National Diabetes Preventenion Program (NDP)
In the opening session of the ADA meeting the leaders of ADA pointed out the importance of a national diabetes strategy in order to prevent the epidemic rise of T2DM and for better treatment of diabetes. There is a lot work to be donet o build a culture of better understanding from politicians and decision makers. The National US Diabetes Prevention Program (NDP) will increase the number of people who know about the opportunities for a better lifestyle – and to get more people into a structured lifestyle program that has been show nto prevent diabetes type 2.
Latest science on acute complication of pediatric diabetes
1) In a symposium with a couple of experts several issues were discussed. At the time of diagnosis 20-40 % of patients will still have a diabetic ketoacidosis (DKA). Children less than 2 years are at greatest risk. The figure is related to the delayed recognition of diabetes. There is a need of an awareness campaign for general practioners. Cerebral edema occurs more commonly in children with DKA.
2) The frequency of Hyperglycemia hyperosmolar syndrome (HHS) is rising in both T1DM and T2DM. The mortlity rate from HHS is 53% in obese children versus 0% in children who are not obese. The complication of HHS include renal failure, arrhytmias, shock and multisystem organ failure. Treatment recommendation call for fluid replacement, delayed administration of insulin, lower doses of insulin, more aggressive electrolyte replacemnt, and routine monitoring and replacement of phosphate, Dr Glaser, Univ California US said.
3) 6 % of deaths in patients less than 40 years old with T1DM are due to nocturnal hypoglycemia, according to Ragnar Hanas, Sweden, suggesting a need to monitor glucose congtrol more often with continuous glucose monitors (CGM). Studies have shown that overnight CGM are effective in detecting hypoglycemia in children. Other ways of detecting hypoglycemia include non-invasive device on the wrist that detects perspiration or a drop in skin temperature, Dr Hanas said.
4) It is important to evaluate youth with diabetes for the presence of eating disorders. We should screen all pediatric diabetes patients and their family for depression and anxiety, according to Barbara Anderson, Texas Children´s Hospital. ”The ADA guidelines call for psychosocial assessment at diagnosis and annual screening for depression of youth 10 years old and older. It is important for the life quality of the patients.
Genetic medicine is moving toward clinical practice
At a symposium someone said that genetics has been a love story for some clinicians, but for most it has tuned into a nighmare of confusion. But now there is a growing sense that genetic medicine may become a reality in the future. But still, only about 2% of diabetes cases results from a specific genetic mutation, suc as MODY. The other 98% results from a complex interplay of genes and enviroment. Large studies in Sweden and
Finland found that family hisory is a more important risk factor for T2DM than any single clinical risk factor, noted Valeriya Lyssenko, Sweden. In fact, she said, a family history of diabetes carries an 8 fold increase in the risk of developing T2DM.
Proper diagnosis of MODY changes treatment, said Katherine Owen, Oxford UK, because patients with MODY are far more sensitive to gliclazide compared to patients with T2DM but equally sensitive to metformin. About 80% of MODY remains undiagnosed in the UK.
Review of incretin-based therapies
These drugs have opened new avenues in the treatment if T2DM. In terms of side effects and efficacy, I don´t think there is any good data to suggest that one DPP4-inhibitors is significantly better than another, said Adrian Vella, Mayo Clinic, US.
In terms of pharmacodynamics and pharmacokinteics there are some differences. All 5 DPP4-inhibitors on the market, sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin, inhibit 80% of DPP4 by blocking the active site of the molecule, she explained. They all produce significant and quite rapid inhibition of DPP4, she added. The agents also have a small but significant affect on both fasting and posprandial glucose levels. But they do not affect gastric emptying.
– GLP-1 receptor analogues are on the go with now 20 new agents in the studies coming up. Two of the drugs are short acting, exenatide and lixtisenatide, but the other 3 exenatide once per week, liraglutide and albiglutide are continuous-acting agents. And all 5 have been compared heat-to-head in nultiple trails.
While the 5 are similar at reducing blood glucose, there are significant differences in activity. The conitnuous-acting agents seem to be more effective at lowering blood glucose. But they also increase the risk of loose their effects. For HbA1c control, it seems better to have a long-cating GLP-1 receptor agonis, but for posprandial glucose reduction, it might be better to have a short-acting agent in parallel with basal insulin and rapid acting ainsulin in T1DM, according to Dr Knop, Denmark.
GLP-1 analogues have been show to erduce the blood pressure and cholesterol levels lowering the risk of cardiovascular events – still, the effect on cardiovascular disease is unclear.
Exenatide is more effective at reducing free fatty acids. On the negative side, exenatide, dulaglitide, and liraglutide have been show to increase the mean heart rate by 1,5 to 10 beats per minute, depending on the study. The only caution I can see for the GLP-1 agonists is increased heart rate, Dr Marso said, Kansas City Heart Institute, US. Whether this increased heart rate translates into increased cardiovascular events has yet to be determined.
There should be more data on the way and cardiovascular trials are currently under way with sitagliptin, alogliptin, saxagliptin, lixisenatide, exenatide once per week, lingliptin and liraglutide.
Benefits and risks of statins in diabetes
There is now robust evidence that statin use is associated with an increase of developing T2DM, Dr Sattar UK, but the overall effect is modest and is dose-dependent, so the risk is higher with more pontent and higher-dose statins. Statins do have fantastic benefit, according to Dr Sattar, but for people with low risk of cardiovascular disease but high risk for diabetes, lifestyle changes should be first and foremost before statins are considered.
Anne Goldberg, Washington Univ Hosp, US, discussed evidence for treating lipids in patients in diabetics. These patients have an increase both in short-term and long-term risk of cardiovascular disease. They also do not do as well after they have a cardiovascular event such as heart attack. We have a lot of clinical trial evidents if you treat a diabetic patient with a statin. Both the CARDS trial with diabetic patients over 40 years and had some additional risk factors, and the HOPE study clearly shows the benefit of simvastatin treatment. Also, diabetic patients who already have had heart attacks or stroke showed a benefit in clinical trials when they were treated with statins.
There also some large-scale metaanalyses of cholesterol trials that shows that as you get further decrease in LDL, the amount of risk reduction for cv events are greater. This is true in both mean and women, and whether they have high blood pressure or not. There are new drugs coming up, new omega-3 fatty acids that are developed for triglyceride lowering, and also new classes of LDL-lowering medications such as PCSK9 inhibitors.
Beta cell regeneration
A session handled this topic. Dr Stainer, San Francisco, US, explained that they have screened about 8 000 compunds looking for molecules that enhance beta cell regeneration and they have identified 5 copunds that double the bumber of beta cells. Four of them act on the adenosine singnaling pathway, a familiar pathway that is involved in a variety of physiological processes.
According to the scientist it is possible to use cell culture screens to identify agents that enhance beta cell proliferation in vitro, cell culture data are limited. They have studies in mice. They use zebrafish model to study molecular pathways that are active in beta cell regeneration. If you think about drug candidates, more than 90% of the drugs on the market are small molecules. The only real question was whether we could find small molecules that can caontrol the differentiation process
Insulin therapy 90 years
This year marks the 90th anniversary of the initial use os insulin therapy, and a historical approach is important to take
a) the first basal insulin replacement therapy used to manage blood glucose fluctuation for T1DM and T2DM was NPH, neutral protamine Hagedorn, insulin in 1946
b) 1978 came continuous subcutaneuous insulin infusion with an insulin pump, 36 years ago, which minimizedthe fluctuations.
c) in 2000 scientists developed insulin glargine, which was less variable in absorption, relatively peakless, and maintained a steady state of action beyond 24 hrs
d) 2004 came insulin detemir, which was less variable in absorption and nearly peakless, but had shorter acting than glargine
e) in 1996 rapid acting insulin entered the marked with insulin lispro. Versus regular human insulin the analogs have earlier onset and peak of biological activity, resulting in lower posprandial glucose levels; a shorter duration of action, resulting in less late postprandial hypoglycemia, and less biologic variability – resulting in fewer glycemic fluctuations.
f) premixed formulations – researchers need to better define which patients will benefit most of them.
g) longer acting basal insulin will be on the market for a year or two, with just one injection three times a week for T2DM
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