Abstract
Type 2 diabetes mellitus (T2DM) is a common chronic metabolic condition. Before receiving this diagnosis, persons typically have a long period of prediabetes. There is good evidence that T2DM can often be prevented or delayed by means of lifestyle interventions (39%-71%), medications (28%-79%), or metabolic surgery (75%). However, despite consistent data demonstrating their efficacy, these tools are underused, and knowledge about them among primary care physicians is limited. In an effort to engage physicians in addressing this public health crisis more effectively, the authors reviewed the evidence that T2DM can be prevented or delayed in persons at risk.
Obesity and obesity-related diseases have reached epidemic proportions in the United States. It is estimated that more than 70% of adults are overweight or obese.
1 In 2017, the Centers for Disease Control and Prevention reported that if the trend continues, more than half of children today will become obese as adults.
2 We expect, therefore, that the obesity epidemic will continue into the foreseeable future, along with many chronic diseases. Type 2 diabetes mellitus (T2DM) is a common metabolic complication of obesity in the United States.
3 It is therefore not surprising that, in 2016, nearly 1 in 10 adults in the United States had diabetes.
3 Furthermore, 1 in 3 adults and 1 in 2 older adults (>65 years) had prediabetes.
3 If nothing changes, it is predicted that, by 2050, 1 in 3 people in the United States will have diabetes.
4
The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) state that screening for diabetes and prediabetes is critically important because prediabetes has no classic signs or symptoms; without effective screening programs, persons with prediabetes are unlikely to take the necessary steps to prevent progression to T2DM. Without knowledge of their prediabetes status, people not only miss out on the opportunity to delay or prevent progression of the disease, but they also put themselves at risk for diabetes-related complications. There are simple and affordable tests that can be used for screening, and there is enough time between the appearance of risk factors and disease development to make such screening an effective tool for prevention. There is strong evidence that T2DM can be prevented or delayed in persons at risk.
5
Numerous medications have been studied for their effectiveness in preventing or delaying the onset of T2DM, with many showing decreased morbidity rates.
9,14-18 However, only metformin and metabolic surgery have been studied sufficiently to show a decrease in mortality rate.
9,19 To date, metformin has been the most-studied medication for at-risk populations. Metformin was less effective than lifestyle interventions but still showed a substantial decrease in the incidence of T2DM at 10 years (18% decrease compared with placebo). This finding shows that metformin may not merely be treating patients with diabetes earlier in the disease spectrum but may also provide legacy benefits beyond the treatment period.
9 Metformin was most effective in younger and obese populations, as well as in persons with gestational diabetes mellitus, and less effective in older and nonobese populations. The additional benefits of metformin are well documented and include reduced levels of fasting plasma glucose, low-density lipoprotein, and triglycerides; modest weight loss; and increased high-density lipoprotein cholesterol levels.
20-22
A number of other pharmaceutical interventions have been effective in reducing new-onset T2DM. α-Glucosidase inhibitors inhibit the enzymes that degrade carbohydrates into simple sugars. The Study to Prevent NIDDM (non–insulin-dependent diabetes mellitus) showed that the use of acarbose reduced new-onset T2DM by 25% (relative hazard, 0.75; 95% CI, 0.63-0.90;
P=.0015).
14 Furthermore, acarbose also significantly increased the likelihood that impaired glucose tolerance would revert to normal glucose tolerance (
P<.001).
14 Another short-term study (<1 year) demonstrated that voglibose was associated with a decrease in the incidence of T2DM compared with placebo (5.6% vs 12.0%, respectively).
23 A third study using acarbose was unable to reproduce the same findings in terms of T2DM prevention or delay.
24
Thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone) are peroxisome proliferator–activated receptor ɣ nuclear transcription gene promoters that increase insulin sensitivity and levels of adiponectin through glucose regulation and fatty acid breakdown. Troglitazone, the first available drug in this class, was shown in the Troglitazone in the Prevention of Diabetes study
25 to reduce new-onset T2DM by 65% in Hispanic women with a history of gestational diabetes. This study was terminated early when troglitazone was taken off of the market because of hepatic toxicity. More recently, rosiglitazone was shown to have strong clinical significance in decreasing the incidence of T2DM by 50.5% compared with 30.3% in the placebo group.
16 Pioglitazone also showed strong clinical significance, with conversion to normoglycemia in 48% of patients, compared with 28% in the placebo group.
15 The lasting positive benefits from thiazolidinediones after discontinuation of treatment differ between rosiglitazone and pioglitazone. Even 5 years after treatment was discontinued, the cumulative incidence of T2DM continued to be lower in the pioglitazone than in the placebo group (10.7% vs 22.3%); in contrast, rosiglitazone conferred no significant lasting clinical benefit after its discontinuation.
26,27
The benefits of these medications are offset by their adverse effects, including weight gain and fluid retention leading to edema or worsening heart failure. Women of childbearing age must use effective contraception, because these agents are teratogenic. These adverse effects should be considered before starting thiazolidinedione treatment. However, a 2016 review suggested that the increased incidence of heart failure with thiazolidinediones is probably due to the exacerbation of existing heart failure and not new-onset heart failure.
28 Considering all of these data, pioglitazone seems to be effective in reducing the incidence of new-onset T2DM during its use and continues to have a legacy effect even after its discontinuation. Pioglitazone may therefore be the most effective agent for preventing T2DM, and the protection it affords seems to be even stronger in older adults.
27
Two categories of incretin agents, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 agonists, both work to reduce glucose by influencing the incretin gastrointestinal glucose axis. There is evidence that liraglutide (3.0 mg/d), prescribed for weight loss, is effective in reducing the incidence of new-onset T2DM by 66% after 3 years of treatment.
29 However, a 2017 Cochrane review found the evidence to be too weak to conclude that these medications produce a clinically significant decrease in the incidence of T2DM.
30 Specifically, there was no evidence of benefit from the dipeptidyl peptidase 4 inhibitors, and the evidence from the liraglutide trial
29 was too weak to support issuing guidance for diabetes prevention with this class of medications.
30
Weight loss is a central treatment target for most chronic diseases because the benefit is spread across numerous conditions. Various pharmacologic and surgical approaches to obesity have also provided benefit for T2DM prevention (
Table 2).
9-19 These methods include orlistat, sympathomimetic, and anticonvulsant drugs (phentermine-topiramate) and metabolic (bariatric) surgery. Orlistat works by inhibiting gastric and pancreatic enzymes. Studies have shown that it induces more weight loss than placebo (6.7 vs 3.8 kg) and a decrease in the cumulative incidence of diabetes (3.0% vs 7.6% for placebo). A follow-up study demonstrated increased efficacy when orlistat was combined with an intensive lifestyle intervention; at 4 years, the cumulative T2DM incidence was 6.2% for this combination vs 9.0% for lifestyle intervention plus placebo.
17,31
Table 2.
Pharmacologic and Surgical Approaches to Prevent or Delay Type 2 Diabetes Mellitus
Intervention | Follow-up Period, y | RRR, % (P Value vs Placebo) | Pregnancy Risk Categorya | Adverse Effects |
Antihyperglycemic Agents | | | | |
Metformin9 | 2.8 | 31 (<.001) | B | GI distress, infection, lactic acidosis, Nausea, Vomiting, diarrhea |
Acarbose14 | 3.3 | 25 (.0015) | B | GI distress/pain, diarrhea, high LFT results |
Pioglitazone15 | 2.4 | 72 (<.001) | C | HF, weight gain, HLD, edema, hepatotoxicity, bladder cancer |
Rosiglitazone16 | 3.0 | 60 (<.0001) | C | HF, weight gain, HLD, edema, hepatotoxicity |
Weight-Loss Interventions | | | | |
Orlistat17 | 4 | 37 (.0032) | X | Headache, GI distress or pain, URTI, hepatotoxicity |
Phentermine plus topiramate18 | 2 | 79 (<.05) | Phentermine: X; topiramate: D | Phentermine: hypertension, palpitations, GI distress, dysphoria, restlessness; topiramate: paresthesias, diarrhea, URTI, drowsiness, dizziness |
Bariatric surgery19 | 10 | 75 (<.001) | … | Dumping syndrome, malabsorption, infection, stenosis |
Table 2.
Pharmacologic and Surgical Approaches to Prevent or Delay Type 2 Diabetes Mellitus
Intervention | Follow-up Period, y | RRR, % (P Value vs Placebo) | Pregnancy Risk Categorya | Adverse Effects |
Antihyperglycemic Agents | | | | |
Metformin9 | 2.8 | 31 (<.001) | B | GI distress, infection, lactic acidosis, Nausea, Vomiting, diarrhea |
Acarbose14 | 3.3 | 25 (.0015) | B | GI distress/pain, diarrhea, high LFT results |
Pioglitazone15 | 2.4 | 72 (<.001) | C | HF, weight gain, HLD, edema, hepatotoxicity, bladder cancer |
Rosiglitazone16 | 3.0 | 60 (<.0001) | C | HF, weight gain, HLD, edema, hepatotoxicity |
Weight-Loss Interventions | | | | |
Orlistat17 | 4 | 37 (.0032) | X | Headache, GI distress or pain, URTI, hepatotoxicity |
Phentermine plus topiramate18 | 2 | 79 (<.05) | Phentermine: X; topiramate: D | Phentermine: hypertension, palpitations, GI distress, dysphoria, restlessness; topiramate: paresthesias, diarrhea, URTI, drowsiness, dizziness |
Bariatric surgery19 | 10 | 75 (<.001) | … | Dumping syndrome, malabsorption, infection, stenosis |
×
Phentermine is classified as a sympathomimetic drug, and topiramate as an anticonvulsant. Neither medication has a primary indication for weight loss, but both have off-label indications based on their natural adverse effect profiles. The combination of phentermine (15 mg) and topiramate (92 mg) with lifestyle intervention yielded a weight loss of 12.1%, compared with 2.5% for lifestyle intervention only. Patients receiving this combination medication should be closely monitored for depression or suicidal ideation.
18,32
Physicians have been slow to adopt the use of weight-loss medications for a number of reasons. They are very costly and are not covered by many insurance programs. Furthermore, they have potential adverse effects, including effects on heart rate and blood pressure, that are problematic for many persons with diabetes. It is also hard to determine how much of their benefit is from weight loss and how much is an incremental benefit from the medications themselves. Conversely, given the overwhelming public health threat of obesity-related disease, including T2DM, insurance coverage for treatments for patients with obesity may have value.
High-level data support the claim that T2DM can be delayed or prevented in persons with prediabetes. The evidence is the strongest for intensive therapeutic lifestyle programs like the NDPP and for metformin, pioglitazone, and metabolic surgery. Consequently, all physicians should have a working knowledge of how to screen for diabetes and prediabetes, should know which interventions delay new-onset T2DM, and should provide access to these interventions for their patients.