Diabetes: What is the Problem?

14407489_xxlType 2 Diabetes Mellitus (T2DM) is reaching epidemic proportion in Singapore, affecting 11.3% of all Singaporeans1, and is expected to worsen to 18.3% in the year 2030.2 Diabetes causes macrovascular complications such as ischaemic heart disease and stroke, and microvascular complications such as retinopathy, renal failure, and neuropathy.3 Diabetes is already the most common cause of end stage kidney failure in Singapore, accounting for 63.5% of all new cases in 20084, and more than 240 patients with T2DM have parts of their feet amputated every year in Singapore.5 What is worse, half the patients do not even know that they have diabetes.1

Diabetes Complications: Can anything be done?
Back in 1998, The United Kingdom Prospective Diabetes Study (UKPDS) had already shown that better diabetes control prevents complications.6 Moreover, the rate of complications is directly proportional to the glycated haemoglobin A1C (Hba1c) level.3 Doctors should, therefore, aim for as low an Hba1c as possible.

Normal Glucose Level in Diabetes: Is it possible?
Despite the fact that Hba1c level is directly correlated with complication rate, a cut-off level at 7% was designated “good” control by most authorities, including the Singapore diabetes guideline.7 Why do we not aim for a normal Hba1c? The main problem is that of hypoglycaemia; it was said that diabetic patients could have a lifetime of euglycaemia if not for the barrier of hypoglycaemia.8 Previously, we only had metformin, sulphonylurea and insulin for the treatment of diabetes. Both sulphonylurea and insulin have a tendency to cause hypoglycaemia.

What are the problems of hypoglycaemia?
Two major randomised controlled trials of diabetes intervention published in 2008 showed that hypoglycaemia was associated with increased mortality, in both the intervention and the control group.9,10 One of the postulated mechanisms of this is that hypoglycaemia is proarrythmic.11 In addition, any episode of hypoglycaemia blunts the counter-regulatory response to hypoglycaemia, creating a vicious cycle when hypoglycaemia gets more and more often and serious.12 In clinical practice, symptoms of hypoglycaemia need to be proactively sought for and managed by the physician in charge.

Dealing with Iatrogenic Hypoglycaemia
For patients who are taking sulphonylurea or insulin, they need to be told to stick to a regular eating regime. Should a meal be delayed, hypoglycaemia may ensue since those two classes of drugs increase the insulin level without regards to the ambient blood glucose level. That is, those drugs continue to cause a high level of insulin even at times when the glucose level is normal. On top of that, patients who follow the advice to cut down on sugars and starch may also develop hypoglycaemia. Therefore, timely monitoring of postprandial glucose and reduction of the dose of sulphonylurea or insulin is important. Otherwise, patients would either go back to the old habits of taking too much carbohydrates or stop taking their medication. At the next visit, their diabetes control remains the same or deteriorates, and the doctor in charge may then increase the dose of anti-diabetic agents. Obviously, the control of diabetes remains terrible, and the patients may understandably not return to the doctor again.

Diabetes Medication that Do Not Cause Hypoglycaemia
Fortunately, we now have new classes of drugs that do not cause hypoglycaemia [Table 1]. Metformin is effective, does not cause weight gain, and likely decreases cardiovascular risk. There is a small risk of lactic acidosis, but mostly in patients with renal failure or heart failure. Thus, it is now the first line medication from most authorities.13,14 DPP-4 inhibitors and GLP-1 agonists stimulate the pancreas to produce insulin through a glucose-dependent mechanism. Thus, when the glucose level is normal, not much insulin is secreted. Alpha-glucosidase inhibitors slow down the digestion and absorption of carbohydrates from the gut and do not stimulate insulin at all. Thiazolidinediones stimulate fat production in the subcutaneous region and decrease fat production in the abdomen, lowering the insulin resistance. They generally cause a drop in insulin level.

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Table 1. Diabetic drugs that do not cause hypoglycaemia13

The New Targets for Patients with Newly Diagnosed T2DM
Since we now have agents that do not cause hypoglycaemia, much lower goals of diabetes control can be reached safely. The American Diabetes Association (ADA) and the European Association of the Study of Diabetes (EASD) published a consensus statement last year, proposing for much lower Hba1c targets of 6.0% to 6.5% for patients with short disease duration, long life expectancy and without cardiovascular disease (CVD).13 The American Association of Clinical Endocrinologists (AACE) agreed with a target of 6.5% for healthy patients without concurrent illness and with low risk of hypoglycaemia.14 Many patients with newly diagnosed T2DM would fit the profiles suitable for aggressive treatment, and should be considered for such.

12932309_xlInitial Therapy for Patients with Newly Diagnosed T2DM
The ADA and EASD advocate starting with monotherapy with metformin, except for patients with newly diagnosed T2DM with Hba1c of 9% or more13, whereas the AACE advocates starting dual therapy for such patients with Hba1c of 7.5% or more with metformin plus another drug; preference was given to a DPP-4 inhibitor or GLP-1 agonist.14 Nonetheless, one can always start with one drug and up-titrate if the target of 6.5% is not reached in three months’ time. All three organisations recognise that hypoglycaemia is dangerous and avoiding it is a priority. Cost-effectiveness research for DPP-4 inhibitors is controversial – two European studies found it cost-effective, but an American and a Canadian study found it not so.15

The Situation in Singapore
Combination pills containing metformin and a DPP-4 inhibitor are available in Singapore, making it very easy to start patients on dual-therapy. However, such combination pills are costly (around S$100 a month) and might not be affordable for the poorer patients with T2DM. One way to make these drugs more affordable is for them to be included in the subsidised Standard Drug List.

Conclusion
Complications of diabetes mellitus can be prevented with good control. Previously, that had been hard to achieve mainly because of the problem of hypoglycaemia, which is associated with higher mortality. With newer agents that do not cause hypoglycaemia, patients with newly diagnosed T2DM (who have more benefits with better control) can be safely managed to achieve an excellent level of diabetes control.

 

References:
1 National Health Survery 2010. Ministry of Health, Singapore
2 Sicree R, Shaw J, Zimmet P. The Global Burden, Diabetes and Impaired Glucose Tolerance. IDF Diabetes Atlas fourth edition
3 Startton I et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–12
4 7th Report of the Singapore Renal Registry 2007/2008. Dr Lina Choong with Ministry of Health Singapore.
5 Yang et al. Risk factors for lower extremity amputation among patients with diabetes in Singapore. Journal of Diabetes and Its Complications 25 (2011) 382–386
6 UKPDS group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53
7 Singapore Diabetes Guideline 2006. Ministry of Health, Singapore
8 Cryer P et al. Hypoglycemia in Diabetes. Diabetes Care 26:1902–1912, 2003
9 ACCORD group. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008;358:2545-59.
10ADVANCE group. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2008;358:2560-72.
11Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia. 2010 Aug;53(8):1552-61. 12Davis et al. Effects of Intensive Therapy and Antecedent Hypoglycemia on Counterregulatory Responses to Hypoglycemia in Type 2 Diabetes. Diabetes 58:701–709, 2009
13Management of Hyperglycaemia in Type 2 Diabetes: A Patient-Centered Approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care Online.
14AACE Comprehensive Diabetes Management Algorithm 2013. Endocrine Practice 2013;19(2): 327
15Karagiannis et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012;344:e1369

 

author
Dr Daniel Wai Chun Hang is an endocrinologist who has been in private practice since 2012. He is the Director and Consultant Endocrinologist of the Diabetes, Endocrine and Endovascular Clinic located at Parkway East Hospital. Before that, Dr Wai was the Director of the Obesity and Metabolic Unit in Singapore General Hospital, and Adjunct Assistant Professor at the Yong Loo Lin School of Medicine, National University Hospital. He had been the Principle Investigator in genetics of cholesterol, visceral fat, cardiovascular risk factors and thyroid eye disease, with funding from the National Medical Research Council and Biomedical Research Council. However, his first love is seeing patients and he was awarded three times the Service with a Heart Award from SGH.
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