Type 2 diabetes: Evolving concepts and treatment
ABSTRACT
In view of new information, we are revising the way we think about and treat diabetes mellitus. In this new view, the insulin-producing beta cells are key, and preserving beta-cell function is paramount. These insights, together with recent outcome studies provide compelling arguments regarding treatments of choice.
KEY POINTS
- At least 11 pathways lead to hyperglycemia; of these, beta-cell dysfunction is central.
- As different classes of diabetes drugs act on different pathways, we can target the pathways contributing to hyperglycemia in the individual patient, using fewer agents and lessening the risk of hypoglycemic episodes.
- In selecting treatment, we should favor drugs that are “gentle” on beta cells, do not cause dangerous hypoglycemia, and improve long-term outcomes as shown in randomized clinical trials.
PROFILES OF DIABETES DRUGS
The sections below highlight some of the recent data on the profiles of most of the currently available agents.
Metformin: Still the first-line treatment
Current guidelines from the ACP, ADA, and AACE keep metformin14 as the backbone of treatment, although debate continues as to whether newer agents such as GLP-1 receptor agonists are superior for first-line therapy.
Pathways affected. Metformin improves insulin resistance in the liver, increases endogenous GLP-1 levels via the gut, and appears to modulate gut flora composition, which is increasingly suspected to contribute to dysmetabolism.
Advantages, benefits. Metformin is easy to use and does not cause hypoglycemia. It was found to modestly reduce the number of cardiovascular events and deaths in a number of clinical outcome studies.15–19
Disadvantages, adverse effects. In some patients, tolerability restricts the use of this drug at higher doses. The most common adverse effects of metformin are gastrointestinal symptoms (diarrhea, nausea, vomiting, flatulence); other risks include lactic acidosis in patients with impaired kidney function, heart failure, hypoxemia, alcoholism, cirrhosis, contrast exposure, sepsis, and shock.
GLP-1 receptor agonists
GLP-1 receptor agonists20–25 are injectable medications approved for adults with type 2 diabetes. Exenatide and liraglutide lower hemoglobin A1c by 1 to 1.5 absolute percentage points and reduce body weight; these effects persist over the long term.26 Newer once-weekly GLP-1 receptor agonists (albiglutide,20 dulaglutide,21 and semaglutide25) have similar benefits. In 2019, new drug applications were submitted to the FDA for the first-in-kind oral GLP-1 receptor agonists, which would improve convenience and adherence and make this class even more attractive.
Pathways affected. GLP-1 receptor agonists address multiple pathways of hyperglycemia. They increase insulin production and release, promote weight loss, and reduce insulin resistance, glucagon secretion, and inflammation. They also increase amylin, help overcome GLP-1 resistance, slow gastric emptying, and favorably modify gut flora.27
Advantages, benefits. The cardioprotective actions of GLP-1 receptor agonists include reducing inflammation and dysfunction in endothelial and myocardial cells; slowing atherosclerosis; reducing oxidative stress-induced injury and scavenging of reactive oxygen species in coronary endothelial, smooth muscle, and other cells; and enhancing endogenous antioxidant defenses.27 GLP-1 receptor agonism has also been found to inhibit apoptosis in cardiomyocytes, as well as in beta cells.
Several large-scale studies have shown improved outcomes with GLP-1 receptor agonists. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial26 found that liraglutide reduced major adverse cardiovascular events by 13% and myocardial infarctions by 22% in more than 9,000 adults with type 2 diabetes who were at high risk of major adverse cardiovascular events compared with placebo. Rates of microvascular outcomes were also reduced.
A retrospective database analysis of 39,275 patients with type 2 diabetes who were treated with exenatide reported a lower incidence of cardiovascular events than in patients not treated with exenatide.28
However, no effect on cardiovascular outcomes was found with a third GLP-1 agent, lixisenatide, in a large-scale trial in high-risk patients with diabetes.29
The most recently evaluated GLP-1 receptor agonist is semaglutide. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) demonstrated a reduced risk of major adverse cardiovascular events.30
Disadvantages, adverse effects. The most common adverse effects in this class include nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase. The nausea can be mitigated by advising patients to stop eating at first sensation of stomach fullness.
DPP-4 inhibitors
Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous enzyme that rapidly degrades GLP-1 and other endogenous peptides.31 Saxagliptin,32 sitagliptin,33 linagliptin,34 and alogliptin35 are approved for use in the United States, and vildagliptin36 is available in Europe.
Pathways affected. These agents modify 3 pathways of hyperglycemia: they increase insulin secretion, decrease glucagon levels, and help overcome GLP-1 resistance.
Advantages, benefits. DPP-4 inhibitors have been used safely and effectively in clinically challenging populations of patients with long-standing type 2 diabetes (> 10 years).
Disadvantages, adverse effects. As this class increases GLP-1 levels only 2- to 4-fold, their efficacy is more modest than that of GLP-1 receptor agonists (hemoglobin A1c reductions of 0.5% to 1%; neutral effects on weight).37
Outcome trials have largely been neutral. Saxagliptin has been associated with an increase in admissions for heart failure. There have been a very small but statistically significant number of drug-related cases of acute pancreatitis.38
The most common adverse effects with this class include headache, nasopharyngitis, urinary tract infection, upper respiratory tract infection, and elevated liver enzymes.
