Overview ã…¡ Effective treatment of type 2 diabetes is uniquely challenging because it encompasses management of lifestyle factors (including diet, exercise, and weight control), use of multiple oral or injectable medications, self-monitoring of blood glucose concentration, and surveillance and treatment for acute and chronic diabetic complications.
Goals of Therapy Including Glucose Targets. The primary goals of diabetes management are to prevent symptomatic hyperglycemia and hypoglycemia and to prevent the vascular complications associated with diabetes. Intensive glycemic control (near-normoglycemia) has been shown to reduce microvascular and neuropathic complications of diabetes, perhaps CVD, but not mortality. Lowering of the HbA1c level to 7% or below is an appropriate goal for most patients with diabetes. More stringent glycemic control (HbA1c level close to the normal range) may be appropriate for some individuals (e.g., young patients with short duration of disease) if it can be achieved without excessive hypoglycemia. Conversely, less stringent goals may be suitable for patients with established vasculopathy, significant comorbidities, or reduced life expectancy. Generally accepted targets for fasting and postprandial glucose levels are 80 to 130 mg/dL and less than 180 mg/dL, respectively. Glycemic targets during pregnancy are different, in part because plasma glucose levels normally are lower during pregnancy and because of the risk of adverse fetal outcomes with even modest hyperglycemia (see, Table 1).
NON-PHARMACOLOGICAL THERAPY
Current approaches for most patients focus on calorie restriction to achieve and to maintain modest (approximately 5 to 10% of body weight) weight loss, moderate carbohydrate intake, and avoidance of concentrated sweets and foods high in saturated fats and cholesterol. An optimal macronutrient distribution for patients with type 2 diabetes has not been established, and individualization of nutrition plans, depending on such factors as renal function, weight status, and the patient's preference, is recommended.
- Low-fat, low-carbohydrate (Atkins-type) diet and a Mediterranean-type diet can each be effective in promoting weight loss and improving glucose control in patients with diabetes.
- Moderate alcohol consumption is not prohibited, with the proper consideration of calorie intake (7 kcal/g) and hypoglycemia risk if alcohol is consumed without food, particularly in insulin-treated patients.
- Referral to a registered dietitian for medical nutrition therapy should be considered for patients newly diagnosed with type 2 diabetes and those who are not achieving glycemic or weight targets.
Regular exercise is an important but often overlooked component of diabetes management. Both aerobic exercise and resistance training can improve blood glucose control, even in the absence of significant weight change. Current recommendations are for a minimum of 150 minutes per week of moderate-intensity physical activity, such as brisk walking, biking, or swimming, and muscle-strengthening exercises two or three times per week. Assessment of cardiovascular status before beginning of an exercise program should be considered for selected patients, but routine screening (e.g., with an exercise stress test) of asymptomatic patients is not recommended.
The presence of some diabetic complications may require restriction of certain activities. For example, in patients with proliferative retinopathy, vigorous aerobic or resistance exercise could precipitate retinal hemorrhage or detachment. The presence of significant sensory loss due to peripheral neuropathy can increase the risk of foot injury, including skin ulceration and Charcot joint destruction. Use of proper footwear and careful foot inspection are recommended, and avoidance of weight-bearing exercise may be required for high-risk patients. Finally, exercise-induced hypoglycemia can occur in patients treated with insulin or some secretagogues (sulfonylureas) and may require adjustment of the medication regimen or added carbohydrate before exercise.
PHARMACOLOGICAL THERAPY
Medications can be broadly categorized as those that enhance insulin availability (insulin and insulin secretagogues), those that enhance insulin action, or a miscellaneous group with other targets.
Metformin (Glucophage). The biguanide drug metformin (insulin Sensitizer) is the most widely used antidiabetic medication and is considered preferred initial therapy for patients with type 2 diabetes. Metformin lowers glucose levels primarily through suppression of hepatic glucose production, but it also may enhance insulin sensitivity (improved insulin-mediated glucose uptake) and limit intestinal glucose absorption.
Modest and sustained weight loss (about 2 to 4 kg) is common with metformin. Metformin is used orally twice a day, and extended-release forms are available for once-daily dosing. Hypoglycemia occurs rarely if at all with metformin monotherapy. The most common adverse effect is gastrointestinal intolerance (dyspepsia, diarrhea), which can be minimized by slow upward dose titration. Vitamin B12 malabsorption, leading to clinical B12 deficiency, has also been reported. For further information, see note on, "Management of vitamin B12 deficiency".
The occurrence of lactic acidosis is the most serious although rare adverse effect, which occurs almost exclusively in patients with renal insufficiency and another precipitating factor, such as sepsis or shock. Renal function should be monitored periodically; metformin must be used with caution in those with an estimated glomerular filtration rate (GFR) of 45 mL/minute or lower and should be discontinued for an estimated GFR of 30 mL/minute or lower. Unique among available antidiabetic therapies, metformin was shown to reduce cardiovascular and all-cause mortality, which adds to its appeal as a first-line agent. Metformin has also been used for diabetes prevention and for treatment of polycystic ovary syndrome.
Thiazolidinediones. The thiazolidinediones (insulin Sensitizer), which include rosiglitazone and pioglitazone, improve insulin-mediated glucose uptake and reduce hepatic glucose production. They bind to a nuclear receptor, peroxisome proliferator-activated receptor γ, and thus regulate the transcription of a variety of genes involved in carbohydrate and lipid metabolism. Thiazolidinedione therapy has pronounced effects on adipose tissue, reducing lipolysis, increasing fat mass, and causing redistribution of fat away from visceral to subcutaneous depots. Thiazolidinediones are given orally in once-a-day dosing. Common adverse effects include weight gain and fluid retention, including precipitation or worsening of congestive heart failure. Also reported have been an increase in fractures in postmenopausal women and increased risk of bladder cancer. The potential cardiovascular toxicity of rosiglitazone remains controversial, and its use has been restricted in many countries; these effects have not been observed for pioglitazone.
Sulfonylureas. Sulfonylureas (insulin Secretagogue) currently in common use include glipizide, glyburide, and glimepiride; older sulfonylureas (chlorpropamide, tolbutamide) are still sometimes used. Their mechanism of action is to bind to the ATP-sensitive potassium channel in the β-cell membrane (at a site termed the sulfonylurea receptor), resulting in membrane depolarization and, ultimately, release of insulin from preformed secretory granules. Therefore the presence of a sufficient mass of intact β cells is required for efficacy of these drugs. They can be used as monotherapy or in combination with other drugs. The major adverse effect of sulfonylureas is their potential to cause hypoglycemia because insulin secretion occurs regardless of ambient plasma glucose. Modest weight gain is also common.
Glinides. Repaglinide and nateglinide are chemically distinct non-sulfonylurea insulin secretagogues that also bind to the ATP-sensitive potassium channel in the β-cell membrane. Their onset and duration of action are much shorter than those of sulfonylureas, and the frequency of fasting hypoglycemia may be less. They are administered orally before each meal, making them somewhat less convenient than medications with a single daily dose but potentially providing an advantage for patients with inconsistent meal timing or content.
Incretin-Based Therapies/GLP-1 Agonists. Exenatide, liraglutide, semaglutide, dulaglutide, and lixisenatide are analogs of the endogenous incretin hormone GLP-1 and stimulate insulin secretion by binding to GLP-1 receptors on β cells. These drugs augment glucose-stimulated insulin secretion and thus have less potential to cause hypoglycemia than sulfonylureas and glinides do. They also suppress hepatic glucose production (by reduction of glucagon secretion), delay gastric emptying, and suppress appetite, resulting in modest weight loss for many patients. GLP-1 agonists are given by injection once or twice a day, and weekly long-acting formulations are also available. Major adverse effects include gastrointestinal intolerance (nausea and vomiting), which can be minimized by initiation with a low dose and gradual titration. An increased risk of acute pancreatitis has been reported with GLP-1 agonists (and DPP-4 inhibitors), but the magnitude of the risk is uncertain and requires additional research. In combination with basal insulin treatment, these agents can improve glycemic control without increasing hypoglycemia and often induce significant weight loss. Liraglutide also reduces all-cause mortality, as well as reducing the risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
Incretin-Based Therapies/DPP-4 Inhibitors. Inhibitors of dipeptidyl peptidase 4 (DPP-4), a ubiquitous serine protease, work by preventing the breakdown of endogenous GLP-1, thus prolonging its effects. DPP-4 inhibitors, including sitagliptin, saxagliptin, and linagliptin, are given orally in a single daily dose. Similar to GLP-1 agonists, they rarely cause hypoglycemia, but they are generally weight neutral and cause fewer gastrointestinal side effects.
SGLT2 Inhibitors. Canagliflozin, dapagliflozin, and empagliflozin are inhibitors of the sodium glucose cotransporter 2 (SGLT2) in the proximal renal tubule. This inhibition prevents the reabsorption of filtered glucose and results in glycosuria, which is accompanied by mild osmotic diuresis and modest weight loss. The most common adverse effect is an increase in mycotic genital infections; hyperkalemia, urinary tract infections, and reductions in blood pressure. Other adverse effects include increased risk of diabetic ketoacidosis, and for canagliflozin, lower extremity amputation.
- Cardiovascular benefit has been reported with canagliflozin, but with a greater risk of amputation, primarily at the toe or metatarsal level. Among patients with evidence of CKD (albuminuria and/or eGFR 30-90 ml/min), canagliflozin can reduce the risk of adverse renal outcomes by 30%.
Other Drugs. Acarbose and miglitol are inhibitors of α-glucosidase enzymes in the intestinal lumen. They are given with meals to slow the absorption of carbohydrates. Gastrointestinal side effects (e.g. flatulence and bloating) are common and limit their use. Pramlintide, bromocriptine, and colesevelam are also approved for treatment of type 2 diabetes. However, they are used infrequently due to side effects and modest glucose-lowering properties.
Insulin Therapy. Insulin treatment can be considered for patients with type 2 diabetes at any point in the course of the disorder, although typically it is used after “failure” of oral or other noninsulin therapies. Insulin may also be preferred therapy in specific situations, such as during hospitalizations (especially in the perioperative period) or in pregnancy. In contrast to patients with type 1 diabetes, patients with type 2 diabetes may be adequately controlled with basal insulin alone or in combination with other antidiabetic medications. Basal insulin is frequently used in combination with oral medications (e.g., metformin, DPP-4 inhibitors) or GLP-1 agonists (e.g., exenatide, liraglutide). Daily insulin requirements tend to be higher for patients with type 2 compared with type 1 diabetes, reflecting the existence of insulin resistance. Use of concentrated insulin preparations (U-200 degludec, U-300 glargine, U-500 regular, U-200 lispro) may be helpful for insulin resistant patients who require insulin doses exceeding 100 units per day.
TREATMENT ALGORITHM
There is general agreement that metformin should be initial therapy for most patients and that subsequent drugs (when needed) are added to but do not replace metformin. The choice of a specific drug combination is driven by a number of factors, including efficacy, cost, side effect profile (e.g., hypoglycemia, weight gain), and preference of the patient (see, Figure 1). Preferential use of drugs shown to have cardiovascular benefits should be considered for patients with established atherosclerotic heart disease or multiple cardiovascular risk factors.
REFERENCES
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Goldman, L., Schafer, A.I. and Cecil, R.L. (2019). Goldman-Cecil medicine. Amsterdam: Elsevier
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020. (2019). Diabetes Care, 43(Supplement 1), pp.S98–S110. Available at: https://care.diabetesjournals.org/content/43/Supplement_1/S98
AACE (2019). Comprehensive Type 2 Diabetes Management Algorithm - EXECUTIVE SUMMARY | American Association of Clinical Endocrinologists. [online] Available at: https://www.aace.com/disease-state-resources/diabetes/clinical-practice-guidelines-treatment-algorithms/comprehensive