The recent publication of the United Kingdom Prospective Diabetes Study (UKPDS) [1, 2] drew several important conclusions which were discussed by Dr. Keith Dawson in some detail in our last issue. Among the conclusions in this study were that only 3% of the entire study group were able to achieve target glycemic goals using lifestyle modifications alone. Equally important was that blood pressure control appeared to be a key factor in preventing complications associated with type 2 diabetes. Thus for the majority of individuals with type 2 diabetes, optimal management requires the use of one or more medications to achieve target glycemic goals and optimal blood pressure levels. This being the case I would like to discuss the medications that are used to treat hyperglycemia in type 2 diabetes.
Insulin has many actions of which the best recognized is the lowering of blood glucose by increasing the uptake of glucose by cells. Insulin also suppresses glucose production by the liver. These actions require relatively high physiologic levels of insulin. With this in mind two factors are necessary for type 2 diabetes to occur. The first and more important factor is impaired insulin action, termed insulin resistance. This is probably due to a number of genetic factors. Insulin resistance is correlated with obesity, particularly abdominal obesity, and to a lesser extent with lack of physical fitness. Hyperinsulinemia (high insulin levels) is the normal compensatory response to insulin resistance. When the body is no longer able to maintain the high insulin levels necessary to overcome this resistance, blood sugar rises (hyperglycemia) and diabetes results. Thus a second factor, insulin secretory failure or insulin deficiency, is required for type 2 diabetes to occur. The mechanisms underlying this phenomenon are poorly understood. As a clinical rule of thumb, the more obese the patient with diabetes, the greater the role of insulin resistance, while the leaner the patient, the greater the role played by insulin deficiency. Diabetes of the elderly is characterized by a greater degree of insulin deficiency than in younger patients.
Normal (non-diabetic) values for blood sugar (glucose) are: 4.0-6.0 before meals and bed and < 7.5 two hours after meals. For people with diabetes, these levels are regarded as “Ideal”. The targets recommended for most people with diabetes are termed “Optimal” and are slightly higher than non-diabetic levels. These are 4.0-7.0 before meals and bed and < 10.0 two hours after meals.
A laboratory measurement called HbA1c (pronounced “hemoglobin A1C”) is an index of blood sugar throughout the day for the past 12 weeks. It is a rolling average, giving more weight to recent sugars, and less weight to sugars earlier in the previous 12 weeks. Normal (non-diabetic or “Ideal”) values are 0.048 – 0.062. “Optimal” values for people with diabetes are < 0.070. There is a strong correlation between blood sugar before breakfast or dinner and HbA1c in most people with diabetes. Thus, once your diabetes is stable, it is possible to predict with some accuracy, in any individual patient, the expected HbA1c. For this reason, once the HbA1c is “optimal” and stable it need be measured only every 6-12 months.
Treatment of Hyperglycemia &mdash Home blood glucose monitoring
The key to improving blood sugar is for the person with diabetes to become empowered to manage their own blood sugar. This is achieved by diabetes education and home blood glucose monitoring (HBGM). By following their own blood sugars, patients are able to get instant feedback (both positive for good results and negative for poor results) and to act appropriately.
Lifestyle modification therapy should be strongly recommended to all patients. It should be continued life-long. In all overweight individuals, weight loss is desirable though difficult to achieve and sustain. Weight loss is particularly beneficial because it reduces insulin resistance, which lies at the heart of type 2 diabetes. Weight maintenance is a more realistic target, as most adults, and particularly diabetic adults tend to gain weight slowly. Diets should focus on reduction of fat by reducing intake of dairy products, fried foods, dressings and non-lean meats. Dietary therapy is otherwise aimed at minimizing the inevitable rise in blood sugar after meals. This is best achieved by redistributing calories as evenly as possible throughout the day (the so-called ‘grazing’ diet – frequent small meals);, reducing simple starches, particularly sugars (sweeten with non-calorific substitutes), and taking the bulk of each meal as complex carbohydrates (grains and vegetables).
A graded exercise program, based on the patient’s past exercise history and co-morbid illnesses, should be prescribed as an adjunct to diet and weight loss in all patients. Patients should be referred to a local gym for instruction and motivation. Exercise burns calories, promotes a greater sense of well-being and when done post-prandially encourages smaller meal portions.
Medication &mdash (Oral hypoglycemic agents)
Unless severely symptomatic, all patients should have a several week trial of lifestyle modification before commencing oral agents.
Metformin works principally by reducing insulin resistance: mostly by reducing the production of sugar by the liver. Metformin is the oral hypoglycemic agent of choice in all patients with type 2 diabetes except those who are thin, elderly or have creatinine > 200 mmol/l or significant heart failure (relative contraindications). Because metformin does not cause insulin secretion, the danger for hypoglycemia (low-blood sugar) when used as a single agent is very low. Metformin should be started at 250-500 mg with the evening meal for 3-4 days then, if side-effects (diarrhea, nausea, epigastric discomfort) are minimal, increased to 500 mg two or three times a day with meals over the next week or two and, if necessary, taken to a maximum of 1000 mg three times a day. Smaller maximal doses should be used in those with relative contraindications.
Sulfonylurea agents (glyburide, gliclazide, tolbutamide, & chlorpropamide) work by increasing insulin secretion. Sulfonylureas may be used as first line agents, particularly in thin (less insulin resistant), or elderly patients (more insulin deficiency), or in those with creatinine > 200 mmol/l or heart failure. I generally use sulfonylurea agents as second-line drugs, which are added to metformin if the response to maximal tolerated metformin alone is sub-optimal. Sulfonylureas cause non-suppressible insulin secretion and therefore have great potential for hypoglycemia. At maximal doses, each sulfonylurea agent is roughly equivalent in efficacy to other members of its class. Dose response is very steep, as most of the effect is achieved with 25% of the maximal dose.
Glyburide is the sulfonylurea of choice. It should be started at 2.5 – 5 mg with breakfast (or 1.25 mg in those predisposed to hypoglycemia such as the very frail and/or elderly or those with significant renal or hepatic disease; ie.kidney and liver) and then rapidly increased to 5 mg twice a day and finally to the maximum dose, 10 mg twice a day. Where fear of hypoglycemia is particularly great (in the very elderly or infirm) tolbutamide or gliclazide, both of which have shorter half-lives (less prolonged effect) than glyburide may be used. The latter two medications may be used starting with small doses (40 mg or 500 mg 4 times a day, respectively).
Where the response to the combination of maximal doses of metformin and sulfonylurea (started in either order) is sub-optimal, insulin therapy is usually indicated. For those patients on maximal oral agents who are fairly close to their glycemic goals a trial of acarbose may be considered. Acarbose is an inhibitor of the starch splitting enzyme a1-6 glucosidase. In small doses it delays the absorption of glucose and thereby reduces post-prandial hyperglycemia. In larger doses it produces flatus and carbohydrate malabsorption characterized initially by increasing volumes of flatus and then by diarrhea. The starting dose is 25 mg (half a pill) with the first bite of the meal three times a a day. There is no theoretical maximum dose as the drug is non-absorbed. In doses of 50 mg three times a day it can be expected to reduce fasting blood sugar by 1.0 – 1.5 mmol and HbA1c by 0.008.
An insulin sensitizing agent, troglitazone, which reduces insulin resistance in a unique fashion, has been available in the United States for 2 years. It is a moderately effective drug (less so than metformin or sulfonylureas and more so than acarbose) but is very expensive (US$ 4-6/day). It is particularly helpful for those patients not responding to large doses of insulin. The starting dose is 200 mg once a day and the maximum dose 600 mg once a day. It is well tolerated. It is very rarely associated with liver dysfunction but regular liver function tests should be performed while this drug is taken.
There are essentially three types of insulin all of which currently require sub-cutaneous injection:
- ultra-short acting (lispro = Humalog = H) which has onset at 10 minutes, peaks at 1-2 hours and is gone by 5 hours;
- short acting insulin (regular = R = Toronto, also known as ‘clear’), which has onset at 30-40 minutes, peaks at 2-4 hours and is gone by 8 hours, and
- intermediate acting insulin (NPH = N, or Lente = L, Ultralente = U: also known as ‘cloudy’) which have an onset of action at 2 hours, peaks at 6-8 hours and is gone by 12-18 hours.
Premixed insulins have been more widely used in the past 5 years. These are named for their proportion of R to N insulin i.e. 30/70 has 30% R and 70% N. Their advantage is that mixing is not required; their disadvantage is lack of flexibility in relative proportions of R or N. Most insulin in current use is recombinant human insulin. The manufacture of Beef/pork insulins (Iletin) has been discontinued though some pharmacies still have stocks. Animal insulins are similar to human insulins but have slightly longer durations of action.
Insulin therapy should ideally be begun in a diabetes education centre. Once the technique has been mastered insulin adjustment can often be made by the patient in concert with the specialist or family doctor.
Insulin has traditionally been injected with a syringe system, though insulin “pens” have become more widely used. Their advantage is that insulin need not be drawn up manually. It is simply dialed up.
The principles of insulin therapy in Type 2 diabetes are somewhat different to those of Type 1 diabetes. In Type 1 diabetes, the patient makes no insulin whatsover, thus both short & long-acting insulins need be given. Because the majority of Type 2 diabetes patients, at least early in the course of their requiring insulin therapy, make some of their own insulin, it is often sufficient to give enough intermediate-acting insulin such that fasting and pre-meal glycemia is relatively normal. Thus twice daily intermediate-acting insulin, pre-mixed insulin such as 30/70 is often recommended for initial therapy. The starting dose is 0.15 units per kg 30 minutes before breakfast and dinner. The dose may be titrated up in increments of 2 units morning and/or evening until sugar falls under 8 mmol. At this stage finer adjustments may be made. Oral agents may be stopped “cold-turkey” when insulin therapy is begun. An alternate approach, particularly in the elderly, is to continue oral agents and to start with a single bedtime dose of intermediate-acting insulin at 0.15 U per kg.
Limitations of Current Therapies
Hypoglycemia is the main limiting factor of intensified and conventional insulin therapy. Hypoglycemia is much less of a problem in Type 2 than Type 1 diabetes because the former is associated, almost by definition, with insulin resistance. Patients who have unacceptable hypoglycemia despite good compliance with diet may be considered for ultra-short-acting insulin. Weight gain is another problem with insulin therapy. If dietary compliance is not problematic, consideration may also be given for ultra-short-acting insulin therapy, with cessation of regular snacks.
There continues to be 10-20 of patients who exhibit marked insulin resistance such that normalization of sugar by any dose of insulin and/or oral agents is not possible. The potential release of troglitazone may help reduce this number. Further developments in pharmacotherapy are awaited with great interest.
Dr. Tom Elliott is an active researcher and educator and the President of the BC Endocrine Research Foundation. He is also a busy physician treating individuals with endocrine disorders.
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) The Lancet, 1998, Vol. 352; pg. 837-853.
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) The Lancet, 1998, Vol. 352; pg. 853-865.