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Management of Diabetes with Cardiac Safety: Sulfonylureas stand test of Time


Management of Diabetes with Cardiac Safety: Sulfonylureas stand test of Time

With a proven efficacy, cost-effectiveness as well as now further validated CV safety in high-risk patients, Sulfonylureas based therapies still remain the preferred choice of physicians in the management of Type 2 diabetes in Indian patients.

It is well known that type 2 diabetes is associated with an increased risk of cardiovascular morbidity and mortality. Although much of this association can be attributed to the long-term complications of this disease, there has been growing interest in determining whether certain antidiabetic drugs influence this risk.

Therefore the endeavour of a treating physician is always to choose a diabetes treatment which has a proven benefit on reducing CV risk and mortality in people with type 2 diabetes and heart disease as well as cardiac safety.

Sulfonylureas have remained a potent, cost-effective and one of the most experienced armamentarium of Indian healthcare practitioners in the management of Type 2 Diabetes for a long time now.

Now in the light of latest evidence, Sulfonylureas seem to have added yet another feather to its cap by establishing its cardiovascular safety – this time in a more vulnerable diabetic population.

Based on the results of recent Trial, treatment in the Sulfonylureas sub-group indicated the relative safety of Sulfonylureas in a high cardiovascular risk population. The findings also indicate fairly insignificant differences in hypoglycaemia between groups treated with or without DPP4-i based therapy.

I. Cardiovascular Safety Studies with Anti-Diabetic Agents – The Need

In view of a number of CV safety concerns associated with certain glucose-lowering agents that emerged in the past, since 2008, evaluation of the CV safety of new glucose-lowering medications, by conducting large non- inferiority studies compared with placebo, became a requirement of both – American and European regulators

II. Interpreting Data from Latest Evidence

  • The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) was designed with the objective to evaluate the cardiovascular safety and kidney outcomes of linagliptin in patients with type 2 diabetes at high cardiorenal risk
  • Patients were randomized to receive linagliptin, 5mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines
  • The study included 6979 patients, followed up for a median 2.2 years, suggested that the use of linagliptin compared with usual care resulted in an incidence of the primary composite outcome (CV death, non- fatal myocardial infarction, or nonfatal stroke) of 12.4%vs 12.1%.
  • The hazard ratio had a 1-sided 97.5% confidence limit of 1.17, which met the criterion for non- inferiority (upper confidence limit <1.3).
  • Among patients with type 2 diabetes and high CV risk, linagliptin, compared with placebo, demonstrated non- inferiority with regard to the risk of major CV events over a median period of 2.2 years.

III. Cardiovascular and Renal Safety of Sulfonylureas subgroup

Some interesting data of this trial from the point of view of Sulfonylureas have been briefly tabulated and summarised as below

a. Baseline Participant Characteristics of Patients included in the primary analysis

 

Characteristics Linagliptin [n=3494] Placebo [n=3485]
Patients on Sulfonylureas (No. in %) 1102 (31.5) 1140 (32.7)

b. Analyses for the primary outcome (3-point MACE) by pre-specified baseline characteristics(in Sulfonylurea Sub-group)

Patient with event/patients analysed Hazard Ratio (95% CI) p-for interaction
Linagliptin Placebo
Patients on Sulfonylurea
No 315/2392 314/2345 0.98 0.84,1.14 0.31
Yes 119/1102 106/1140 1.15 88, 1.49

c. Subgroup analyses for the secondary kidney outcome by pre-specified baseline characteristics(in Sulfonylurea Sub-group)

Patient with event/patients analysed Hazard Ratio (95% CI) p-for interaction
Linagliptin Placebo
Patients on Sulfonylurea
No 252/2392 220/2345 1.10 0.92, 1.32 0.21
Yes 75/1102 86/1140 0.87 0.64, 1.19

d. Hypoglycaemic Events by both the Groups

Adverse Events No. (%) Linagliptin [n=3494] No. (%) Placebo [n=3485]
Hypoglycaemic  Events
  • Investigator reported hypoglycaemia
1036 (29.7) 1024 (29.4)
  • Confirmed hypoglycaemic adverse events with plasma glucose <54 mg/dl or severe events
557 (15.9) 572 (16.4)

Based on this most recent evidence, treatment in the Sulfonylureas sub-group indicated the relative safety of Sulfonylureas in a high cardiovascular risk population. The findings also indicate fairly insignificant differences in hypoglycaemia between groups treated with or without DPP4-i based therapy

IV. Possible Implications for Indian Healthcare Practitioners 

India has an estimated 72.9 million individuals living with Diabetes, in a milieu where there is still significant burden on the patient for out-of-pocket spending on healthcare. The magnitude of the problem has been substantiated by the results of an Indian study published earlier, which indicated that “financial constraints” account for non-compliance to anti-diabetic drugs in about “32 %” of the diabetic patients.

In view of such promising affirmation, suggesting non-inferiority with regards to major CV events in the Sulfonylurea subgroup group of this trial, which included Type 2 diabetes patients with high CV risk, it is time to reiterate the safety of Sulfonylureas.


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