Type 2 diabetes: Evolving concepts and treatment

SGLT2 inhibitors

Drugs of this class currently available in the United States are canagliflozin,³⁹ dapagliflozin,⁴⁰ empagliflozin,⁴¹ and ertugliflozin.⁴²

Pathways affected. SGLT2 inhibitors lower the glucose reabsorption threshold in the kidney so that more glucose is excreted in the urine; they also decrease insulin resistance in muscle, liver, and fat cells (via weight loss) and possibly preserve beta-cell function by reducing glucotoxicity. A nonrenal mechanism—delayed gut absorption reducing postprandial glucose excursion—has been proposed to contribute to the glucose-lowering effects of canagliflozin.⁴³

Advantages, benefits. These agents reduce hemoglobin A_1c by about 0.5% to 1.0% from a baseline of about 8%. Because their action is independent of insulin, they can be used at any stage of type 2 diabetes, even after insulin secretion has significantly waned. Additional potential advantages include weight loss (up to 3.5% of body mass index) and lowering of systolic blood pressure (2–4 mm Hg) and diastolic blood pressure (1–2 mm Hg).^39–42

Canagliflozin was shown in the Canagliflozin Cardiovascular Assessment Study (CANVAS)⁴⁴ to significantly reduce the overall risk of cardiovascular disease by 14% and risk of heart failure hospitalization by 33% while significantly slowing the progression of renal disease.

In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME),⁴⁵ empagliflozin reduced heart failure hospitalizations by 35%, cardiovascular deaths by 38%, and all-cause mortality by about 32%. These benefits are thought to be due to less arterial stiffness, lower sympathetic tone, and decreased arrhythmias. Notably, these dramatic benefits accrued in only about 3 years with use of add-on therapy, even though the reduction in hemoglobin A_1c was modest (0.6%), suggesting that pleiotropic effects are at work.

Disadvantages, adverse effects. The most common adverse effects of this class include urinary tract infections, yeast infections, dehydration, and hypovolemic symptoms; these can often be prevented. A trend toward increased incidence of amputations in earlier studies was not borne out in a 2018 meta-analysis of 4 observational databases.⁴⁶

Thiazolidinediones

There are currently 2 approved thiazolidine­diones in the United States, pioglitazone⁴⁷ and rosiglitazone.⁴⁸ Only pioglitazone is in common use, as rosiglitazone is associated with safety issues.⁴⁹

Pathways affected. Pioglitazone reduces insulin resistance in muscle, liver, and adipose tissue.

Advantages, benefits. Decreased levels of low-density lipoprotein cholesterol and triglycerides and increased high-density lipoprotein cholesterol levels⁴⁹ could plausibly account for the cardiovascular benefits reported in the Prospective Pioglitazone Clinical Trial in Macrovascular Events.⁵⁰ Pioglitazone has also been found to improve insulin secretion, endothelial function, and diastolic dysfunction; reduce inflammation; decrease plasminogen activator inhibitor 1; reverse lipotoxicity; and help correct nonalcoholic fatty liver disease and steatohepatitis.

Pioglitazone has also been found to reduce plaque in carotid and coronary arteries⁵¹; improve outcomes in patients with heart failure and myocardial infarction compared with insulin-sensitizing drugs⁵²; and reduce stroke and myocardial infarction in patients with insulin resistance (but not diabetes) and a recent history of ischemic stroke or transient ischemic attack (in the Insulin Resistance Intervention After Stroke trial).⁵³ It may also help maintain beta-cell function; the Actos Now for the Prevention of Diabetes Study found that pioglitazone reduced the risk of conversion of impaired glucose tolerance to frank diabetes by 72%.⁵⁴

Disadvantages, adverse effects. The most common adverse effects seen with this class include weight gain and salt retention, swelling, edema,⁵⁵ and related cardiovascular consequences in certain patients. While this may be mitigatable with lifestyle changes or use in combination with a GLP-1 receptor agonist or SGLT2 inhibitor,⁵⁶ pioglitazone is contraindicated in patients with heart failure, hemodynamic instability, or hepatic dysfunction.

Concerns that pioglitazone might increase the risk of bladder cancer seem to have been put to rest when a study in nearly 200,000 patients found no statistically significant association,⁵⁷ but the warning remains in the US label.

Long-term use of this class of drugs has been associated with an increased risk of bone fractures,⁵⁸ which warrants a risk-benefit assessment in each patient.

Injected insulin: Less safe than thought

Recent research suggests that injected insulin has a less favorable safety profile than previously thought.^15–19,59 Studies of the long-term safety of insulin therapy have had inconsistent results but suggest that injected insulin is associated with poorer cardiovascular and renal outcomes (in some of the same studies that showed metformin or other agents to improve outcomes),^17–19 and the association was dose-dependent. Several studies attempted to cancel out the poorer outcomes by adjusting for hemoglobin A_1c levels, stage of disease,^{17–19,26,27} or severe hypoglycemic episodes.⁶⁰ However, it may be inappropriate to reduce the impact of these variables, as these may themselves be the mediators of any deleterious effects of exogenous insulin.

When exogenous insulin is introduced into the peripheral circulation it causes a state of persistent iatrogenic hyperinsulinemia, which leads to insulin resistance and also appears to compromise the cardiovascular system. In contrast, endogenous insulin is released into the portal system in tightly controlled amounts.^5,61 This suggests that the same insulin peptide may not be equivalently beneficial when introduced in an artificial manner.

Before starting insulin therapy, consider its side effects such as weight gain and hypoglycemia. Most (about 85%) episodes of hypoglycemia occur with basal-bolus insulin regimens.⁶² Moreover, iatrogenic hyperinsulinemia can damage the vascular system.^63,64

We recommend. Insulin therapy is used early in the course of the disease as a short-term intervention for glucolipotoxicity. However, this can be accomplished without attendant risks of hypoglycemia and weight gain by using agents such as SGLT2 inhibitors and incretins. When insulin therapy is necessary, using it as add-on therapy might be considered instead of drug-switching. We have found alternate pharmacologic approaches successful in avoiding or delaying bolus insulin therapy. And in some patients taking insulin, we have had success in progressively introducing a noninsulin agent and were ultimately able to eliminate insulin altogether.