As another new year begins, we can reflect on the ingenuity of the past. Early in the 19th century, Royal Artillery surgeon John Rollo first used the term ‘diabetes mellitus’ to describe the excessive production of sweet urine by a “large corpulent person”.
Rollo differed from his peers, deducing that the problem arose from metabolism and not urination. He proposed appetite suppression with nauseating substances and a regulated low-carb diet “of animal food principally”. Sound familiar?
Rollo’s early methods are surpassed by the global collective wisdom of generations of clinicians, scientists and entrepreneurs. The 1920s provided insulin and metformin, while the 1940s brought sulfonylureas. Since 1990, many other drug classes have been commercialised.
Management guidelines grow fatter as more therapies and expanding research change best practice. Summary flowcharts still channel nostalgia for ‘stepwise’ management plans, but struggle to succinctly describe myriad options for numerous situations. Some basic concepts will help navigate this confusing landscape.
What is the overall treatment objective?
Is the objective of a professional football club to win matches? If a mediocre team has packed stadia and huge profits every season, it might risk ruin by buying better, but expensive players. Winning titles may lead to success, but not always. Diabetes is defined by high blood sugar, so we dutifully treat glucose. However, the main objective is really to maximise length of life free from amputation, heart disease, dialysis and blindness. Lowering glucose may achieve this, but not always.
Key messages
- Glycaemic control alone is inadequate for cardiovascular protection if attempted after years of hyperglycaemia.
- Prioritise SGLT2i or GLP1RA in certain T2DM cohorts for improved longevity, reduced hospitalization, and protection from cardiovascular and renal disease regardless of glucose effects.
- You can call the Diabetes Connect hotline for GPs on 9436 6270 to speak to an endocrinologist for advice. This service is run by Diabetes WA and supported by the Australian Government.
Glucose lowering with a bonus of organ protection
Rigorously adhering to stringent targets (e.g. HbA1c <7%) delays microvascular complications. If applied early from diagnosis and for as long as possible, macrovascular disease and mortality is also delayed. These benefits persist even if there is less diligent control later. However, there is a narrow window of opportunity, as stringent glucose control becomes insufficient for preventing death, MI and stroke in patients with chronically suboptimal levels.
Rollo frequently observed treatment failure due to “the careless and faulty application of [his methods] by most physicians” and “rebellion of patients”. Avoid procrastination and hit targets by intensifying therapy. Metformin is usually recommended as first-line. After that, it’s your choice. I am often asked if sulfonylureas are “bad”, or if early use of insulin should be avoided. All agents should be on the table, chosen for the clinical context, and always subject to review.
New potent incretin agents such as the weekly GLP-1 receptor agonists (GLP1RA) and twin GIP/GLP1 agonist tirzepatide enable the realistic possibility of diabetic utopia: normoglycaemia (HbA1c <5.7%) without hypoglycaemia. We are clearly not helpless for want of effective options.
However, throwing more medications at the problem won’t work if intolerance provokes non-compliance. Always consider the positive or negative impacts of proposed treatments on girth, gut, hypos, sanity and bank accounts. Allied health review for diabetes education and lifestyle modification will improve patient buy-in. Also, weight loss by any method (especially >15% below baseline) can achieve prolonged normoglycaemia without glucose lowering agents. However, a rebound in weight will see the return of elevated blood glucose.
Organ protection with a bonus of glucose lowering
GLP1RAs and SGLT2 inhibitors (SGLT2i) have outsized value for those with high cardiovascular risk, symptomatic heart failure and nephropathy. The cardiovascular and kidney preserving benefits are unrelated to lowering glucose.
In contrast, other classes of diabetes medications only lower glucose as their sole therapeutic benefit – except for pioglitazone which has an unfavourable side-effect profile. The special roles for GLP1RA and SGLT2i have been acknowledged in major guidelines since 2018. Yet, uptake has been glacial in those with the greatest need.
In patients with specific comorbidities, a glucocentric strategy must be supplanted by an organ protecting strategy. We need to change paradigms – SGLT2i and GLP1RA are actually agents for longevity and preventing cardio-renal disability, with a bonus of glucose lowering.
Potent incretin agents also improve obesity, sleep apnoea and metabolic fatty liver disease. Therefore, if patients have a relevant comorbidity, add or switch to SGLT2i or GLP1RA even if glycaemic goals are met with other agents. And don’t forget the lipids and blood pressure.
Author competing interests – Author has received educational grants or honoraria from Eli Lilly, Novo Nordisk and Astra Zeneca.
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