There are currently four SGLT-2 inhibitors licensed for the treatment of diabetes. Canagliflozin, dapagliflozin, empagliflozin and ertugliflozin.
At the 2020 virtual conference of the America Diabetes Association the results of the cardiovascular outcomes study for ertugliflozin were released. This was the final drug in the group to release the results of a cardiovascular study although full publication in a peer reviewed medical journal is still pending.
We already know that these drugs are effective in reducing HbA1c, blood pressure and body weight. We also know that this group of medicines reduce hospital admissions for heart failure and renal function decline. However there is variation in the impact on cardiovascular outcomes. Empagliflozin reduced cardiovascular events and cardiovascular deaths; canagliflozin reduced cardiovascular events, but not deaths; while dapagliflozin was not statistically significant in either of these areas. This latter finding may be explained in part by the much higher proportion of patients without overt signs of cardiovascular disease (60% compared to 0% in the empagliflozin study and 35% and 50% in the canagliflozin studies).
So what does this new study add? It was conducted in just over 8,000 patients and exclusively in secondary prevention patients who were followed up for around 3 years. The study failed to demonstrate a reduction in major cardiovascular events compared to placebo. Nor did it show reductions in cardiovascular deaths or renal-related outcomes. It did demonstrate a 30% reduction in the risk of heart failure related hospital admission.
It was hoped that this study would mirror the results of the empagliflozin study and demonstrate reductions on cardiovascular endpoints and death, thus confirming a group of medicines that deliver cardiovascular benefits to patients with diabetes. Although previous and updated meta-analyses indicate there is a statistically significant reduction in cardiovascular events in secondary prevention patients, there is only a trend in primary prevention patients. And these findings are not replicated for all of these drugs in individual studies.
Based on the current evidence it would seem that this group of drugs do reduce hospital admission for heart failure. Furthermore, as a group, they also seem to reduce cardiovascular endpoints, cardiovascular deaths and renal outcomes. But there is only one drug in the group that has shown individually that it does all of these things in a single trial; and that drug is empagliflozin.
Based on the curent evidence then, it would seem prudent, despite ertugliflozin being less expensive, to use empagliflozin as the agent of choice in patients diabetes who need treatment intensification who:
- also have established cardiovascular disease
- are at risk of hospital admission for heart failure
- are at risk of renal function decline
Patients who are not in one of these groups could be offered an SGLT-2 inhibitor of lowest acquisition cost as an option alongside other classes of drugs that are available to treat hyperglycaemia with discussion of the relative advantages and disadvantages before commencing treatment.
Action: Clinicians should be aware of the emerging evidence for this group of drugs and bases treatment decisions on the best available evidence.
Following the recent cardiovascular and fracture risk safety concerns associated with the glitazones and the introduction of a new class of hypoglycaemic, it seemed timely to review the Formulary Advice for type 2 diabetes.
Blood pressure remains more important than blood glucose because tight blood pressure control was found to contribute to reductions in deaths from long term complications, strokes and serious deterioration in vision in the United Kingdom Prospective Diabetes Study (UKPDS).
Metformin remains the first line choice based on its glucose benefits and the reductions in cardiovascular events observed in (UKPDS).
Sulphonylureas are second line agents based upon their well known efficacy and safety profile compared to the emerging safety concerns associated with the glitazones and the unknown safety profile of the newer gliptins.
Patients should have hypoglycaemic drugs added if they continue to have symptoms of diabetes, or if all other cardiovascular risk factors arecontrolled while HbA1c remains suboptimal. Drugs can be substituted if the patient experiences adverse drug reactions.
- Metformin for all patients, titrate to maximum tolerated dose
- Add (or substitute) Sulphonylurea (gliclazide or glipizide) and titrate to maximum tolerated dose
- If either metformin or a sulphonylurea is not tolerated, add pioglitazone provided the patient does not have heart failure and is not at high risk of developing heart failure
- If either metformin or a sulphonylurea is not tolerated and the patient has existing heart failure or is at high risk of heart failure, add a gliptin (sitagliptin is the only available option at the time of posting although more agents are expected)
As a rule of thumb hypoglycaemics reduce HbA1c by approximately 1%. In patients who are unlikely to reach an optimal level through combined use of oral agents consideration should be given to earlier initiation of insulin.
Earlier this year the Summaries of Product Characteristics (SPC) for Atorvastatin (Lipitor®) and Ezetimibe/Simvastatin (Inegy®) were updated. These new documents list details of the expected reductions in total cholesterol from untreated baseline results.
A previous article has suggested a stepped approach to lipid management however the information in the updated SPCs has changed this advice.
Simvastatin 40mg is still the first line choice. Based upon an expected additional cholesterol reduction, atorvastatin 40mg is second line. Third line is atorvastatin 80mg.
Reversion to simvastatin 40mg with the addition of ezetimibe is no longer recommended as a third line option as the additional reduction in cholesterol is very small. The expected reduction in total cholesterol is 39% compared to a 38% expected reduction with the second line choice.
Action: The revised stepwise approach to lipid management is as suggested below:
- Simvastatin 40mg tablets - expected total cholesterol reduction of 30%
- Atorvastatin 40mg tablets - expected total cholesterol reduction of 38%
- Atorvastatin 80mg tablets - expected total cholesterol reduction of 46%
The National Institute of health and Clinical Excellence (NICE) published a technology appraisal on the secondary prevention of osteoporotic fractures in postmenopausal women in January 2005.
NICE are also working on a similar appraisal aimed at primary prevention but until this is published it will be difficult to assess who to treat as primary prevention should be based upon a risk assessment.
The Secondary Prevention appraisal recommends that unless patients have an adequate dietary calcium intake and are vitamin D replete that they be provided with supplementation. Continual monitoring and assessment of diet would be required in order to assure adequate levels of calcium and vitamin D are maintained and therefore provision of supplementation may be sensible in most cases. Suitable supplements (which should be prescribed by brand to avoid confusion) are as follows:
- Adcal-D3® tablets
- Calcichew-D3® Forte tablets
- Calceos® tablets
- Calfovit D3® granules
The NICE appraisal recommends that Bisphosphonates should be prescribed to women who have already had an osteoporotic fragility (low impact) fracture providing they are:
- Aged over 75 years old
- Aged 65 to 74 years old and T-Score from a DEXA scan is at least -2.5 SD
- Aged below 65 years old and T Score from a DEXA scan is at least -3 SD or -2.5 SD and the patient has at least one additional risk factor
The appraisal also recommends that choice of bisphosphonate is based upon an assessment of efficacy against tolerability and adverse effects in individual patients.
There are currently four bisphosphonates available on the NHS in the UK that are licensed for use in osteoporosis, these are:
The main aim of treatment is to prevent hip fractures due the impact these have on morbidity, mortality and quality of life. Studies of the bisphosphonates have looked the drugs beneficial effects on the rate of vertebral and non-vertebral fractures.
All of these drugs reduce the rate of vertebral fractures, but hip fractures are included in the non-vertebral data. Currently, only alendronate and risedronate have shown reductions in the rates of non-vertebral fractures. Clinical evidence ranks both of these drugs as beneficial. Choosing between alendronate and risedronate as a first line treatment option therefore must involve an assessment of acquisition cost. Alendronate is now off patent and therefore has a lower acquisition cost making it the first line choice where a bisphosphonate is indicated.
Action: Clinicians who encounter postmenopausal women with fragility fractures should be aware of the NICE Technology Appraisal. Adequate calcium and vitamin D supplementation should be provided where appropriate and alendronate is the first-line evidence-based bisphosphonate.
Seasonal Allergic Rhinitis or Hayfever is a common condition that may affect up to 10% of the population between May and August. Treatment is based upon use of oral antihistamines and nasal corticosteroids.
Prodigy categorises symptoms as follows:
- Mild intermittent
- Mild persistent or moderate-severe intermittent
- Moderate-severe persistent
Treatment selection can be based upon the severity of symptoms and patient preference for oral or topical treatment. Prodigy and the MeReC Bulletin titled Common questions about hay fever (2004) recommend that:
- Mild intermittent symptoms are treated with oral antihistamines
- Mild persistent or moderate-severe intermittent are treated with oral antihistamines or intranasal corticosteroids
- Moderate-severe persistent are treated with intranasal corticosteroids
A previous MeReC Bulletin titled Treatment of seasonal allergic rhinitis (hay fever) (1998) stated "There is no difference in efficacy between the individual nasal steroids". Similarly, Clinical Evidence can find no evidence to support preferential use of any individual oral antihistamine.
Based upon the above the main consideration becomes cost-effectiveness of individual treatments. Cetirizine and Loratadine are half the price of other drugs in the class including desloratadine, fexofenadine, levocetirizine and mizolastine.
Intranasal corticosteroids can vary four-fold in cost depending upon the dose used. It would seem sensible to use the lowest effective dose for the shortest duration to minimise adverse effects. Beclometasone and Budesonide 100mcg nasal sprays 25-50% less expensive than alternative product depending upon the dose used.
Action: Depending upon the severity of symptoms, patients with seasonal allergic rhinitis should be offered first line treatment with Cetirizine or Loratadine where an oral antihistamine is indicated and Beclometasone or Budesonide 100mcg where an intranasal corticosteroid is indicated.