Medscape: Next generation insulins

Adapted from Medscape interview with Ulrik Pedersen-Bjergaard MD

Dr Pedersen-Bjergaard is based in Denmark.

Once weekly insulins are under development and are at the pre-clinical study level. These are expected to be a lot more convenient. Novonordisk’s is at the most advanced stage. They are basal insulins that cause no change in the HbA1Cs or body weight when used in type two diabetics. (Who still produce some insulin in their pancreatic beta cells). The new insulin called Icodec has been trialled against Glargine / Lantus and it is equally safe.

Blue tooth technology has been developed that will tell you how many units of insulin you injected and when you injected it, via an integrated pen unit. The unit will have automated titration recommendations via your blood sugar meter. This will give improved glucose readings and HbA1Cs.

Ultra rapid insulins are being developed. These reduce the one and two hour blood sugar spikes after meals but have not been optimised for pump use yet.

Insulin Degludec shows reduced hypos compared to Glargine/Lantus in type ones.

Should I stockpile insulin ahead of Brexit?

insuline supplies on the Diabetes Diet website

I picked up my repeat prescription this week, and asked the all-important question. By the time I’m ready for the next one, Brexit is supposed to have taken place*. Will the UK’s insulin supplies run out?

As one of life’s optimists, I tend to ignore worst-case scenario planners, which makes me either naive, stupid or just someone who prefers to live in the now, as worrying about the future and events I have little control over seems pointless. It’s likely I’m all three.

Anyway, at the pharmacy I asked the chemist if I should stockpile insulin, seeing as very little of it is manufactured in the UK and insulin seems to get mentioned in the same sentence as food whenever people talk about stockpiling. As it happens, I have lots of one particular insulin, the rapid acting stuff, while my supplies of the long-acting stuff needs regular replacing. If the worst comes to the worst, I can beg an insulin pump from someone and use that…

No-one’s talking about it…

“If they are stock-piling, no-one’s talking about it,” the chemist told me, “And we’ve heard nothing officially.”

She didn’t then add, “If I were you, though, I’d make sure you’ve got four months’ supply at least and contemplate taking your diet as low-carb as possible so you don’t need as much.” I’ve made that advice up, obviously, but she didn’t add any caveats so either someone higher up in the medical supplies chain has decided on a policy of silence or the fears aren’t justified.

Ms Stupid/Naive/Live in the Moment has decided to leave worrying about her insulin supplies for now. There are many other factors which could affect insulin supplies in the future too—climate change, fuel shortages, war or the Zombie apocalypse, coming to a town near you all too soon.

And of course, the biggest factor is the soaring rates of type 2 diabetes. According to a recent report, about 33 million people who need insulin currently do not have access to the drug. That figure is expected to rise to 41 million by 2030. A lot of these shortages apply to people in Africa and Asia where increasing urbanisation, more sedentary lifestyles and changes to diet have led to soaring numbers of type 2 diabetics. In the States, however, insulin shortages also affect the population as prices have risen sharply over the last few years. Three companies dominate the market, and proof once again that free market systems seldom contribute to the greater good.

*And goodness knows what will happen on the 29th.

Brexit and Insulin Shortages

a plstic box c ontaining insulin on The Diabetes DietInsulin shortages and low-carb dishes—no obvious connection, I grant you but bear with me.

The first relates to a news item on Channel 4 last night, which warned of insulin shortages post-Brexit in the UK as the country produces little to no manufactured insulin (apart from a factory which makes the stuff derived from pigs).

Sir Michael Rawlins, the chair of the Medicines and Healthcare products Regulatory Agency, told the Pharmaceutical Journal last Friday that, “We make no insulin in the UK. We import every drop of it. You can’t transport insulin around ordinarily because it must be temperature-controlled. And there are 3.5 million people [with diabetes, some of whom] rely on insulin, not least the Prime Minister.”

412,000 people on insulin

Strictly speaking, that’s no true as the Channel 4 story pointed out. Wockhardt UK produces the animal insulin, but its products are used by some 1,500 to 2,000 patients every year. And that’s less than 0.5 percent of the estimated 421,000 people in the UK who rely on insulin.

Channel 4 News spoke to the major manufacturers, Sanofi, Novo Nordisk and Lilly. All of them make insulin in Europe.

The Healthcare Distribution Association (HDA) UK which represents medical suppliers in the UK wrote to the UK Government post the referendum in 2016 to warn of serious upsets to the supply chain should Brexit negotiations go wrong.

Buffer stocks

HDA UK said the UK medicines supply chain had “inbuilt resilience” and “flexibility”, and that they were aware of proposals by the government and manufacturers to develop plans for a buffer stock of all medicines.

A spokesperson for the Government said they were confident of reaching a deal, there were contingency plans in place to ensure no disruption to supplies.

Channel 4 News’ fact check conclusion is that as the companies and the Government don’t anticipate shortages, we should be okay.

Back to low-carb recipes and my tenuous attempt to link the two. If you follow a low-carb diet and you use insulin, in general you don’t need to take as much insulin. If shortages come, you’ll have more time to use your insulin while the powers-that-be attempt to sort out this almighty mess.

Cue plug for this blog and The Diabetes Diet! Is that distasteful of me?! Probably.




Study Finds Some Type 1s DO Produce Insulin

Free stock photo of health, medical, medicine, prickAn article in Medical New Today caught our eye this week – research recently found that people with type 1 diabetes produced some insulin.

Yeah, yeah, I thought, it’s the newbies again. But apparently not. The Uppsala University in Sweden’s researchers found that nearly half of patients who’d had the condition for more than ten years did produce insulin.

Type 1 diabetes is routinely described as a condition where the body doesn’t make insulin. The researchers found that the insulin-producing patients had higher levels of immune cells that produce a protein called interleukin-35 (IL-35). This is believed to suppress the immune system and reduce inflammation in the body.

The findings were reported by the study’s co-author, Dr Daniel Epses, in Diabetes Care.

Type 1 diabetes happens when the immune system mistakenly attacks insulin-producing cells or beta cells in the pancreas.

This was believed to lead to a complete loss of insulin production in type 1 diabetics, but studies in recent years have shown that some patients still have functioning beta cells.

Dr Epses and his colleagues wanted to work out if there are any immunological mechanisms that could explain why some type 1 diabetics still produce small amounts of insulin.

The study looked at 113 patients aged 18 and over. All of them had been living with diabetes for at least ten years.

Researchers measured the levels of C-peptide in the blood – an indicator of insulin production. They also measured circulating cytokine levels, including IL-35. Cytokines are proteins that are secreted by the immune cells and they play a major role in cell signalling.

The team found that almost half the patients were C-peptide positive – in other words, they had some level of insulin production. The results also showed that patients who were C-peptide positive had significantly higher levels of IL-35 in their blood, compared with the patients who were C-peptide negative (the ones who had lost all insulin production).

Previous research has indicated that IL-35 can suppress auto-immune disease. It is possible that in some type 1 diabetics, the protein prevents the immune system from attacking and destroying beta cells.

Dr Epses and his colleagues, who are based at the Department of Medical Cell Biology at Uppsala University, couldn’t determine if C-peptide positive patients had higher IL-35 levels at type 1 diabetes diagnosis, or whether levels of the protein increased over time because of a reduced immune system attack on insulin-producing beta cells.

More study is needed to gain an understanding of how IL-35 might relate to insulin production. The researchers believe, however, that their findings show the potential of IL-35 as a treatment for type 1 diabetes. As the findings also show that almost half of patients with type 1 diabetes produce some insulin, the team thinks it might be possible to encourage regeneration of their remaining beta cells and so boost insulin production.



What’s new for type one diabetics?

NICE have released their new guidelines for type one adults. This paper was given some prominence in September’s BMJ as well as other papers that could be of interest to diabetics, their carers and health professionals.

In many respects the adult guidelines are similar to the children’s guidelines. Structured education gets support as does advice to aim for a hba1c of 6.5% (48) or lower provided hypos can be minimised. Of course this is virtually impossible if a high carb diet is followed but is much easier if the low carb dietary advice and precision meal to insulin matching as we describe in our book is done.

Levemir twice a day is the recommended basal insulin for all new patients and Lantus is advised only for those who refuse to use a twice daily bolus or perhaps need assistance from others for injection. We know that Lantus has some gaps in coverage as a 24 hour insulin and that it is less stable in heat and light than Levemir. It also stings on injection. Levemir also gives fewer hypos. Of course if someone is happy with Lantus, they can stay on it.

Life expectancy for type ones is currently 13 years less than for people without the condition. Fewer than 30% of adults achieve a hba1c of 7.5% or less.

Although the Cochrane collaboration noted a small degree of success with a low glycaemic diet strategy for type twos, this was not seen in the research that NICE looked at for type ones and therefore they don’t recommend low glycaemic as a dietary strategy.

Blood sugar targets are suggested to be ideally 5-7 first thing in the morning, 4-7 before meals and 5-9 at least 90 minutes after meals. Adults are advised that 4-10 blood sugar tests may be required each day. Before each meal and before bedtime are minimum testing times.

NICE want type ones to stick to their finger tips for blood sugar testing. This is the most accurate as hypos can be missed if other parts of the upper limb are used.

It is recommended that hypos are evaluated at least annually by a scoring system. The idea is to seek out those people for whom these are a problem and then fix it. NICE say this should not involve simply raising blood sugar targets. The obvious thing is to match insulin to meals, activity and basal needs more closely. If structured education around this appears to fail then the person should be considered for pump therapy and real time glucose monitoring.

Meal insulin boluses are recommended before meals. After meals is a strategy that works for toddlers but adults are expected to be able to adjust their insulin to meals and that means that they must be able to carb count.

So what can we expect from the implementation of these guidelines? There is still no clarity over diet and exactly how patients will get near normal blood sugars just by carb counting without actually restricting the amount they consume isn’t explained. There certainly will be a lot more adults who could be considered for pumps. But these are relatively expensive and require a lot of training. Setting strict blood sugar targets and hoping that technology will solve the problem has been going on for decades now. Why should it work now? NICE admits it hasn’t worked so far with more than 70% of type one adults having wildly high blood sugars. I would have been very interested to know what percentage of adults with diabetes achieved the target blood sugars of 6.5% or 48.

NICE do admit that to implement their proposals the medical workforce will need to be sufficiently trained to deliver the structured education and to help individual diabetics with their problems.

Forthcoming Drug Recommendations for Type 2 Diabetics from NICE

NICE have some drug recommendations to make for diabetics in their forthcoming guidelines later this year. It can be seen that NICE are heavily influenced by drug costs. So what could these new guidelines mean for you?

The blood pressure recommendations have scarcely changed but the use of Repaglinide first or second line for blood sugar control is a change from previously. Blood sugar targets have tightened up a bit and structured education is expected for insulin users. Cheaper, older insulins are favoured. Blood sugar testing is being rationed considerably. Aspirin is out of favour but drugs for erectile dysfunction are in. Erythromycin is being adopted for the very difficult to manage problem of gastroparesis.

The medications you will need to take to improve your life with diabetes will depend on many factors. Primarily, what do you want a medication to do for you?

The answer to this will depend on how well you are managing lifestyle changes, how long you have had the condition, the presence of any complications, and how tight you want glycaemic control, blood pressure and lipids to be. The targets need to be individualised to you, and this can be done by becoming more informed about your condition and discussing it with other health care providers and people with diabetes. We discuss these factors in our book, the Diabetes Diet, and I will be updating you on some of the new recommendations in further articles.

This article covers the changes to blood pressure medications, glycaemic targets and drugs to control blood sugar, self-monitoring of blood sugar, insulin initiation and the management of complications.

Blood pressure

For diabetics the BP target is 140/80 if there are no blood vessel complications such as kidney, eye or cerebrovascular disorders. If these are present the target is 130/80. BP lowering can improve peripheral neuropathy as well as stroke, MI, blindness and renal failure. 25% of those with type 2 diabetes develop nephropathy within 20 years of diagnosis.

Because ACE inhibitors and sartans reduce progression to renal disease better than other classes of anti-hypertensive agent they should be used first in diabetics unless they are a woman who could get pregnant as this class of drug is teratogenic. First line for women in this situation is a Calcium channel blocker CCB instead.

For Afro-Caribbean use ACE + diuretic or ACE + Calcium channel blocker. This is because this group respond less well to ACEs and sartans so should have add on drugs right from the start.

For those who can’t tolerate an ACE use a sartan unless there is renal deterioration or hyperkalaemia.

If BP is still not controlled add a CCB or thiazide diuretic.

If still not controlled use any of an alpha blocker e.g. Doxasozin or a beta blocker e.g. Bisoprolol or potassium sparing diuretic e.g. Spironolactone.

If someone has already had a heart attack or heart failure they will probably be on a beta blocker anyway. Carvedilol was superior to metoprolol in metabolic terms for renal protection in one study.

Use spironolactone with caution if someone is already on a sartan or ACE because they all can raise potassium.

Glycaemic control


All-cause mortality rises as hbaic rises and decreases as hbaic reduces. The risk of microvascular complications increase over hba1c of 6.5% (48 mmol/mol) or 7% (53) for macrovascular complications. Fasting blood glucose levels influence MI but not stroke or angina.  Amputation rates rise over the age of 60 for any given hbaic. Therefore it can be seen that to improve life expectancy and the quality of life that in general the tighter the blood sugar control the better.  At the same time doctors are asked to adopt an individualised approach to blood sugar targets and consider life expectancy, personal preferences, co-morbidities, risks of polypharmacy and they should consider stopping ineffective drugs.


NICE felt they could not comment on hba1c under 6% because only one study they looked at achieved this. Hba1cs in the 4s or 5s are not uncommon in low carbing diabetics however so don’t let this put you off your stride. NICE do say that if adults reach a lower blood sugar target than they were expecting and are not having hypoglycaemia the doctor should encourage them to maintain it.

They suggest:

6.5% for non-drug using diabetics or on drugs that don’t cause hypos e.g. metformin, pioglitazone, gliptins, victoza.

7% for the rest e.g. repaglinide, sulphonylureas, insulin.

7.5% intensify treatment, but individual circumstances e.g. life expectancy, co-morbidities, hypos need to be taken into account.

Drug step-laddering:

The first step for most diabetics is to offer metformin as the initial drug treatment.  But don’t give or stop metformin if the kidney test, the egfr is below 30 and use with caution if under 45. Regular metformin can give diarrhoea and if this is a problem the long acting version can be used.

If there is symptomatic hyperglycaemia, such as thirst and weight loss consider a sulphonylurea or insulin first. Other drugs may be considered once the blood sugars have stabilised. .

Next they suggest Repaglinide on its own or with metformin. Repaglinide is not licenced with other drugs. For people who could not tolerate metformin and repaglinide are the most cost effective treatment option.

If repaglinide was not suitable or is not achieving the desired blood sugar target any of pioglitazone, a sulphonylurea or a gliptin can be used.  The choice can be tailored to the patient.

Sulphonylureas had the most hypos and gliptins the least. Metformin had the best weight loss. Sulphonylurea and Pioglitazone had the most weight gain. NICE prefer doctors to use the lowest cost gliptin because they are relatively expensive.

Reducing hypoglycaemia should be a particular aim for those on insulin or a sulphonylurea. As blood sugar monitoring is necessary for these drugs, this factor can increase the cost considerably over and above the costs of the medication.

Consider GLP1 mimetic i.e. Byetta or Victoza if the BMI is over 35.  Only continue it if hba1c goes down by 1% and weight goes down by 3% over six months.

Insulin is considered to be the “last option”. There is currently research being carried out on the effects of early use of insulin in type two diabetes and this may change practice in the future.

Only offer insulin + Victoza in specialist care setting.

Insulin initiation

When starting insulin use support from an appropriately trained health professional and give:

Structured education

Telephone support

Frequent self monitoring

Dose titration to target

Dietary understanding

Hypoglycaemia management

Management of acute rises in blood sugar

Continue metformin

The usual first choice insulin is NPH insulin at bedtime or twice daily.

The more expensive Lantus or Levemir may be considered if a carer would be able to cut to once daily injections or if hypoglycaemia is a problem or otherwise the patient would need twice daily NPH and oral drugs or they can’t use the NPH device.

If hbaic is 9% (75) consider twice daily pre-mixed bi-phasic insulin.

Blood sugar testing

NICE recommends that self- monitoring of blood sugars is to be avoided unless a person is on insulin, has symptomatic hypoglycaemia, or oral medication that causes hypos or driving or operating machinery, pregnant or trying for a baby.  It may be worth considering if a patient is on oral or intravenous steroids.

Doctors or nurses should reassess the need for self monitoring annually to see if it remains worthwhile.

Self monitoring produced only a 0.22% reduction in hbaic. It was considered by NICE to be not helpful for most people with type two diabetes though more hypos were detected with it.


Anti-platelet therapy for cardiovascular protection

There is no overall benefit to taking aspirin or clopidogrel in type 2 diabetes unless they already have cardiovascular disease.

Managing complications

Autonomic neuropathy symptoms are: gastroparesis, diarrhoea, faecal incontinence, erectile dysfunction, bladder disturbance, orthostatic hypotension, gustatory and other sweating disorders, dry feet and ankle oedema.

Treatments for gastroparesis are metoclopramide, domperidone and erythromycin.

Refer to a specialist if severe or persistent vomiting occurs or the diagnosis is in doubt.

Nocturnal diarrhoea may indicate autonomic neuropathy.

Tricyclics are often given for neuropathic pain but can increase postural hypotension.

Erectile dysfunction

Offer men the chance to speak about this at their annual review. Offer Viagra, Cialis and similar and refer if these don’t work.

Eye damage

Diabetic eye damage is the single largest cause of blindness before old age.

Refer to the emergency ophthalmologist if:

Sudden loss of vision

Rubeus’s Iridis

Pre-retinal or vitreous haemorrhage

Retinal detachment

Send for rapid review if there is new vessel formation.

So what do you think of the new NICE recommendations?  Do you think these changes will affect your medications?