Glucose Control in Type 2 Diabetes 2009
Recommendations for managing blood glucose levels for type 2 diabetes mellitus

The vital importance of this topic is underlined by the following facts:
  • In the Canada, type 2 diabetes is the sixth leading cause of death, directly causing more than 10,000 deaths annually and contributing to more than 30,000 deaths.
  • In adults, type 2 diabetes is the leading cause of renal failure and new cases of blindness, and the disease is an important cause of lost workforce productivity.
  • Of more than 9 million people in Canada with type 2 diabetes, 2 million do not have a diagnosis.
  • Type 2 diabetes disproportionately affects ethnic and racial minorities.
Derangement of glucose homeostasis and the eventual development of diabetes is a multifactorial process involving genetics, ethnic and racial heritage, and environmental factors. Although the precise interplay of these factors is not yet fully understood, long-term trials have provided evidence to support aggressive efforts to prevent and manage this disease. The Canadian Diabetes Association recommends a hemoglobin A1c (HbA1c) goal of less than 7% and maintaining blood glucose levels as close to normal as possible without causing hypoglycemia, based on evidence validated by clinical trials. Three strategies highlighted by evidence-based guidelines for the treatment of type 2 diabetes include intensive lifestyle intervention; aggressive management of cardiovascular risk factors; and normalization of blood glucose levels, with target HbA1c level less than 7%.

Recommended lifestyle interventions include incorporating 150 minutes per week or more of physical activity; a low-fat, reduced-energy diet; and weight loss with an initial goal of 7% of baseline weight, which has been shown to lower the incidence of type 2 diabetes by 58%. It is estimated that 6.9 persons would need to undergo intensive lifestyle intervention to prevent 1 new case of type 2 diabetes in 3 years. Exercise and weight loss may reduce triglyceride levels and visceral adiposity and lower HbA1c levels by 0.6%.

To lower cardiovascular risk and improve survival, multifactorial interventions are recommended. Cardiovascular risk factors such as hypertension, dyslipidemia, and microalbuminuria should be aggressively managed with aspirin, statins, and angiotensin-converting enzyme inhibitors or Angiotensin receptor blockers..

Daily low-dose aspirin is recommended for patients older than 40 years with type 2 diabetes or for those who have additional risk factors for cardiovascular disease (CVD). Patients with type 2 diabetes and CVD, or who are older than 40 years with type 2 diabetes and have 1 other CVD risk factor, should take statins (cholesterol lowering agents), irrespective of cholesterol level.

The hallmarks of type 2 diabetes are insulin resistance, reduced insulin secretion, and increased hepatic glucose output. Each class of available diabetes medications targets 1 or more of these characteristics.

Compared with lifestyle intervention alone or placebo, monotherapy with any hypoglycemic agent more effectively decreases HbA1c levels, with absolute reductions ranging from 0.5% to 1.0% for incretin therapies, and alpha-glucosidase inhibitors to 1% to 2.5% for sulfonylureas, thiazolidenediones and metformin. However, short-term glucose control may not be indicative of longer-term outcomes, and not all hypoglycemic agents have been shown to decrease morbidity and mortality rates.

Metformin, a biguanide, is considered a first-line agent and has been shown to reduce progression from glucose intolerance to type 2 diabetes and to reduce mortality rates in patients with type 2 diabetes. The mechanisms of action of metformin are to decrease hepatic glucose output and sensitize peripheral tissues to insulin. To prevent 1 case of type 2 diabetes, the number needed to treat with metformin is 13.9.

Other medications include sulfonylureas and nonsulfonylurea secretagogues, alpha-glucosidase inhibitors, and thiazolidinediones. Sulfonylureas and other secretogogues can cause weight gain, and although they increase insulin secretion, they lack sufficient evidence of benefit for cardiovascular outcomes.

In patients newly diagnosed with type 2 diabetes, insulin can be used acutely to normalize blood glucose levels. It may also be added to treatment with oral agents for better glycemic control if fasting blood glucose levels are consistently greater than 14 mmol/L (250 mg/dL) or if random glucose level is greater than 16.5 mmol/L (300 mg/d)L. Because of potential teratogenicity with oral medications, insulin is the agent of choice for all pregnant women with type 2 diabetes. Although home monitoring can be used to adjust medication doses between measurements of HbA1c levels, it is expensive and time consuming. Especially in relatively well-controlled patients, home monitoring of blood glucose levels is of questionable value except for patients taking multiple insulin injections. Home monitoring should be used as indicated based on individual patient needs because there are no evidence-based recommendations regarding the optimal frequency of home glucose monitoring.

Specific key clinical recommendations, and their accompanying level of evidence rating, are as follows:
  • Patients with impaired glucose tolerance should receive counseling and education regarding weight loss and physical activity (level of evidence, A).
  • In patients with type 2 diabetes, the only medication proven to reduce mortality rates is metformin (level of evidence, A).
  • Acarbose appears to be associated with a lower risk for CVD events (level of evidence, B).
  • Oral agents should be continued initially when insulin is added to a regimen of oral medication. Long-acting insulin should be used at first, with initial dosage usually 10 units/day or 0.17 to 0.5 units/kg/day, and it should be titrated in increments of 2 units approximately every 3 days to achieve a fasting glucose level consistently between 4 and 7 mmol/L (70-125 mg/dL) (level of evidence, C).
What do we do after Metformin:

CDA-Clinical Practice Guidelines 2008 are clear that all people with diabetes should have counseling in diet and physical activity with a goal of modest weight loss and 150 minutes a week of exercise.

If this does not achieve glycemic control then Metformin should be added. We should initiate Metformin in a modest dose such as 250 mg once a day and then titrate up to achieve control. The usual maximal therapeutic dose is 2000 mg/day, usually 2x500 mg twice a day), higher doses do not lead to improved effect and indeed may cause deterioration in control. The main side effects of Metformin are GI irritation, diarrhea, cramps or dyspepsia. If we do not achieve glycemic control (A1c <7%) with lifestyle measures and Metformin, we need to add another agent, tailoring this agent to individual patient needs.

If glucose values are very high (A1c >10%) or there is metabolic decompensation then insulin should be added. We would normally start with a basal insulin (NPH, Lantus or Levemir) starting with 10u a day (at bedtime in the case of NPH) and titrate this dose up until we achieve a fasting glucose level between 4 & 7 mmol/L. If we still are not achieving target of A1c <7% then we will need to add bolus (mealtime) insulin.

If A1c is modestly elevated between 7% and 8% and fasting glucose levels are close to the target of <7 mmol/L, then the major contributor to the elevated A1c is post prandial glucose so we need to tailor our treatments to primarily lower post prandial glucose levels.

Treatments that predominantly effect post prandial glucose:

DPP-4 inhibitors, sitagliptin (Januvia) 100 mg once a day. Will lower A1c about 0.7%, well tolerated, does not cause hypoglycemia or weight gain. Require a functioning pancreas in order to work so they are not effective in the end stage patient with >8 years of diabetes, these people will require insulin.

GLP-1 analogues or mimetics: Liraglutide (Victoza) 1.2 or 1.8 mg injection/day, exenatide (Byetta) 5 or 10 mcg injection twice a day. Side effects of nausea (decreases over time), frequent weight loss.

Acarbose (Glucobay) 50-100 mg with the first bite of each meal. Will lower A1c about 0.5%, potential side effects of GI distress or gas, does not cause hypoglycemia or weight gain.

Short acting secretagogues: Repaglinide (Gluconorm) 0.5-4 mg with each meal or nateglinide (Starlix) 120 mg with each meal. Will lower A1c 1%. Moderate risk of hypoglycemia, minimal weight gain. Require a functioning pancreas in order to work so they are not effective in the end stage patient with >8 years of diabetes, these people will require insulin. Short acting insulin analogues: aspart(NovoRapid), glulisine(Apidra), lispro(Humalog) with each meal. Dose needs to be individualized to achieve a 2 hour post prandial glucose level of 5-8 mmol/L. Will lower A1c up to 2%. High risk of hypoglycemia or weight gain.

If A1c is markedly elevated >8% and or fasting glucose levels are high (>7 mmol/L) then the major contributor to the elevated A1c is fasting glucose levels so we need to tailor our treatments to primarily lower fasting glucose levels. If the person has a long history of diabetes of more than about 8 years with progressive deterioration of insulin production, it is likely that insulin treatment will be required.

Treatments that predominantly effect fasting glucose:

Sulphonylureas: glyburide (Diabeta) 2.5-10 mg BID, glimepiride (Amaryl) 1-4 mg OD, gliclazide 80-160 mg BID, gliclazide MR (Diamicron MR) 30 mg, 1-4 tabs given once a day; stimulate the pancreas to produce more insulin. High risk of hypoglycemia or weight gain. Gliclazide and glimepiride have a lower potential for hypoglycemia and are recommended in the elderly. Require a functioning pancreas in order to work so they are not effective in the end stage patient with >8 years of diabetes, these people will require insulin.

Thiazolidenediones: pioglitazone (Actos) 15, 30 or 45 mg OD; rosiglitazone (Avandia) 2, 4 or 8 mg OD. Improve insulin resistance and preserve pancreatic functioning. They are best use early in the course of diabetes while there is some pancreatic functioning to preserve. May delay the time until insulin is required. Side effects of weight gain & fluid retention, should not be used in people at risk of heart failure. Require a functioning pancreas in order to work so they are not effective in the end stage patient with >8 years of diabetes, these people will require insulin.

Basal insulins:

NPH: (Novolin GE NPH, Humulin N) usually started as 10 units at bedtime then titrate dose up to achieve fasting glucose less than 7mmol Long Acting Analogues: detemir (Levemir), glargine (Lantus) start at 10u once a day and titrate up to achieve fast less than 7 mmol/L. Risk of hypoglycemia moderate, risk of weight gain high.