerance, or diabetes on follow-up. The authors therefore recommend that living donors should only be used under very special circumstances (21).

References

1. Sherr J, Sosenko J, Skyler JS, Herold KC. Prevention of type 1 diabetes: the time has come. Nat Clin Pract Endocrinol Metab. 2008;4:334-43.
2. Gaede P, Valentine WJ, Palmer AJ, Tucker DM, Lammert M, Parving HH, et al. Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study. Diabetes Care. 2008;31:1510-5.
3. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, Clemons R, et al. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008;359:1464-76.
4. Hirsch IB, Abelseth J, Bode BW, Fischer JS, Kaufman FR, Mastrototaro J, et al. Sensor-augmented insulin pump therapy: results of the first randomized treat-to-target study. Diabetes Technol Ther. 2008;10:377-83.
5. De Block C, Vertommen J, Manuel-Y-Keenoy B, Van Gaal L. Minimally-invasive and non-invasive continuous glucose monitoring systems: indications, advantages, limitations and clinical aspects. Curr Diabetes Rev. 2008;4:159-68.
6. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ; A1c-Derived Average Glucose Study Group. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31:1473-8.
7. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433-46.
8. Gallego PH, Craig ME, Hing S, Donaghue KC. Role of blood pressure in development of early retinopathy in adolescents with type 1 diabetes: prospective cohort study. BMJ. 2008;337:a918.
9. Dale AC, Vatten LJ, Nilsen TI, Midthjell K, Wiseth R. Secular decline in mortality from coronary heart disease in adults with diabetes mellitus: cohort study. BMJ. 2008;337:a236.
10. Undas A, Wiek I, Stêpien E, Zmudka K, Tracz W. Hyperglycemia is associated with enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis in patients with acute coronary syndrome. Diabetes Care. 2008;31:1590-5.
11. Ruggenenti P, Iliev I, Costa GM, Parvanova A, Perna A, Giuliano GA, et al.; Bergamo Nephrologic Diabetes Complications Trial Study Group. Preventing left ventricular hypertrophy by ACE inhibition in hypertensive patients with type 2 diabetes: a prespecified analysis of the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT). Diabetes Care. 2008;31:1629-34.
12. Stettler C, Allemann S, Wandel S, Kastrati A, Morice MC, Schömig A, et al. Drug eluting and bare metal stents in people with and without diabetes: collaborative network meta-analysis. BMJ. 2008;337:a1331.
13. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al.; for the LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. [Epub ahead of print 2008 Sep 24].
14. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al.; for the DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. [Epub ahead of print 2008 Sep 7].
15. Linnebjerg H, Park S, Kothare PA, Trautmann ME, Mace K, Fineman M, et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept. [Epub ahead of print 2008 Jul 16].
16. Ekbom P, Damm P, Feldt-Rasmussen B, Feldt-Rasmussen U, Jensen DM, Mathiesen ER. Elevated third-trimester haemoglobin A 1c predicts preterm delivery in type 1 diabetes. J Diabetes Complications. 2008;22:297-302.
17. Skogsberg L, Fors H, Hanas R, Chaplin JE, Lindman E, Skogsberg J. Improved treatment satisfaction but no difference in metabolic control when using continuous subcutaneous insulin infusion vs. multiple daily injections in children at onset of type 1 diabetes mellitus. Pediatr Diabetes. 2008;9:472-9.
18. Freemantle N, Holmes J, Hockey A, Kumar S. How strong is the association between abdominal obesity and the incidence of type 2 diabetes? Int J Clin Pract. 2008;62:1391-6.
19. De Fine Olivarius N, Richelsen B, Siersma V, Andreasen AH, Beck-Nielsen H. Weight history of patients with newly diagnosed Type 2 diabetes. Diabet Med. 2008;25:933-41.
20. Fajardo Montañana C, Hernández Herrero C, Rivas Fernández M. Less weight gain and hypoglycaemia with once-daily insulin detemir than NPH insulin in intensification of insulin therapy in overweight Type 2 diabetes patients - The PREDICTIVE™ BMI clinical trial. Diabet Med. 2008;25: 916-23.
21. Kumar AF, Gruessner RWG, Seaquist ER. Risk of glucose intolerance and diabetes in hemipancreatectomized donors selected for normal perioperative glucose metabolism. Diabetes Care. 2008;31:1639-43.