Pharmacotherapy of type 2 diabetes
Overview
Effective treatment of type 2 diabetes is uniquely challenging because it requires managing lifestyle factors (diet, exercise, and weight control), using multiple oral or injectable medications, self-monitoring of blood glucose, and continuously monitoring for acute and chronic complications of diabetes.
Goals of Therapy and Glucose Targets: The primary goals of diabetes management are to prevent symptomatic hyperglycemia and hypoglycemia and to reduce the risk of vascular complications associated with diabetes. Intensive glycemic control (near-normoglycemia) has been shown to reduce microvascular and neuropathic complications, and potentially cardiovascular disease, although not mortality. Lowering the HbA1c level to 7% or below is appropriate for most diabetes patients. Stricter control (HbA1c near the normal range) may benefit some individuals (e.g., young patients with short disease duration) if achievable without significant hypoglycemia. Conversely, more relaxed targets may be suitable for patients with vascular complications, major comorbidities, or reduced life expectancy. Common glucose targets are fasting levels between 80 to 130 mg/dL and postprandial levels under 180 mg/dL. Pregnancy-specific targets are lower due to naturally lower plasma glucose levels and potential adverse fetal effects with even mild hyperglycemia. "see table 1".
Non-pharmacological therapy
For most patients, non-pharmacological management includes calorie restriction to achieve and maintain modest weight loss (approximately 5-10% of body weight), moderate carbohydrate intake, and avoidance of concentrated sweets, saturated fats, and high-cholesterol foods. There is no established optimal macronutrient distribution for patients with type 2 diabetes, so individualizing nutrition plans based on factors like renal function, weight, and personal preferences is recommended.
- Diet approaches: Low-fat, low-carbohydrate (Atkins-type) diets and Mediterranean diets can both support weight loss and improve glucose control in diabetes.
- Alcohol: Moderate alcohol intake may be allowed if caloric intake (7 kcal/g) and hypoglycemia risk are considered, especially for insulin-treated patients.
- Referral: Consider referring newly diagnosed patients or those not meeting glycemic or weight goals to a registered dietitian for medical nutrition therapy.
Exercise: Regular exercise is crucial for diabetes management but is often overlooked. Both aerobic and resistance exercises can help with glucose control, even without significant weight loss. The recommendation is a minimum of 150 minutes per week of moderate-intensity activities (e.g., brisk walking, biking, or swimming) and muscle-strengthening exercises 2-3 times weekly. Cardiovascular assessment may be necessary for some patients before starting an exercise regimen, but routine screening (e.g., stress testing) for asymptomatic patients is not typically recommended.
Diabetic complications and exercise safety: Some complications may limit certain activities. For instance, vigorous aerobic or resistance exercises can risk retinal hemorrhage or detachment in proliferative retinopathy. Patients with significant sensory loss from peripheral neuropathy should wear proper footwear, inspect feet regularly, and may need to avoid weight-bearing exercises to prevent injury. Additionally, insulin or sulfonylureas may lead to exercise-induced hypoglycemia, necessitating medication adjustments or added carbohydrates before activity.
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)
Metformin, a biguanide insulin sensitizer, is the most commonly prescribed initial treatment for type 2 diabetes. It primarily lowers blood glucose by reducing hepatic glucose production and may also enhance insulin sensitivity (insulin-mediated glucose uptake) and reduce intestinal glucose absorption.
Metformin use is often associated with modest, sustained weight loss (approximately 2-4 kg). It is typically taken orally twice daily, though extended-release options allow for once-daily dosing. Hypoglycemia is rare with metformin monotherapy. Gastrointestinal side effects, such as dyspepsia and diarrhea, are common but can be reduced by gradual dose increases. Metformin can also cause vitamin B12 malabsorption, potentially leading to deficiency. For more details, see "Management of Vitamin B12 Deficiency".
The most serious but rare adverse effect of metformin is lactic acidosis, primarily seen in patients with renal insufficiency combined with other risk factors (e.g., sepsis or shock). Regular monitoring of renal function is recommended. Metformin should be used cautiously if the estimated glomerular filtration rate (eGFR) is 45 mL/min or lower, and discontinued if it drops to 30 mL/min or lower. Unique among antidiabetic drugs, metformin has been shown to reduce cardiovascular and all-cause mortality, supporting its role as a first-line treatment. Metformin is also used for diabetes prevention and in managing polycystic ovary syndrome (PCOS).
Thiazolidinediones
Thiazolidinediones, including rosiglitazone and pioglitazone, are insulin sensitizers that improve insulin-mediated glucose uptake and reduce hepatic glucose production. These drugs work by activating the nuclear receptor PPARγ, which influences the transcription of genes involved in carbohydrate and lipid metabolism. Effects on adipose tissue include decreased lipolysis, increased fat mass, and redistribution of fat from visceral to subcutaneous areas. Thiazolidinediones are taken orally once daily. Common side effects include weight gain and fluid retention, which may exacerbate congestive heart failure. Increased fracture risk has been reported in postmenopausal women, along with a potential increased risk of bladder cancer, specifically with rosiglitazone. The cardiovascular safety of rosiglitazone remains a subject of ongoing research, while pioglitazone appears to have a more favorable profile.
Sulfonylureas
Sulfonylureas, such as glipizide, glyburide, and glimepiride, are insulin secretagogues that bind to the sulfonylurea receptor on β-cells, promoting insulin release. This mechanism requires a sufficient population of functioning β-cells to be effective. Sulfonylureas may be used alone or in combination with other antidiabetic drugs. Adverse effects include the risk of hypoglycemia due to insulin release that is independent of blood glucose levels, as well as modest weight gain.
Glinides
Glinides, including repaglinide and nateglinide, are non-sulfonylurea insulin secretagogues that act on the ATP-sensitive potassium channel in β-cells. With a rapid onset and shorter duration of action compared to sulfonylureas, glinides present a lower risk of fasting hypoglycemia. They are taken orally before each meal, which may be advantageous for patients with variable meal timing.
Incretin-based therapies/GLP-1 agonists
GLP-1 agonists, such as exenatide, liraglutide, and semaglutide, mimic the incretin hormone GLP-1, stimulating glucose-dependent insulin secretion. They reduce hepatic glucose production, delay gastric emptying, and suppress appetite, leading to modest weight loss. GLP-1 agonists are administered by injection, with options available for daily or weekly dosing. Side effects include gastrointestinal symptoms (e.g., nausea and vomiting), which can be managed with gradual dose escalation. An association with acute pancreatitis has been observed but requires further research. Liraglutide has demonstrated cardiovascular benefits, reducing all-cause mortality and major adverse cardiovascular events.
Incretin-based therapies/DPP-4 inhibitors
DPP-4 inhibitors, such as sitagliptin and saxagliptin, work by inhibiting the enzyme DPP-4, which breaks down GLP-1, thereby enhancing the activity of endogenous GLP-1. These agents are administered orally once daily, are weight-neutral, and have a low risk of hypoglycemia. Gastrointestinal side effects are minimal compared to GLP-1 agonists.
SGLT2 Inhibitors
SGLT2 inhibitors, including canagliflozin and dapagliflozin, inhibit glucose reabsorption in the renal tubules, causing glycosuria and a mild diuretic effect, which may aid in weight loss. Common side effects include genital infections, and patients may experience urinary tract infections and mild blood pressure reductions. Serious but rare adverse effects include diabetic ketoacidosis and, specifically for canagliflozin, an increased risk of 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 inhibit α-glucosidase enzymes in the intestine, which slows carbohydrate absorption when taken with meals. However, these drugs often cause gastrointestinal side effects, such as flatulence and bloating, which can limit their use. Additional options for type 2 diabetes include pramlintide, bromocriptine, and colesevelam, though these are used less frequently due to modest glucose-lowering effects and side effect profiles.
Insulin therapy
Insulin therapy can be considered at any stage of type 2 diabetes, especially when oral or non-insulin treatments are insufficient. Insulin may also be preferred during specific situations, such as hospitalization or pregnancy. Unlike in type 1 diabetes, some type 2 patients may achieve adequate control with basal insulin alone or combined with other antidiabetic medications (e.g., metformin, DPP-4 inhibitors). Basal insulin is commonly combined with oral agents or GLP-1 receptor agonists (e.g., exenatide, liraglutide). Due to insulin resistance, daily insulin needs are often higher in type 2 diabetes, making concentrated insulin formulations (e.g., U-200 degludec, U-300 glargine) beneficial for patients requiring over 100 units daily.
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
- 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.
