New Medicines in Diabetes Management

Current medication

According to the World Health Organization (WHO) bulletin, the mortality rate related to Diabetes has been rising steadily since the 1980s. In the period between 2000-2016, it caused an additional 5 per cent increase in premature mortality.

In the case of traditional medications, (metformin, sulphonylureas, pioglitazone, insulin etc.) they offered excellent control on the blood sugar levels. However, such a glucose-centric approach does not result in a significant reduction iinsulin etc.) they offered excellent control on the blood sugar levels. However, such a glucose-centric approach does not result in a significant reduction in the in the rates of Diabetes-related complications. Though blood sugar control is effective in arresting microvascular complications (eye disease and kidney disease) yet the macrovascular complications (heart disease) and associated risk of death have remained largely overlooked.

Effects of medication

Every medication has its share of side effects and this is not unique to the newer ones. If we look at pioglitazone, it has one of the longest lists of adverse effects including anaemia, worsening of macular oedema (build-up of fluid in the eye which affects vision), heart failure, fracture risk and risk of bladder cancer, to mention a few. Even metformin is associated with gastritis, diarrhoea, nausea, vitamin 812 deficiency in the long run.

However, the most feared adverse event which scares both physicians and people with Diabetes is hypoglycaemia - low blood sugar levels. The two groups of anti-diabetic medications that are directly associated with it are sulphonylureas and insulin.

Newer drugs are also associated with their share of side effects like genital fungal infections caused by SGLT-2 inhibitors (a class of drugs that lowers blood sugar levels by removing the excess sugar through urine) and risk of pancreatitis, gastric irritation with GLP-1 receptor agonists (a class of drugs that stimulates insulin secretion). However, most of these complications are easy to handle with proper patient counselling. In addition, the significant impact these agents bring to the table dwarfs the associated side effects.

Diabesity

All the recent scientific findings including the guidelines prompted the research community to assess the cardio-renal risk in all people with Type 2 Diabetes before choosing the most appropriate medication for them. The very recent, SIMPLE algorithm, endorses using combination therapy for all people with Type 2 Diabetes with one agent chosen from those capable of altering outcomes (Disease Modifying Anti-Hyperglycaemic Agent) and one or more from the glucose-lowering group (GLA).

It is equally important to identify people who are at risk of adiposopathy (the propensity of weight gain and fat accumulation in people who are ill). The recent INSPIRED study by Mohan et al. documented a significant impact on pancreatic health in those below 40 years of age with a normal body mass index (BMI). Identification of those with an increased risk of metabolic diseases as well as associated complications is missed by assessing people with international BMI values. Using BMI based on Indian cut-off values and waist circumference in those with a normal BMI (according to the international values) is extremely important in identifying at-risk individuals.

Diabesity (Diabetes + Obesity) is associated not only with metabolic disorders but also with significant comorbidities like osteoarthritis, NASH (liver disease) and obstructive sleep apnoea (sleep disorder). A treating physician needs to identify diabesity and institute a holistic Dr Samit Ghosal is a consultant Endocrinologist in Nightingale Hospital, Kolkata.

Dr Ghosal is current Vice President of IDEA (Integrated Diabetes and Endocrinology Academy) and Secretary of EKDG (East Kolkata Doctors Group).management plan. To tackle diabesity effectively, the target weight loss is

5 percent from baseline, with a 15 per cent reduction from baseline being the most effective strategy. Amongst the available SGLT-2 inhibitors and GLP-1 receptor agonist, at current doses, achieving 5 per cent weight loss from baseline is rarely attained except for a lucky few.

Semaglutide and tirzepatide

The most effective treatment options for diabesity is offered by liraglutide 3 mg and semaglutide once weekly at a dose of 2.6 mg. In India, we are expecting the launch of injectable semaglutide for weight loss sometime in the next year. It would fulfil the unmet need for the management of diabesity.

Research studies have shownthat nearly 67.5 per cent of people achieved HBAlc <6.5 per cent and a 6.2 per cent weight loss from baseline with semaglutide.

With 3 mg liraglutide and 2.6 mg semaglutide opening the door to more effective management of diabesity, the dual GIP and GLP-1 receptor agonist is a take-off from that baseline. Studies suggest a 10 per cent weight loss and HBAle reduction of around 2 per cent with tirzepatide. These are some very exciting news and I think the entire medical community is looking forward to this value addition.

As of now, we can only refer to oral semaglutide as the oral equivalent of a GLP-1 receptor agonist. The metabolic benefits of oral formulation compared to their injectable counterpart is attractive. However, in the absence of a dedicated cardiovascular outcome trial (CVOD) demonstrating its superiority, not all people can be handed over this advantage.

Future of Diabetes management

The direction of Diabetes management for the future can be assessed and estimated by looking at the research projects in the pipeline. A bulk of research is concentrated on classes of drugs like GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonists, dual GLP-1 receptor agonists/GCCR and triagonists (GLP-1 receptor agonists/GIP/glucagon).

The predominant focus of these drug combinations is on managing diabesity and its associated adverse outcomes. Along with SGLT-2 inhibitors, these medications are expected to make a sea-change in the way Diabetes will be managed in the future.

Organ protection

The shift from Diabetes management to organ protection could be well witnessed in the present times. The presence of overwhelming scientific evidence in support of the latter does not validate the glucose-centric approach anymore. Such a paradigm shift has already happened in the cardiology - heart-related (benefits of statins beyond lipid-lowering) and nephrology - kidney-related (benefits of ACEi and ARBs beyond blood pressure control). Now it is time to do the same with blood sugar management.