Latent autoimmune diabetes in adults (LADA)

Dr Louise Johnson explains why the correct diagnosis can prevent unnecessary complications, especially in latent autoimmune diabetes in adults (LADA).


Diabetes is the world’s fastest growing non-communicable (non-infectious) disease. Diabetes is more diverse than the crude subdivision into Type 1 and Type 2 diabetes.4

LADA, or latent autoimmune diabetes in adults, is a common hybrid form of diabetes with features of both Type 1 and Type 2 diabetes. The incidence of LADA is 2-12% of all cases of diabetes in the adult population.

LADA is a diverse disease characterised by a less intensive autoimmune (antibodies against the pancreas) process than Type 1 diabetes and sharing features of Type 2 diabetes, such as abnormal cholesterol, higher blood pressure and a wider waist circumference.

Autoimmune diabetes is characterised by the presence of specific autoantibodies directed against pancreatic beta cells and initial requirement of insulin therapy.This condition is as prevalent in adulthood as in childhood.

In 1977, Irvine showed that 11% of individuals initially diagnosed as Type 2 diabetes had antibodies against the beta cells.The term LADA was introduced in 1993 and described as a subset of diabetes sharing the autoantibodies of Type 1 diabetes and the phenotype (look like) of Type 2 diabetes.

The diagnosis of LADA is based on three criteria

  1. Adult age of onset of diabetes. Usually older than 30 years of age. The person can have the phenotype (look like) of Type 2 diabetes but there tends to be fewer signs of the metabolic syndrome, such as healthier lipids, lower BMI and better blood pressure profiles.
  2. Autoantibodies against the beta cells of the pancreas, called GAD antibodies.
  3. Insulin requirements within six months after diagnosis.

The early detection of LADA among newly diagnosed Type 2 diabetes patients seems crucial since the autoimmune process against the beta cells of the pancreas can cause rapid beta cell loss if treated wrong. Treatment to prevent beta cell failure is needed and should be implemented early.

Autoantibodies and C-peptide

It is very difficult to distinguish Type 1 diabetes from LADA on a blood test. The antibody load against the beta cell of the pancreas is larger in Type 1 diabetes than in LADA.

The functionality of the beta cell of the pancreas that produce insulin can be measured by C-peptide. This is a blood test that can be done in South Africa. In Type 1 diabetes, the C-peptide is very low or absent where in LADA the C-peptide is low.

The antibody that can be measured to confirm LADA is called glutamic acid decarboxylase autoantibody (GAD). A regular laboratory in South Africa can measure this and if this is positive, it confirms the presence of autoimmunity (antibodies against the pancreas) and if diabetes is also present then this person has LADA.

C-peptide values can be used to help in determining the treatment of LADA patients:

  1. Below 0,3nmol/L – This group needs insulin and can be treated according to the guidelines for Type 1 diabetes with insulin at bedtime and before meals.
  2. More than 0,3 and less than 0,7nmol/L -This is a grey area and it’s suggested to treat this group at first with therapy that preserve beta cells. The classes of medication considered would be: DPP4i (sitagliptin, saxagliptin, vildagliptin) or GLP1-receptor agonist, such as liraglutide, exenatide or dulaglutide. The newer class of SGLT2 inhibitors empagliflozin or dapagliflozin can also be considered in some patients.
  3. C-peptide levels of more than 0,7 nmol/L needs to be treated as insulin resistant patients with metformin and the above-mentioned therapy in 2. Their antibodies need to be repeated to make sure it wasn’t a false positive and their C-peptide levels need to be followed-up.

Treatment strategies for LADA

It’s important to evaluate all newly diagnosed Type 2 diabetes patients with a test for antibodies as to not miss the diagnosis of LADA.

The reason why this is important is that certain Type 2 diabetes drugs can worsen the autoimmunity in the pancreas and accelerate the loss of beta cells. The drugs that should be avoided in LADA patients are sulfonylureas. Drugs such as gliclazide, diaglucide, glimepiride and the rest of the class.

Insulin

This is essential in all people where the C-peptide level is very low or undetectable. Insulin administration supports the declining beta cells and improves the attack of antibodies against the pancreas. This process is called insulinites.

 DiPeptidyl Peptidase 4 (DPP4) inhibitors

This is a class of drugs that work in the gut by inhibiting the enzyme DPP4 that is responsible for secretion of insulin, inhibition of glucagon and production of incretin. Incretin helps to keep the satiety level up and prevent weight gain. In LADA patients, the DPP4 inhibitors protect against beta cell loss. Drugs in this class are vildagliptin, sitagliptin and saxagliptin.

Glucagon Like Peptide Receptor Agonist (GLP RA)

This group of drugs works like the DPP4 inhibitors but are injectable and more potent. They cause weight loss of 4-5kg and a greater reduction in glucose if that is needed. They are also protective against heart disease. Drugs in this class are liraglutide, exenatide and dulaglutide.

The overlap

Patients with LADA show midway features between Type 1 and Type 2 diabetes. Although adults with high GAD antibody tests are clinically closer to Type 1 diabetes than Type 2 diabetes, an overlap does exist. The overlap causes a misdiagnosis of 5-10%. This is the reason that we recommend the testing of antibodies in new type 2 diabetes.5

It’s important to remember that the misdiagnosis of LADA in Type 2 diabetes can lead to an increase of complications due to the fact that glucose control is a lot more difficult in this group, if not treated correctly.

In the new millennium that we are living with available technology, all newly diagnosed Type 2 diabetes patients should have a GAD antibody test. Type 2 diabetes patients that are struggling to control glucose on tablets should also be evaluated. The correct diagnosis can prevent unnecessary complications. Remember information can save a life riddled with complications.


References:

  1. Pieralice S et. al. “Latent autoimmune diabetes in adults: A review on clinical implications and management Diab Metab J 2018;42:451-464
  2. Bluestone JA et. al. Genetics, pathogenesis and clinical interventions in type 1 diabetes” Nature 2010 ;464: 1293 -300
  3. Buzetti et al. Management of Latent autoimmune diabetes I adults: A consensus statement from an International expert panel. Diabetes oct 2020 vol 69
  4. Tuomi T et. al. The many faces of diabetes: a disease with increasing heterogeneity. Lancet 2014, 383;1084
  5. Mishra et. al. 2018 
Dr Louise Loot

MEET THE EXPERT


Dr Louise Johnson is a specialist physician passionate about diabetes and endocrinology. She enjoys helping people with diabetes live a full life with optimal quality. She is based in Pretoria in private practice.


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The importance of clinical trials

Amina Goondiwala, a principal study coordinator, explains the importance and benefits of clinical trials.


The World Health Organisation has defined clinical trials as: “A type of research that studies new tests and treatments and evaluates their effects on human health outcomes. People volunteer to take part in clinical trials to test medical interventions, including drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioral treatments and preventive care.”

Authorities of clinical trials

A clinical trial is carefully designed, reviewed and submitted to South African Health Products Regulatory Authority (SAHPRA) and ethics committees prior to being implemented at different sites. Updates during a study and at the end are also submitted to these regulatory bodies to ensure proper conducts of these studies are completed.

The Food and Drug Authority (FDA) has overall authority on trials for drugs and biologics and medical device products regulated by the agency. The purpose of an Institutional Review Board (IRB) review is to ensure that appropriate steps are taken to protect the rights and welfare of participants in the research. If the risks to participants are found to be too great, the IRB will not approve the research, or it will specify changes that must be made before the research can be done. As part of their review, IRBs consider participant inclusion and exclusion requirements to be sure that appropriate people have been identified as eligible for the trial. They often look at how and where recruitment for clinical trials will occur.

Patients’ medical records are reviewed for consideration on who can participate in a clinical trial. All patients are given an Informed Consent where the benefits and possible side effects of the medication is described. It is on a voluntary basis and a patient may stop at any time and continue with their previous treatment regime with their primary healthcare provider.

The goal of a trial is to answer specific questions on new therapies and medications. These studies are conducted in three phases and may take about 10 to 15 years before a product is approved for use in a country.

Diabetes clinical trials

Many studies have been completed for diabetes and many new trials are available for participation, not because of a last resort but to help pharmaceutical industries develop better-suited medication to control diabetes and avoid complications.

Patients with elevated glucose levels may be considered for these trials and not only will they receive medication but also have frequent clinic visits with regular blood tests and ECG monitoring. Patients may also be included in Oral Diabetic Studies or Insulin Controlled Studies.

These patients will also be contacted regularly during their scheduled visits to ask how they are feeling, and should any new symptoms develop that need to be monitored. Nurses or site staff spends time with each patient addressing their concerns regarding their conditions. Social and economic factors may also be addressed with patients having a difficult time maintaining their glucose levels. All patients are encouraged to engage in some form of exercise or activities to ensure a healthier outcome.

Benefits of participating in a clinical trial

There are many benefits to enrolling on a clinical trial. For example, you can take a more active role in your healthcare, such as learning the importance of taking your medication on time and how to deal with a hypoglycemic episode; gain access to optimal medical treatment and adherence to standard of care; get expert advice at these facilities and help others by contributing to medical research.

You may also involve your primary care provider on your achievements during a trial. At some facilities, they also invite family members to each appointment, so they may also learn on how to help you manage your diabetes. Eating plans where portion sizes and choosing the healthier option, specifically for diabetes, are discussed. Patients may receive glucose monitoring devices and shown how to take their glucose levels daily.

Patients are reminded that medication is not to be shared between friends and family as other diabetic patients may have other conditions as well and the prescribed medication may only be suitable to you.

Inform your treating doctor

Please speak to your primary healthcare provider prior to enrolling in any clinical trial or changing your diabetic medications. It is best to seek medical advice first before making any decisions.

Amina Goondiwala

MEET THE EXPERT


Amina Goondiwala is the senior study coordinator at Soweto Clinical Trials. She has 19 years’ experience in clinical trials, having participated in over 110 trials since 2002, and was awarded Study Coordinator of the Year in 2010 by the South African Clinical Research Association.


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The measure of it – Time in range

Dr Angela Murphy discusses diabetes control in the 21st century, specifically time in range.


After the discovery of insulin in 1922, people with diabetes (PWD) were living longer and, thus, diabetic complications started to emerge. The goal in managing diabetes started to focus on preventing these complications and improving overall quality of life. With the advent of large-scale clinical trials, the relationship between glucose levels and risk of complications was revealed.

The Diabetes Control and Complications Trial (DCCT), which involved Type 1 diabetes patients, released its results in 1990. It conclusively showed that improved glucose control reduced the risk of microvascular (small blood vessel) complications of the eyes, kidneys, and nerves.

Large trials done in Type 2 diabetes patients, such as the United Kingdom Prospective Diabetes Study (UKPDS), confirmed these reductions in microvascular complications with good diabetes control.

Initially, the data didn’t show the same benefit in macrovascular (large blood vessel) complications, viz: coronary artery disease, stroke, and peripheral vascular disease where blood supply to the feet is blocked. However, trials that followed-up patients beyond 15 years did show that there was indeed benefit. We now had proof that good glucose control prevented complications. So, what constitutes good diabetes control?  How do we measure that?

Blood glucose measurement

The impetus to test glucose in the early days of diabetes was centred on diagnosis. Hence, initial urine test kits would just have established if glucose was present or not.

Then PWD wanted to assess the degree of improvement in their glucose levels using the different treatment regimens available. Another strong reason to test would have been to establish hypoglycaemia.

Blood glucose testing was greatly improved in the mid 1960s with the invention of the Ames dextrostix and gradually home glucose testing kits became available.

When continuous glucose monitoring (CGM) devices were released, even more accuracy was expected. Blood glucose targets were partly determined from knowing what the non-diabetic blood glucose range is, but also from the data of the trials. There are three parameters that are used for these targets: fasting blood glucose, post-prandial (two hours after a meal) blood glucose, and HbA1c.

HBA1C – glycated haemoglobin

In 1968, Iranian born Samuel Rahbar started studying the haemoglobin (Hb) molecule (which carries iron and oxygen in our blood). By chance he came across an unusual variant in diabetic blood and went on to work at the Albert Einstein College of Medicine with Helen Ranney. They found that their diabetic Hb matched the previously described subtype of HbA and so was named HbA1c.

HbA1c is formed when excess glucose in the blood attaches to the haemoglobin molecule, a process called glycation. Red blood cells are renewed on average every three months, so HbA1c is regarded as an average of blood glucose control over a three-month period. In fact, it was HbA1c that was used in the DCCT and UKPDS trials to show that good glucose control prevented diabetes complications. Without HbA1c, this would have been nearly impossible to demonstrate.

Figure 1 demonstrates the concept of a lower HbA1c, <7,0%, being good, so it’s green, whereas a higher HbA1c is dangerous and thus, is in red. HbA1c can be affected by several conditions that may make it less reliable, such as kidney failure, pregnancy, smoking and ethnicity.

Home glucose monitoring

In this era of data overload, it’s truly useful to be reminded why we advocate blood glucose testing in the management of diabetes. It should not just be about going through a routine to provide the doctor with readings at the consultation, but also to empower the PWD.

In 2011, the Structured Testing Program Study showed that getting PWD to do structured testing in the three days before their doctor’s visit improved their HbA1c by 0,3%. There was no medication change, just behavioural change.

The participants in the study used the AccuCheck 360’ tool (below) and did a seven-point profile for those three days. This involved testing before each meal, two hours after each meal and at bedtime. I have adapted this tool for my clinical practice and use it frequently. It helps me advise patients with medication changes, but it’s just as valuable for the patient to see what else influences the glucose levels. This can range from food to medication, activity, illness and even stress. It is particularly useful when patients are new to the practice and their diabetes regimen needs to be assessed.

Continuous glucose monitoring

The first generations of CGMs approved by the Food and Drug Administration (FDA), beginning in 1999, were able to provide significant clinical benefits as an adjunct to standard self-monitoring of blood glucose.  These are the machines of many a PWD’s dreams: a way of seeing the blood glucose at any time of day or night without having to open a conventional glucometer and prick a finger.

As the CGM devices became more advanced, they not only showed the current glucose reading, and of course the tracing of where the glucose had been but could predict where the glucose would go. In this way, PWD could be forewarned of a hypoglycaemia or hyperglycaemia and take appropriate action to avoid these. When this type of CGM technology works in tandem with insulin pumps, we see the makings of an artificial pancreas.

Time in range

What data from CGM showed acutely is that we cannot always rely on average blood glucose levels, even HbA1c, to fully assess overall diabetic control. Averages do not show the extent of the high and low glucose readings.

Let me explain. If there are three blood glucose values of 6,0mmol/L, then obviously the average blood glucose is 6,0mmol/L. However, three readings of 12mmol/L, 2mmol/L and 5mmol/L will also give an average of 6,0mmol/L and yet only one reading is in the target range.

Figure 3 shows how all HbA1c’s are truly not equal. The same HbA1c of 7,0% can have completely different glucose profiles. This variation in glucose levels is called glucose variability. CGM demonstrates patterns of glucose over a 24-hour period in detail so the swings in blood glucose levels are easily seen. There is strong evidence to show that increased glucose variability predicts the risk of hypoglycaemia. Specifically, it predicts severe hypoglycaemia in Type 1 diabetes and non-severe in Type 2 diabetes.

Severe hypoglycaemia is defined as low blood glucose <4mmol/L and the PWD requires assistance to treat the low glucose. The more frequently the blood glucose levels swing from highs to lows, the higher the glucose variability. There is concern that this variability can damage blood vessels and thus, may be implicated in diabetic complications.

Glucose targets

Based on data from all the large diabetes trials over the years, we can set targets for good diabetes control. This is not a one-size fits all range. Age, duration of diabetes, presence of complications, risk of hypoglycaemia and pregnancy all affect the target blood glucose levels.

In older PWD who have diabetic complications, particularly of the heart and kidneys, glucose levels are slightly higher than a young, newly diagnosed PWD. Table 1 shows advised targets for FBG, PPG, HbA1c.

TABLE 1 – BLOOD GLUCOSE TARGETS FROM SOCIETY OF ENDOCRINOLOGY AND METABOLISM SOUTH AFRICA 2017

 

 

HbA1c FBG (fasting blood glucose)mmol/L PPG (2-hour post prandial blood

glucose)mmol/L

     YOUNG <6.5% 4-7 4.4-7.8
     MOST <7.0% 4-7 5-10
     ELDERLY <7.5% 4-7 <12

In 2019, the International Consensus in Time in Range (TIR) was released and defined the concept of the time spent in the target range between 4 and 10mmol/L while reducing time in hypoglycaemia, for patients using CGM.

Several studies have now shown a good correlation of TIR with HbA1c. In one, more than 90% participants with a TIR of >80% has HbA1c values of ≤ 7.0%.

At present, TIR is only verified with the use of CGM. Intermittent testing, even doing seven-point profiling does not seem to be as predictable. Several medical aids will now consider reimbursement for CGM devices for Type 1 diabetes patients, which will significantly increase the use of CGM in South Africa.

Summary

To achieve good diabetes control, we try to get as close to physiological glucose levels as is safe which has been proven to decrease both microvascular and macrovascular complications. Good control is not only a good average but also stability of glucose levels over time. It is this latter attribute which is measured with Time in Range and which may become the most important of all glucose measurements in the future.


References:

  1. Parkin G, Zhihong Jelsovsky, Bettina Petersen, Matthias Schweitzer, Robin S. Wagner. Structured Self-Monitoring of Blood Glucose Significantly Reduces A1C Levels in Poorly Controlled, Noninsulin-Treated Type 2 Diabetes. Diabetes Care Feb 2011, 34 (2) 262-267; DOI:2337/dc10-1732 
  1. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, Bosi E, Buckingham BA, Cefalu WT, Close KL, Cobelli C. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diab Care. 2019;1(42):1593–603.
  1. Gabbay, M.A.L., Rodacki, M., Calliari, L.E. et al.Time in range: a new parameter to evaluate blood glucose control in patients with diabetes. Diabetol Metab Syndr 12, 22 (2020)
  1. Hirsch IB, Welsh JB, Calhoun P, Puhr S, Walker TC, Price DA. Associations between HbA1c and continuous glucose monitoring-derived glycaemic variables. Diabet Med. 2019;36:1637–42.

MEET THE EXPERT


Dr Angela Murphy is a specialist physician working in the field of Diabetes and Endocrinology in Boksburg. She is part of the Netcare Sunward Park Bariatric Centre of Excellence and has a busy diabetes practice.