BMJ: Flozin effects in type one diabetes

 Adapted from BMJ 13 April19 Efficacy and safety of dual SGLT 1/2 inhibitor sotagliflozin in type one diabetes Musso G, Gambino R. Cassader M, Pascheta E. BMJ 2019:365:1328

Flozins are increasingly used for patients with “double diabetes” in practice. The authors of this study searched for randomised controlled trials for the drug Sotagliflozin to find out how effective they were and what safety issues were apparent. Over three thousand patient responses were studied. There were six trials that were of moderate to good quality and they ran between four weeks and a year. The relative pluses and minus are listed.

lowered HbA1c by  0.34% (small)

reduced fasting and post meal blood sugars

reduced daily total, basal and meal insulins

reduced time in target blood sugar range

reduced body weight by 3%

reduced systolic blood pressure by 3 mmHg

reduced protein in the urine

reduced the number of hypoglycaemic events

reduced the number of severe hypoglycaemic events

On the other hand these factors were increased:

Ketoacidosis increased by a factor of x 2 to x 8 depending on the study looked at

genital tract infections increased by a factor of x 2 to x 4.5

diarrhea increased up to x 2

volume depletion events increased by up to x 4

Patients got better blood sugar results from the higher dose of 400mg Sotagliflozin compared to the 200mg dose without increasing the risk of adverse events.

Most DKA episodes occurred as the drug was being started and patients cut their insulin dose too much, in anticipation of reduced blood sugars.

My comment: The risk of DKA in type twos is not very common but is a known effect of flozins, so it is not that surprising that this is increased in type ones too. The reduction in hypoglycaemia events and severity is a new finding and suggests an increasing role for flozins in type one management.

 

 

 

Type ones on low carb diets experience less hypoglycaemia

Adapted from Why low carb diets for type one patients? Jun1 2019 by Emma Kammerer Pharmacy Doctorate Candidate Bradenton School of Pharmacy originally published in Diabetes in Control.

Both Dr Jorgen Neillsen and Dr Richard Bernstein have shown that insulin users have fewer attacks of hypoglycaemia and that the attacks are less severe.  A new randomised controlled study by Schmidt et al confirms this finding.

Studies have shown that when a high carb diet is consumed there 20% greater error in carbohydrate estimation compared to when a low carb diet is chosen. This then affects the insulin dose administered, and thus the resulting blood sugars.

Schmidt wanted to look at the long term effects on glycaemic control and cardiovascular risk in type one patients on a low carb diet compared to a high carb diet.

The study was a randomised open label crossover study involving 14 adults who had had diabetes for more than 3 years, to eliminate the honeymoon effect. The patients went on one diet for 12 weeks, had a washout period of another 12 weeks, and then took up the other diet.  This was done so that the glycated haemoglobin levels would not be carried over from one diet to the next.

A low carb diet was defined as less than 100g carb a day and a high carb diet as over 250g per day.

Patients were given individualised meal plans and education on how to eat healthy carbs, fats and proteins. They all were experienced insulin pump users. They were asked to record total carbohydrate eaten but not the food eaten. Measurements were taken on fasting days on the first and last day of the study periods.

Blood glucose levels were downloaded from continuous glucose monitoring devices.

Four patients dropped out of the study so ten completed the test which was considered satisfactory by the statistician involved.

Results showed that the time spent in normal blood sugar range 3.9 to 10 mmol/L ( USA 56-180) was not significantly different for each diet.

The time spent in hypoglycaemia, below 3.9 (USA 70) was 25 minutes less a day on the low carb diet, and six minutes less a day below 3.0 (USA 56).

On the low carb diet glycaemic variability was lower and  there were no reports of severe hypoglycaemia.

On the high carb diet, significantly more insulin was used, systolic blood pressure was higher and weight gain was more.

There was no relevant changes in factors for cardiac risk between the two study arms.

The study showed that a low carb diet can confer real advantages to type one patients but education on how to conduct a low carb diet and manage the lower doses of insulin is required.

Schmidt, Signe et al. Low versus high carbohydrate diet in type 1 diabetes: A 12 week randomised open label crossover study. Diabetes, Obesity and Metabolism. 2019 March 26.

 

 

Hypoglycaemia: the neglected complication

Adapted from Hypoglycaemia: the neglected complication by Sanay Kalra et al.

Indian J Endocrinol Metab. 2013 Sep-Oct; 17(5): 819-834

Hypoglycaemia is an important complication of glucose lowering therapy in patients with diabetes mellitus. Attempts made at intensive glycaemic control invariably increases the risk of hypoglycaemia. A six fold increase in deaths due to diabetes has been found in patients with severe hypoglycaemia compared to those not experiencing severe hypoglycaemia.

Repeated episodes can lead to hypoglycaemia unawareness. Complications  of hypoglycaemia include stroke, heart attacks, cognitive dysfunction, retinal cell death and loss of vision. Apart from this there are the effects on quality of life regarding sleep, driving, employment, exercise and travel.

To maintain good glycaemic control, minimize the risk of hypoglycaemia and thereby prevent complications, there are steps that need to be taken: recognise risk factors for hypoglycaemia, use appropriate self monitoring of blood sugar, select treatment regimens that have little or no risk of incurring hypoglycaemia and teach health care professionals and patients how to avoid hypoglycaemia.

Although the DCCT showed that complications were reduced when blood sugars were brought under a HbA1C of 7%, other trials have noted a three fold risk of hypoglycaemia when the level is reduced under 6.5%. This tends to negate any improvements in long term complications.

Insulin users are most at risk. Those who have had diabetes for more than 15 years are particularly at risk. The DARTS study showed that the risk of severe hypoglycaemia was 7.1% for type one patients, 7.3% for type two patients and 0.8% for type twos on sulphonylureas. This causes increased cost for their healthcare as hospitalisation for around a week is needed in the average case.

The majority of hypos are due to medications but there are other potential causes such as: pancreatic or islet cell tumours, dietary toxins, alcohol, stress, infections, sepsis, starvation and excessive exercise.

In diabetics not eating enough food was the most common cause. Others were physical exercise, insulin miscalculation, stress, overtreating a high blood sugar, and impaired glycaemic awareness.

Nocturnal hypoglycaemia is seen in half of diabetic children, particularly under the age of 7. Dead in bed syndrome causes 5-6% of all deaths in type one youngsters.  Contributory factors are increased exercise that day or delayed meals.

In type two patients additional causative factors are alcohol ingestion and liver disease and duration of insulin over ten years. As in type ones there tends to be more hypoglycaemic unawareness as the person ages. In type twos  there is a 9 fold increase in deaths in those with hypoglycaemic unawareness.

Severe hypos in elderly patients increase the risk of dementia, functional brain failure and cerebellar ataxia. There are clear signs of neuronal death in specific brain areas at post mortem in these patients and a history of fits make these more extensive.

Hypos in elderly patients promote cardiac ischaemia. Arrhythmias are more likely due to catecholamine release during hypos. Prolonged QT intervals lead to increased heart rate, fibrillation and sudden cardiac death.  Inflammatory cytokines are released during hypos, abnormalities of platelet function and the fibrinolytic system occur.

Hypos can cause double vision, blurred vision and dimness of vision.  Blindness can occur due to retinal cell death.

Recurrent hypos make people feel powerless, anxious and depressed. Acute hypos cause mood swings, irritability, stubbornness and depression.  Quality of life scores are worse in patients with recurrent hypos.

Driving ability is affected by hypos. The affected driver can inadvertently cross lanes and speed and generally drive worse.

Hypos at night may be recognised by sleep disturbance, morning headaches, chronic fatigue and mood changes. In young children fits and bed wetting may occur.

Hypos at work can be awkward, embarrassing and frightening. Hypos are particularly dangerous for those who work at heights, underwater, on railway tracks, oil rigs, coal mines, handling hot metals or heavy machines.

Expert medical advice and planned action counselling can help workers. So can self blood glucose testing, healthy food options in canteens, flexible meal times, arrangements to carry and use emergency glucose/sugar, storage and disposal sites for medications and sharps, and time off for medical appointments. Work time and productivity due to hypos can be reduced and nocturnal hypos can also have a knock on effect the next day.

Hypos in children tend to be increased in summer months when they are more active. In adults, intense prolonged exercise following an episode of recent severe hypoglycaemia can damage skeletal muscle and the liver and can cause severe neurological symptoms.

Travelling long distances, particularly over times zones can cause insomnia, tiredness, stress, reduced appetite, nocturia,  gastric disturbance, muscle aching and headaches. Psychological symptoms include low mood, irritability, apathy, malaise, poor concentration. These deficits in both physical and mental performance can profoundly affect decision making.

The fear of hypos can affect patients more profoundly than the fear of long term complications.  Withholding of insulin can occur. Sometimes patients refuse to start it when they need it and sometimes they miss out their doses.

About 30% of type one patients are affected by hypoglycaemia unawareness and under 10% of type two patients are thus affected. Duration of insulin use is the main common factor.

Educating patients about how to detect, treat and prevent hypoglycaemia must be understandable to the patient and their family.

In 2013 the ADA recommended that insulin users test their blood sugars 6-8 times a day.

Basal insulin needs to be matched to the patients needs. If hypos persist, particularly overnight, switching to pump therapy may help.

Newer diabetic medications, which do not cause low blood sugars such as the gliptans and gliflozins, may be preferable in type two patients who have multiple co-morbidities, are elderly,  who live alone, are at high risk of falls, and who have hypoglycaemia unawareness or who otherwise could not effectively deal with a hypo.