New Therapies for Type II Diabetes: Professor Tony Barnett

The UKPDS (United Kingdom Prospective Diabetic Study) showed (by extrapolation of data) that for every 1% reduction in HbA1C there was a 20% reduction in death rate, 14% reduction in MI, and 40% reduction in eye, kidney and neuropathy problems. But note that all the patients were newly-diagnosed diabetics.

We were suprised by recent studies (e.g.the ACCORD trial) which have showed an increased risk of mortality from tight control, but this should not deter us from aggressive early control in newly diagnosed diabetics, as these studies were in older people who were  (arguably unethically) "over-treated" which led to a lot of hypoglycaemias and whose consequent arrhythmias led to deaths!

Note that even 10 years after the UKPDS was stopped, and the two groups therefore "converged" metabolically, the "legacy effect" of early good diabetic control still resulted in profound benefits for that group. Therefore go for good early control - to get the HbA1C < 6.5 on 2 drugs if necessary. If A1C is >7 go on to step 3. (NICE did get this one right!) It is easier to not lose control than to try to get control back once you have lost it! Since there is doubling of CV risk in patients with IFG (Impaired fasting glucose - "pre-diabetes" - i.e. fasting glucose 5.5 - 7.0) arguably we should be intervening even earlier with lifestyle modification and even metformin!

Metformin is still the first line drug with so much to recommend it - well-established (no surprises round the corner after all this time), weight neutral and no attenuation of effect with time.

Sulphonyureas - still useful, but lose their effect fairly quickly, cause weight gain (e.g. 5kgm in 1st 3 yrs of UKPDS) and risk of hypoglycaemia.

....And Hypoglycaemia is very important! Only 20% of significant hypos are known to their GP (recent study) and 1:5 pts on sulphonylureas p.a. have a hypos. Hospitalisation for hypos are far from rare and up to 1/3rd of them die; mostly elderly with co-morbidities, reflecting the dangers of hypos in this group.

Glitazones are insulin-sparing and treat insulin resistance brilliantly, but worrying reports on Cardiovascular safety of Rosiglitazone; all new glitazone patients (at the very least) should opt for pioglitazone (not Rosiglitazone).

Diabetes is a progressive disease, but it isn't the insulin resistance which worsens; it is the islet cell dysfunction, so our main focus is to treat the insulin resistance and to try to preserve islet cell function.

Oral glucose stimulates a far better glucose-lowering effect from the pancreas than intravenous and this is mediated mainly by the "Incretins" (GLP1 and GIP). GLP1 is most important, increasing insulin secretion, decreasing glucagon, slowing gastric emptying and promoting satiety; if you gave a continuous infusion of GLP1, diabetes would not be apparent; unfortunately GLP1 only lasts 1 - 2 minutes in the body, being rapidly removed by DPP4.

The pharmaceutical industry has come up with 2 ways around this problem of the short half-life of GLP1:

1. To produce a GLP1 analogue which is not degraded. e.g. exenatide (Byetta) which in one study at least performed as well as glargine insulin without causing the weight gain! But expensive and must be given by injection.

2. "Sabotage" the DPP4 e.g. vildagliptin ("Galvus"). This can be given by mouth and the big advantage is that there are no significant hypos on this regime; indeed in some combinations, it seems to protect against hypos!

The consequences of hypoglycaemia can be devastating physically, socially and work-wise and vildagliptin offers some considerable advances on previous treatments as an add-on therapy in reducing hypos with the added benefit of no weight gain.