The National Institute of Health and Care Excellence (NICE) in its latest guidance published recently, recommended three new drugs, ‘Canagliflozin, Dapagliflozin and Empagliflozin’, for curing type 2 diabetes mellitus.
These drugs are administered as forms of monotherapy and offer alternatives to contraindicated antidiabetic drugs such as; metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas and pioglitazone. These drugs provide remedies for patients whose glucose management is out of control due to a lack of exercise and diet control procedures.
Carole Longson, Director, NICE Centre for Health Technology Evaluation (CHTE), said, “For many people whose blood glucose levels aren’t controlled by diet and exercise alone, metformin is the first drug treatment that they’ll be offered. But some people may experience nausea and diarrhea, and they may not be able to take it if they have kidney damage. For people who can’t take a sulfonylurea or pioglitazone, then the three drugs recommended in this guidance can be considered. This is as an alternative to the separate group of drugs called dipeptidyl peptidase-4 inhibitors.”
These drugs go by the following names; Canagliflozin as Invokana, Dapagliflozin as Farxiga and Empagliflozin as Jardiance.
Basis For This Guidance
This guidance is based on a systemized literature review conducted by the assessment group (AG) of NICE. Data related to mono-therapies and the safety and efficacy of all the three drugs i.e. Canaglifozin, Dapagliflozin and Empagliflozin was analyzed.
Observed patients were those individuals whose diabetes conditions remained uncontrolled despite exercising, maintaining a balanced diet and using metformin. The AG collected and analyzed the data from 7 relevant clinical trials conducted in different parts of the world including Japan and China, for all three drugs. The data for Canagliflozin and Dapagliflozin was compared with the placebo whereas for empagliflozin, the data was compared with other DPP4 inhibitors.
It was observed that all the patients were suffering from diabetes for less than five years, with the average BMI (body mass index) being 25-34 kg/m2, HbA1c levels ranging from 7.5 to 6.4% and 10.6 to 11.5% and the mean age falling between 50- 60 years.
The primary outcome for all the clinical trials was any level of change in HbA1c . On average it was concluded that all of the aforementioned therapies reduced the HbA1c levels from -0.39% to -1.17%, which was higher than placebo treatment. For secondary outcomes, parameters such as effects on body weight, blood pressure, monitoring of cholesterol levels and hypoglycemia were considered. All three drugs were found to reduce the body weight from 0.97kg to 3.9 kg (which was more compared to the placebo) and reduce blood pressure. It was also found that SGLT-2 inhibitors did not cause hypoglycemia and that they can increase all types of cholesterol. The adverse effects of all the SGLT-2 inhibitors included mild to moderate urinary tract infections, found commonly in females.
Due to the scarcity of direct evidence-based data, both SGLT-2 manufacturers and the AG conducted a meta-analysis by comparing the trial data of SGLT-2 inhibitors with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonyl ureas, pioglitazone and repaglanide.
For that purpose, data of type 2 diabetic patients whose glucose levels could not be controlled by diet and exercise was analyzed. Outcomes such as changes in the HbA1c levels, body weight, incidence of hypoglycemia and changes in blood pressure were evaluated.
The Janssen network meta-analysis demonstrated the results of the use of 100mg of Canagloflozin. It showed an increased weight reduction when compared with Dapagliflozin and 10mg of Empagliflozin. However, no change in blood pressure was observed. Yet it reduced HbA1c to a greater extent when compared to DPP-4 inhibitors.
Similarly, in comparison with pioglitazone, Canagloflozin use demonstrated a good impact on controlling blood pressure and weight. On the other hand, no significant difference was observed regarding the use of sulfonylureas.
The AstraZeneca network meta-analysis was based on the comparison of different classes of the anti-diabetic drugs rather than specific drugs. The SGLT-2 inhibitors, in comparison with the DPP-4 inhibitors and pioglitazone, showed no significant differences for HbA1c and hypoglycemia while demonstrating better results for reducing weight and blood pressure.
The meta- analysis conducted by the Boehringer-Ingelheim network concluded that in all its dosages, Empagliflozin, along with the other SGLT-2 inhibitors, demonstrated greater reduction in HbA1c levels when compared to placebo treatments. Additionally, a greater reduction in systolic blood pressure and body weight was observed in comparison with the placebo and SGLT-2 inhibitors.
Similarly the network meta-analysis of the Assessment group (AG) concluded that all the SGLT-2 inhibitors were more effective for reduction in HbA1c and weight levels compared to the placebo. It was also observed that the inhibitors were more effective than sitagliptin was for HbA1c and weight change. Similarly, they demonstrated no significant differences in HbA1c levels compared to the sulfonylureas but were more effective in controlling weight.
The AG also assessed evidences from patients and various clinical experts regarding the safety and efficacy of SGLT-2 inhibitors. It also conducted a cost effectiveness analysis of the therapy with SGLT-2 inhibitors, comparing it with other antidiabetic drugs. Consequently, all of these studies finally concluded that the three SGLT-2 inhibitors were clinically effective, improved the patient’s quality of life and were cost-effective. Therefore, they can be employed as treatment options for adult type 2 diabetes mellitus.
About The Three Drugs
All of these three drugs i.e., Canagliflozin (Invokana by Janssen), Dapagliflozin (Farxiga by AstraZeneca) and Empagliflozin (Jardiance by Boehringer Ingelheim and Eli-lilly UK) are available as tablets for oral administration. They belong to a class of drugs called SGLT-2 (sodium glucose cotransporter-2) inhibitors and help in ensuring proper glycemic controls by promoting the elimination of excessive glucose through the urine. Furthermore, these drugs also stop the reabsorption of the glucose through the kidneys. The mechanism of their behavior is independent of insulin action.
All of these drugs possess marketing authorization for treating adult type 2 diabetes mellitus in the UK. They can be administered as monotherapies among patients in whom metformin is contraindicated or if they are intolerant to it. If proper glycemic controls in such patients cannot be attained through exercise and diet control plans, these drugs can be used. These drugs can also be prescribed as additional combination therapies along with other hypoglycemic medications such as insulin, in addition to exercise and diet.
Canagliflozin (Invokana) is a product of Janssen and is available in tablet form in the strengths of 100 and 300 mg. The treatment can be started from the initial recommended dose of 100 mg once a day. However, the dosage can only be increased to 300mg once daily if glycemic levels cannot be controlled by the initial starting dose and if the patient can tolerate the additional dose.
The most commonly reported adverse drug reactions include constipation, polyuria, and urinary tract infections such as vulval and vaginal candidiasis, nausea, balanitis and an increase in hematocrit volume.
Dapagliflozin (Farxiga) is manufactured by AstraZeneca and is available in the form of film-coated tablets in the strengths of 5 mg and 10 mg. Its recommended dose, when given as a single therapy, is 10 mg administered once a day. Although it can be prescribed as additional therapy along with other anti-diabetic drugs and insulin, it is not recommended for patients with any type of renal abnormality.
Major adverse effects include dysurias, dyslipidemias, polyuria and infections of the urogenital tract. Other side effects may include balanitis, backache and an increase in hematocrit volume.
Empagliflozin (Jardiance) is manufactured by Boehringer Ingelheim and Lilly, and is currently available as 10mg and 25 mg film-coated tablets meant for oral use. The initial recommended dose for the monotherapy with empagliflozin is 10mg once daily. The dose can be increased up to 25mg once daily among tolerant patients with an increase in the dose being unavoidable in ensuring proper glycemic control. Common side effects associated with this drug include infections of the urinary tract, pruritis, polyuria and vaginal moniliasis.
About Type 2 Diabetes Mellitus
It is a group of progressive metabolic disorders that is characterized by increased blood glucose levels, known as hyperglycemia. It occurs due to the absence of a hormone called insulin or due to the development of resistance associated with its actions. The condition worsens with respect to time.
It is estimated that in 2013, approximately 2.7 million people were diagnosed with diabetes in England. Out of these people, 90% were suffering from type 2 diabetes. It was observed that the increased prevalence of this disease was related to a lack of physical activity, increase in obesity and changes in lifestyle.
People suffering from this disease often find it difficult to tackle their condition since the therapy affects their daily lives. Furthermore, they can develop other complications such as eye-sight problems and neuropathy. They can also experience additional difficulties in managing their blood glucose levels if they are unable to control their diet, exercise or take medications regularly.
Controlled blood sugar levels can help in limiting the risks for the development of other complications such as anxiety and depression associated with the failure of glucose management.
Sometimes patients are hesitant to inject insulin, thus if other options such as the previously-mentioned three drugs, are available, they will not require insulin injections at regular intervals. Finally, it is worth repeating that the condition can be managed through proper diet and exercise, through the use of oral tablets or through insulin administration.