Anti-Diabetic Medications: Time for an upgrade on National Formularies?
Dr. C.V. Alert, MB BS, DM.
In late 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) produced “new” Guidelines for the management of type-2 diabetes mellitus,T2DM, introducing a few new classes of anti-diabetic medications, including two incretin-related classes: the Glucagon-like peptide -1 receptor agonists (GLP1 RAs, or GLP1s), and the Dipeptidyl Dipeptase-4 inhibitors (DPP4- inhibitors). The sodium-glucose co-transporters 2 inhibitors (SGLT-2) soon followed, giving the world a new collection of drug classes. Should these drugs appear on National Formularies in the Caribbean?
The older drug classes: Metformin (a biguanide), various sulphonylureas (SUs) and Insulin- at least some of the older ones, remained the cornerstone of anti-diabetic drug therapy in most Caribbean countries.
The latter three classes have been around for some time, but have failed to reduce all-cause mortality or cardiovascular mortality in diabetic patients, internationally and certainly locally. Thus diabetes is always viewed as being a very deadly disease, with a majority of diabetic patients developing one or more of the major complications like renal disease, cardiovascular disease, blindness, and amputations. The ‘cardiovascular disease’ complication opens a whole new series of illnesses, including heart diseases and strokes (cerebrovascular disease).
These ADA/EASD guidelines have been updated annually, and other major organizations have based their guidelines on this 2012 prototype.
For some time there has been a suspicion that one of the main classes of anti-diabetic medications, the sulphonylureas (SUs), may actually contribute to deaths in T2DM patients. This has attracted the attention for almost half-a-century, following up on an impression from one of the initial studies of the SUs that this class of drugs may ultimately be causing more harm than good, in spite of their blood-glucose lowering properties. Should the SUs prove to be dangerous to the health of the diabetic patient, the options were limited : the biguanides were associated with ketoacidosis, a complication of high morbidity and mortality, and there were many issues associated in getting many diabetics who probably needed insulin to actually use insulin optimally. Apart for the needle stick itself, the great fear was hypoglycemia: many a patient swore never to use insulin again after a severe hypoglycemic episode.
In the Caribbean, the reluctance to use insulin to better manage blood sugars seems to be shared by both physicians and their patients. It is note-worthy that the recently launched Barbados Diabetes Research and Education Task Force, a composite group that includes members from the Ministry of Health and the UWI Faculty of Medical Sciences (FMS), the Barbados Diabetes Foundation and the Barbados Diabetes Association, have launched an electronic learning module that hopes to re-energize the use of insulin in Barbados. It is hoped that this can contribute to a much needed improvement in diabetes related morbidity and mortality.
Since 2008, regulatory authorities in the USA and Europe have mandated that all new classes of anti-diabetic medications undergo trials with specific emphasis on cardiovascular outcomes. Outcome studies of drugs belonging to at least two new classes, the DPP-4 inhibitors, and the SGLT-2 inhibitors, were recently published, and a few more are scheduled to be completed in the next few years. Early results, from the TECOS and the EMPA-REG studies, support good cardiovascular outcomes for the individual drugs tested. If other drugs in the two classes produce similar results, then the role of these ‘new’ drugs in T2DM management will command priority consideration.
On the other hand, the evidence on the negative cardiovascular effects of the SUs still remains controversial. Data presented at the 2015 EASD meeting included an analysis of 84 Randomized Controlled Trials (RCTs) and 26 observational studies, involving over 1.5M patients, showed that treatment with a SU was associated with a higher all-cause mortality and cardiovascular mortality when compared with all other treatments (1).
One particular sulphonylureas, gliclazide MR, was involved in the ADVANCE study and the (follow-on) ADVANCE-ON studies which followed over 10000 patience (ADVANCE) and 8000 (ADVANCE-ON), over at least 5 years, was associated with good cardiovascular and renal outcomes. In this, gliclazide MR is an ‘atypical’ SU, and the cardiovascular outcomes seem similar to available outcomes for the DPP-4s.
So where does this leave the Caribbean physician who relies on the National Formulary? Certainly Metformin (a biguanide) and gliclazide MR (a SU) appear in the formulary: current available guidelines support the use of these drugs. Metformin is also low cost, and has a good safety profile. Many of the other SUs, though currently ‘tolerated’, promote weight gain and can cause hypoglycemia, increasing the risk for a cardiovascular event; in the Caribbean we have no shortage of cardiovascular events that we can barely afford to manage. The SUs also seem to accelerate exhaustion of the pancreas, leading to ‘secondary failure’ a few years after the patient began to use them: at this point ‘insulin or death’ become the patient options.
Knowing that most of our diabetic patients are overweight or obese, knowing that the #1 cause of death is cardiovascular disease, and knowing that T2DM is a progressive disease in which there is progressive destruction of the beta-cells, why would we use drugs that promote weight gain, that can cause hypoglycemia which amplifies the cardiovascular disease, and which accelerate the destruction of the beta cells? We now have classes of drugs that cause weight loss or, at the worst, are weight neutral; they do not cause hypoglycemia, and preserve or enhance (at least in animal models) beta cell function.
There are obvious legal implications associated with the continued use of drugs that may increase the risk for a cardiovascular event. The lawyers of a diabetic patient who dies from a heart attack, for example, may try to convince the court that it was the medication and the physician who prescribed it, rather than the underlying disease, that killed his patient, and the physician who used certain medications may find himself/herself on a sticky-wicket in defending against such charges, based on current medical data about these drugs.
Since the majority of local patients utilize the free polyclinic services, and physicians attached to these polyclinics tend to rely on the drugs available on the National Formulary, then some sort of reassessment of this arrangement is needed.
Thus there are at least medical and legal reasons, and certainly financial ones, why the antidiabetic drugs on the National Formulary needs to be reviewed. The Barbados Health of the Nation (HotN) study, published early in 2015, clearly showed that a majority (62%) of known T2DM patients were not attaining glycemic targets (HbA1c < 7%). The government’s reduction of funding for primary (and tertiary) services is likely to cause further deterioration in the health situation, unless a major restructuring exercise is implemented. If we want to improve the health of our patients we need to upgrade the services we make available to them: part of this includes making better drugs available. And if we think that the cost of the new medications are expensive, stop for a moment and think about the sums involved in medical litigation, which include the costs of legal fees. Can we afford not to upgrade our antidiabetic armamentarium?
If we continue to dream about medical tourism becoming a potential income-earner in the near future, then we need to wake up quickly, and both the medical services and the legal infra-structure, at a minimum, need significant strengthening. Meanwhile, we need to take better care of our own people: making better anti-diabetic drugs available for our patients is but one of many steps needed.
1. Baxter, C et al. EASD Annual Meeting 2015. Abstract 128.