University of Toronto - Faculty of Medicine

 

Author
The revision of this chapter (except for section 5.7) was prepared by Jeremy Gilbert, MD
The revision of section 5.7 was prepared by Jeannette Goguen, MD, MEd, FRCPC

In North America, 90% of individuals with diabetes mellitus have type 2 diabetes. Obesity, particularly central obesity is a common risk factor. Other risk factors are listed in Table 5.1. In most populations around the world, the prevalence of Type 2 DM is increasing. Type 2 diabetes is becoming a worldwide epidemic especially affecting developing countries. The impact of diabetes on the morbidity and mortality of subjects affected by it necessitates an aggressive and comprehensive approach of primary (prevention of diabetes) and secondary (prevention of diabetes complications) prevention. Screening for diabetes is recommended every three years in people at or above age 40. Earlier and more frequent screening is recommended for high-risk patients. The screening test recommended is fasting plasma glucose (see Chapter 2) or a 75 gram oral glucose tolerance test. Given the high prevalence of macro and microvascular complications, even at the time of diagnosis (almost 50%), diabetes complications must be thoroughly screened for and additional risk factors (e.g. dyslipidemia, hypertension, microalbuminuria/proteinuria) aggressively treated. Therapy often begins with modification of lifestyle and diet and frequently requires treatment with antihyperglycemic agents.

TABLE 5.1 Risk Factors for Type 2 Diabetes Mellitus
Age >40 years First-degree relative with Type 2 diabetes Member of high-risk population (Aboriginal, Hispanic, South Asian, Asian or African descent) History of IGT or IFG* Presence of complications associated with DM Vascular disease* History of GDM	Delivery of a macrosomic infant Hypertension* Dyslipidemia* Overweight* Abdominal obesity* Polycystic ovary syndrome* Acanthosis nigricans* Schizophrenia
* Components of the metabolic syndrome

 

• To achieve optimal or normal levels of glycemia in order to decrease the occurrence or progression of microvascular and possibly macrovascular complications (Table 5.2)
• To minimize hypoglycemia.
• To use appropriate pharmacological treatment to reduce complications.
• Modify cardiovascular risks factors such as dyslipidemia, hypertension and smoking.

 

Lifestyle Modification
Since the control of hyperglycemia and other metabolic abnormalities in Type 2 DM is frequently influenced by the patient's lifestyle, individuals should be encouraged to maintain a desirable body weight and to obtain regular physical activity (see Chapter 15).

Blood Glucose Control

• The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated that a policy of intensive glycemic control significantly reduces microvascular complications.
• There was also a tendency for less macrovascular disease in the same study.
• The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Action in Diabetes and Vascular Disease (ADVANCE) trial have shown that intensive glucose lowering (median A1C ~6.5%) in Type 2 diabetes does not reduce mortality or major cardiovascular events. In the ADVANCE trial there was a significant reduction in microvascular events, largely contributed by reduced nephropathy.
• It is to be anticipated that in order to achieve optimal or ideal glycemic control and risk factor modification, most individuals with Type 2 DM will require multiple pharmacological agents in conjunction with a program of lifestyle management.
• Target glucose control levels are the same for type 1 and type 2 diabetes (see Table 5.2).

TABLE 5.2 Glycemic Targets
	A1C	Fasting/Preprandial	2 hour postprandial
Target	≤ 7%	4.0 - 7.0 mmol/L	5.0 - 10.0 mmol/L (5.0 - 8.0 if A1C targets not being met)
* Treatment goals and strategies must be tailored to the patient with consideration given to individual risk factors

 

• If diet and physical activity do not result in the desired glycemic control within 2-3 months in patients with mild elevation in A1C (<9%), an antihyperglycemic agent(s) is recommended. See Table 5.4.
• However, if there is marked hyperglycemia (A1C >9%) antihyperglycemic agents should be used at the same time as lifestyle management. The agents recommended are shown in Table 5. 4.
• There are now six major classes of antihyperglycemic agents available - Insulin secretagogues: sulfonylureas (SU) and meglitinides, biguanides (metformin), alpha- glucosidase inhibitors, thiazolidinediones, incretins (see section 5.7) and insulin. (Table 5. 3).
• Early utilization of combination therapy with sub maximal doses of oral antihyperglycemic agents is preferred to using maximum dose of monotherapy. The benefits include greater effectiveness and fewer side effects.
• The goal is to attain target A1C within 6-12 months by adjusting anti-hyperglycemic agents.
• The first line choice of an oral agent is dependent on the clinical situation, the risks and benefits of known side effects, clinician experience with the drug, and drug cost. Generally, metformin should be the first drug used. The order of antihyperglycemic agents in the algorithm in Table 5.4 is a consensus recommended by the Canadian Diabetes Association Clinical Practice Guidelines for the Prevention and Management of Diabetes Mellitus in Canada.

Oral antihyperglycemic agents (also see Table 5.3)

Biguanides

• Metformin is the only biguanide available in Canada..
• The mechanism of action is to reduce hepatic glucose production (decrease gluconeogenesis) and to some extent decrease insulin resistance.
• Metformin in overweight patients resulted in equivalent glucose reduction to sulfonylureas in the UKPDS.
• In the UKPDS a significant decrease in microvascular and macrovascular complications was seen.
• Side effects are mostly gastrointestinal- diarrhea and anorexia with 8% of patients unable to tolerate the drug. This can be minimized by starting at a lower dose and increasing the dose slowly.
• Lactic acidosis is a rare but serious side effect and is only described in cases where the drug is used in patients with significant renal (creatinine clearance <30 ml/min), hepatic or circulatory failure or where the individual had another predisposition to lactic acidosis.
• Metformin as a sole agent is not associated with hypoglycemia and there is usually no weight gain associated with its use.

Sulfonylureas

• Sulfonylureas have been used in the treatment of Type 2 DM for decades.
• Sulfonylureas increase insulin secretion in a non-glucose dependent manner.
• Most sulfonylureas used at equipotent doses result in equivalent reduction in glucose levels.
• The major side effects are hypoglycemia and weight gain.
• Glyburide appears to be associated with more, and gliclazide and glimeperide with less severe hypoglycemia, especially in the elderly.
• Chlorpromide has a very long half life, and can cause prolonged hypoglycemia, can cause hyponatremia and is therefore rarely used.
• Tolbutamide is rarely prescribed.

Meglitinides (non- sulfonylurea insulin secretagogues)

• Meglitinides are rapid and short acting insulin secretagogues given before each meal.
• Nateglinide and repaglinide are available in Canada.
• They may cause hypoglycemia, but are less likely to do so than sulfonylureas.
• They may improve post-prandial glucose more than sulfonylureas.
• Nateglinide decreases A1C less than repaglinide.

Alpha Glucosidase Inhibitors

• Acarbose is a competitive inhibitor of intestinal disaccharidases.
• Its mechanism of action is to decrease digestion and delay absorption of dietary carbohydrates.
• It has been shown to significantly decrease post-prandial blood glucose as well as A1C.
• It has only minimal effects on fasting glucose levels.
• Acarbose is not absorbed systemically except in renal failure.
• The side effects are primarily gastrointestinal consisting of increased gas, bloating and diarrhea.
• Starting at low doses and gradually increasing the dose can minimize side effects. Side effects tend to decrease with prolonged use.
• Acarbose use as a sole agent is not associated with hypoglycemia or weight gain.

Thiazolidinediones

• Pioglitazone and rosiglitazone are agents available in Canada.
• These agents are agonists of the nuclear receptor PPAR Gamma.
• The major mechanism of action is to enhance insulin effects on target tissues and hence are considered insulin sensitizers.
• Major target tissue is fat cells.
• Efficacy in lowering glucose is equivalent to secretagogues and metformin.
• They are not usually associated with hypoglycemia when used alone.
• The main side effects are fluid retention, weight gain, congestive heart failure in patients with poor left ventricular function and a slight decrease in hemoglobin concentration. There are rare occurrences reported of macular degeneration. Fractures occur in frequencies as high as 10% in postmenopausal women.
• Possibility of increased risk of cardiovascular events with rosiglitazone awaits further study
• These drugs are contraindicated in patients with congestive heart failure and should be used with caution in individuals with CAD.
• As compared to a previous member of this group, troglitazone, they are not hepatotoxic. Monitoring of liver enzymes is recommended before starting these medications and as clinically indicated thereafter. If AST is >2.5X upper normal before commencing treatment, do not start the medication.
• Other potential benefits of this group include: reduction of free fatty acids (thereby increasing insulin secretion and decreasing resistance, reduction in LDL/HDL ratio, decreased triglyceride levels (pioglitazone), decreased systolic blood pressure and microalbumin excretion (rosiglitazone), decreased hsCRP, homocysteine and increasing adiponectin. In animal studies Beta-cell preservation is noted.
• The ADOPT study showed longer duration of glycemic control with monotherapy compared with metformin or sulfonylureas.

Incretin Therapy

• Two new classes of agents have recently been developed for the treatment of Type 2 diabetes based on incretin action: glucagons-like peptide-1 receptor agonists or incretin mimetics and dipeptidyl peptidase-4 (DPP-4) inhibitors or incretin enhancers.
• The only agent currently available in Canada is sitagliptin (Januvia®) , which is a DPP-4 inhbitor.
• It has been shown to be safe and effective as monotherapy or when added to metformin.
• Advantages of this agent include being weight neutral, less hypoglycemia, and improving postprandial blood sugars.
• The long term safety of this agent is unknown at this time.

Combination of Oral Antihyperglycemic Agents

• Monotherapy could be effective in attaining treatment targets in patients with newly diagnosed diabetes. However by 3 years, 50% of individuals and by 9 years, 75% of individuals require the addition of a second agent.
• Combination of two classes of drugs has been proven to improve glycemic control.
• There is no rationale for combining two different drugs from the same class (e.g. two insulin secretagogues).
• Triple therapy may be needed to attain treatment targets. Alternatively addition or substitution of insulin could be undertaken.

Insulin

• It is recommended that insulin be used initially in patients with type 2 diabetes when treatment with diet and physical activity is inadequate especially if severe hyperglycemia (A1C >9%) or with metabolic decompensation exists.
• In the patient with ketosis and/or unintentional weight loss, insulin therapy should be initiated immediately.
• Insulin may also be needed temporarily in the ill or hospitalized patient.
• Individuals with Type 2 DM may require large doses of insulin because of significant degrees of insulin resistance.
• Insulin can be used alone as basal insulin (NPH, glargine or detemir) or basal and meal insulin in either a multiple daily injection (MDI) regimen: basal insulin at bedtime and daily with regular insulin or rapid-acting analogue insulins (aspart, lispro or glulisine or two doses of premixed insuilin with NPH + regular or analogue rapid-acting insulin, or other combinations.
• Insulin can also be used in combination with oral antihyperglycemic agents (see below).

Combination Therapy of Insulin with Oral Agents

• When target glucose levels are not attained by combinations of oral antihyperglycemic agents, or if some or all of the antihyperglycemic agents are contraindicated or cause side-effects, insulin may be used in combination with oral agents.
• The combination of sulfonylurea and insulin is called BIDS (Bedtime Insulin Daytime Sulfonylurea) has been shown to decrease insulin dosage required to attain treatment targets, reduce weight gain and hypoglycemia.
• Combination of insulin and biguanides or insulin and non-sulfonylurea insulin secretagogues has been proven to be beneficial with similar advantages to BIDS.
• Combination of insulin and thiazolidinediones is not an approved indication in Canada and may lead to excessive fluid retention.

TABLE 5.3 Oral Antihyperglycemic Agents
Type	Tablet Size (mg)	Maximum Daily Dose (mg)
Biguanides      Metformin	500 850	2500/d in 2 to 3 doses 2550/d in 3 doses
Sulfonylureas      Glyburide      Gliclazide      Gliclazide MR      Glimepiride      Tolbutamide      Chlorpropamide	2.5/5 80 30 1,2,4 500 100/250	10 bid or 20 od 160 bid 120 8 1000 bid 500 od
Alpha Glucosidase Inhibitors      Acarbose	50	100 tid
Meglitinides      Repaglinide      Nateglinide	0.5,1 & 2 120	16 120 tid
Thiazolidinediones      Pioglitazone      Rosiglitazone	15,30,45 2,4	45 8
Combination: Avandamet      Avandaryl	2/500, 2/1000, 4/500, 4/1000 4/1, 4/2, 4/4, 8/2, 8/4	8mg rosiglitazone and 2g metformin 8 mg rosiglitazone and 4 mg glimepride
Incretin Agent: DPP-4 Inhibitor      Sitagliptin	25, 50, 100	100

 

Blood Pressure

• Control of BP to values below 130/80 is recommended.
• Agents of choice are ACE-I (angiotensin converting enzyme inhibitors), ARBs (angiotensin receptor blockers. thiazide diuretics and dihydropyridine calcium channel blockers. Cardioselective beta blockers and non-dihydropyridine calcium channel blockers could be used if other agents are not sufficient to reach blood pressure targets or are contraindicated. Special consideration for ACE-I and ARB agents should be given due to their renal protective effect. Patients with diabetes mellitus and hypertension require an average of 3.2 antihypertensive medications to reach treatment targets.

Dyslipidemia

• People with diabetes mellitus over 30 years of age are considered at a high risk for cardiovascular disease with a 10 year event risk of >20%. Compared to people without diabetes, the risk of cardiovascular disease is increased 2-4 fold.
• LDL is the primary target of therapy and should be targeted at LDL<2.0 mmol/L in high risk individuals.
• Secondary target is total Cholesterol/HDL ratio and should be targeted < 4.0.
• In some cases, plasma apoB levels can be measured and should be <0.9g/L in high risk patients.
• Life-style changes and concomitant use of pharmacological treatment is recommended if these values are exceeded.
• Some studies suggest that irrespective of LDL levels, patients with type 2 diabetes have reduced vascular events with the use of statins.

ACE Inhibitors or Angiotensin Receptor Blockers

• In people with diabetes over 55 years of age with one other cardiovascular risk factor, the HOPE Study found that the use of ramipril 10 mg daily for 4.5 years resulted in significant reduction in mortality, myocardial infarction and stroke.
• The EUROPA study looked at patients with type 2 diabetes who were considered at high risk of cardiovascular disease, and found decreased clinical endpoints using perindopril as the ACEI.
• ARBs have been shown to be equivalent to ACEI in patients with diabetes who are at high risk for a cardiovascular event.
• If there are no contraindications for ACE-I or angiotensin receptor blocker, such drugs should be used in this group of patients.
• The use of ACE-I and ARBs in vascular protection in other patient populations should be individually assessed.

ASA

• Aspirin has benefit in secondary prevention for cardiovascular disease and therefore is recommended in patients with diabetes and coronary artery disease.
• Less evidence supports the use of Aspirin in primary prevention for cardiovascular disease in people with diabetes and the decision to use Aspirin in this context should be made individually.
• Clopidogrel may be used in patients who do not tolerate Aspirin.

 

• Individuals with Type 2 DM should be encouraged to perform self-monitoring of blood glucose (SMBG).
• The frequency of testing depends on the treatment regimen used.
• A1C levels should be checked every three months.

 

• Individuals need to be seen regularly by the diabetes care team. Chronic complications are common in type 2 diabetes.
• Patients should therefore be examined by an experienced professional at diagnosis and every 1-2 years thereafter. The frequency of the examination in patients with diabetic retinopathy needs to be individualized. Patients with diabetic retinopathy should be referred to ophthalmologists with expertise in treating such condition.
• Patients should also be monitored regularly for the neuropathy, microalbuminuria/proteinuria, hypertension, dyslipidemia, and foot problems (see Chapter 16).

 

• Many individuals seek advise about or use alternative therapies in the management of diabetes. Complementary and alternative medicine (CAM) includes herbal medications, dietary supplements, minerals, vitamins and other micronutrient typically used in conjunction with yoga and/or acupuncture. These therapies are used by up to 30% of patients with diabetes for multiple indications. However, they may result in: potential side effects, drug interactions and increased cost to the patient.
• For the most part, the evidence for the use of CAM is weak due to: (1) small, short trials; (2) publications are often not available (only 10% referenced in MEDLINE); (3) deficient standardization and purity of available compounds, including their contamination with regular medications and toxic compounds.
• The authors of these management guidelines do not recommend the use of the following compounds but acknowledge that diabetes health care providers should be aware of alternative therapies that have been claimed to have benefit to people with diabetes.

Improved glycemic control in adults with T2DM	Ineffective for glycemic control in adults with T2DM	Conflicting evidence for affecting glycemic control
Aloe vera	Syzgium cumini	Cinnamomum cassia (Chinese cinnamon)
Ipomoea Batatas (caiapo)	Tinospora crispa	Momordica charantia (bitter melon or bitter gourd)
Coccinia indica	French maritime pine bark	Trigonella foenum-graecum (fenugreek)
Ganoderma lucidum	garlic	ginseng
Gymnema sylvestre	soy phytoestrogens	chromium
Ocimum tenuiflorum (holy basil or tulsi)	Coenzyme Q10 vitamin E Glucosamine sulfate, used to treat osteoarthritis, does not affect glycemic control (27).	vanadium
Pinitol		magnesium
Pterocarpus marsupium (vijayasar)		lipoic acid
Salacia reticulata		vitamin C
Touchi		carnitine

References

1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2008;32(suppl 1): S53-61.
2. UK Prospective Diabetes Study Group. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and the risk of complications in patients with type 2 diabetes: UKPDS33. Lancet 1998;352:837-53.
3. UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes: UKPDS34. Lancet 1998;352:854-65.
4. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS38. BMJ 1998;317:703-13.
5. Hansson L, et al. Effects of intensive blood pressure lowering and low-dose Aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998;351:1755-62.
6. Canadian Hypertension Education Program. The 2008 Canadian Recommendations for the Management of Hypertension: Diagnosis and Therapy.Canadian recommendations for the management of hypertension. http://www.hypertension.ca/chep
7. Clinical Practice Guidelines: Dyslipidemia in Adults with Diabetes. Canadian Journal of Diabetes 2006; 30: 230-240.
8. Effect of Ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE sub study. Lancet 2000; 355:253-9.
9. Fox, KM. European Trial on Reduction of Cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, Multicentre Trial. (The EUROPA Study). Lancet 2003; 362: 782-788
10. Heart Protection Study Collaborative Group MRC/BHF. Heart Protection Study of Cholesterol lowering with Simvastatin in 5963 people with diabetes: A randomized placebo controlled trial. Lancet 2003; 361: 2005-2016
11. Colhoun, HM et al. Primary Prevention of Cardiovascular Disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre, randomized, placebo-controlled trial. Lancet 2004; 364: 685-696.
12. Kahn SE, Haffner SM, Heise MA, et al. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. N Eng J Med. 2006; 355: 2427-2443.
13. Kahn SE, Zinman B, Lachin JM, et al. Rosiglitazone Associated Fractures in Type 2 Diabetes. An Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care. 2008; 31: 845-851.
14. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiovascular Outcomes- An Interim Analysis. N Eng J Med. 2007; 357: 28-38.
15. The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD). Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Eng J Med. 2008; 358: 2545-2559.
16. The ADVANCE Collaborative group. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. N Eng J Med. 2008; 358: 2560-2572.
17. Aschner P, Kipnes MS, Lunceford JK et al. Efect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with Type 2 diabetes. Diabetes Care. 2006; 29:2632-2637.
18. Charbonnel B, Karasik A, Liu J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with Type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29: 2638-2643.

References for section 5.7 Alternative Therapies

1. Yeh GY, Eisenberg DM, Kaptchuk TJ, et al. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care. 2003;26:1277-1294.
2. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2008;32(suppl 1):S91-94.