Type 2 Diabetes, new oral tablet, SGLT2 inhibitor

Management of hyperglycaemia is still a challenge in patients with type 2 diabetes mellitus despite an increase in the pharmacological options. Although metformin is the first drug to be started for the treatment of type 2 diabetes mellitus, some patients may not tolerate it and the many patients do not get adequate control with metformin alone and an additional drug will become necessary.

Use of sulfonylureas is complicated by hypoglycaemia and weight gain. Although DPP4 inhibitors have lesser risk of hypoglycaemia and weight gain, they are expensive. In most of the patients with type 2 diabetes on oral antidiabetic drugs (OADs), the disease progresses and Insulin becomes necessary for the treatment.

SGLT2 inhibitors are the new armour in the hands of the physicians for the treatment of type 2 diabetes. Two SGLT2 inhibitors dapagliflozin and canagliflizon are already available in the market and the third one empagliflozin is expected to commercialise in the near future. SGLT-2 belongs to the family of sodium glucose co-transporters which are located in various tissues including kidney, brain, liver, heart, thyroid and muscle.

The transporter SGLT2 is responsible for 90% of the glucose reabsorption from the kidneys. The physiological role of SGLT2 inhibitors in non-renal tissues has not been identified. SGLT1 is present in intestine, kidney, heart, trachea, brain, testes among others. Selective inhibition of SGLT2 is important because inhibition of SGLT-1 transporter can lead to glucose malabsorption and diarrhea.

Most glucose filtered through the glomeruli is reabsorbed in the proximal renal tubule, mediated by SGLT-1 (10%) and SGLT-2 (90%). Inhibition of SGLT-2 promotesrenal glucose excretion.

Efficacy depends on the amount of glucose filtered through the glomeruli. The glycosuria induced by glomeruli has been linked with various metabolic responses in type 2 diabetes mellitus patients including increased total glucose removal, improved beta cell function, and shift in glucose utilisation from glucose to lipid.

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Reabsorption of glucose form kidney through SGLT1 and SGLT2 receptors

 

Clinical trials comparing SGLT-2 inhibitors and DPP-4 inhibitors

There are only a few clinical trials comparing SGLT-2 inhibitors and DPP4 inhibitors available.The DPP-4 inhibitor that is used in all the trials is sitagliptin 100mg. The details of the phase 3 studies have been enumerated in Table.

Canagliflozin has showed non inferiority when compared with sitagliptin and subsequent analysis showed superiority with greater reductions in body weight, FPG, and blood pressure over the period of 52 weeks. Overall adverse events were similar with canagliflozin and sitagliptin but higher incidence of genital mycotic infections and osmotic di

uresis related adverse events were observed with canagliflozin. Incidence of hypoglycaemia was low for both the drugs.

Empagliflozin also showed similar or greater reductions in HbA1C with clinically relevant reductions in weight and systolic blood pressure. The adverse effects reported were slightly increased incidence of genital infections and benign urinary infections. Incidence of hypoglycaemia was low for both the drugs. No such comparison in available for dapagliflozin.

Since the clinical trials comparing SGLT-2 inhibitors with DPP-4 inhibitors are for short term, conclusions about long term safety of the drugs are difficult to make. And also there is not much data available on the durability of glycaemic control with SGLT-2 inhibitors.

Therefore, at present it is difficult to choose between the two classes of drugs for the control of hyperglycaemia considering the advantages and disadvantages of each drug. More prospective, long term, randomized control trials may help us to choose between the two drugs in the future.

On the other hand GLP-1 receptor agonists, e.g. liraglutide as monotherapy or as add on to metformin appears to offer greater glycaemic control and similar weight loss benefits in patients with T2DM, than therapy with the SGLT-2 inhibitors, dapagliflozin and canagliflozin. However, liraglutide is associated with greater weight loss in patients with higher baseline BMI. No interaction between baseline BMI and weight reduction has been observed for dapagliflozin.

Table 1: Details of phase 3 studies comparing SGLT-2 inhibitors and DPP-4 inhibitors

 

Patients

Change in HbA1c %

Change in fasting plasma glucose

mmol/l

Change in Post prandial plasma glucose

mmol/l

Change in systolic blood pressure

Mm hg

Change in body weight

kg

Conclusion

SCHERNTHANER et al.

(52 weeks)

Canagliflozin 300mg

Sitagliptin 100mg

377

378

-1.03

-0.66

-1.70

-0.3

-3.3

-2.2

-5.1

-0.9

-2.3

0.1

Demonstrated non inferiority of canagliflozin and subsequent assessment showed superiority withgreater reductions in FPG, bodyweight and blood pressure compared to sitagliptin

Roden et al.

(24 weeks)

Placebo

Empagliflozin 10mg

Empagliflozin 25mg

Sitagliptin 100mg

228

224

224

223

0.08

-0.66

-0.78

-0.66

0.65

-1.08

-1.36

-0.38

NA

-0.3

-2.9

-3.7

0.5

-0.33

-2.26

-2.48

0.18

Similar or greater reductions in HbA1C with clinically relevant reductions in weight and systolic blood pressure.

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