The incidence of diabetes has been growing and the complications arising from uncontrolled blood glucose has been increasing along with it. It is estimated that more than 80% of deaths in developing countries are associated with life-threatening complications associated with diabetes.
Various treatment approaches have been implemented to avoid these complications and deaths related to diabetes. The mainstay of therapy for diabetes has been diet and exercise in conjunction with glucose-lowering drugs. Each of these agents are implicated with a potential benefit in health outcomes and mortality.
Agents from metformin have proven to be the first-line treatment due to its long-term benefits and improved glycemic control, to thiazolidinediones, which were falling out of favor due to their effects on heart failure and now proves to be beneficial in stroke.
Ongoing research efforts have compared various treatment modalities in head-to-head trials in order to understand glycemic events in diabetes. In a recent meta-analysis conducted by Giovanni F.M. Strippoli, PhD at the University of Bari, it is explained that sometimes these trials fail to dive into the cardiovascular mortality of these medications due to its inability to compare all treatment modalities simultaneously.
Strippoli and colleagues wanted to estimate the relative efficacy and safety of glucose-lowering medications. They extracted data from 301 clinical trials, which took into account 1,417,367 patient-months. All of these trials were 24 weeks of duration or longer. They included biguanides, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 agonists, basal insulin, meglitinides, and alpha-glucosidase inhibitors.
All of those studies that looked at medication regimens no longer supported by treatment guidelines or that have been withdrawn from the market were excluded from the study.
The primary endpoint of the study was the association of drug treatments with cardiovascular mortality.
Secondary endpoints were stratified into two endpoints, individual safety and individual efficacy. Secondary efficacy endpoints included all-cause mortality, myocardial infarction, stroke, A1c levels, and treatment failure.
Secondary safety endpoints included serious adverse events, hypoglycemia, and body weight.(My comment: the pros and cons that patients and doctors are most interested in)
After randomization, trials were separated into those where patients were given a monotherapy regimen, other drugs were added to metformin, or where other drugs added to metformin and sulfonylureas.
In those trials where drugs were used as monotherapy, there was no significant difference in the drugs used as monotherapy and the odds of death from cardiovascular complications. Nonetheless, these were associated with lower A1c levels. However, there was insufficient data to determine treatment rankings for these effects.
There was a greater risk of hypoglycemia with basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) or sulfonylureas (OR, 3.13 [95% CI, 2.39 to 4.12]; RD, 10% [95% CI, 7% to 13%]) as monotherapy. Furthermore, when analyzing those drugs added to metformin there was no significant association between any drug classes and the risk of death, despite 45 cardiovascular deaths reported in 26 trials. Similar findings were seen in all-cause mortality and myocardial infarction when adding other drugs to metformin therapy. However, there was lower risk of stroke in those regimens that included metformin and DPP-4 inhibitors when compared to metformin and sulfonylureas (OR, 0.47 [95% CI, 0.23 to 0.95]; RD, −0.2% [95% CI, −0.4% to −0.04%).
Treatment failure was noted less often in those patients receiving metformin and SGLT-2 inhibitors. In terms of weight and hypoglycemia, the use of metformin and sulfonylureas ranked worse when compared to all different treatment modalities. Furthermore, in the third set of trials that looked at drugs added to metformin and sulfonylureas, there was no association between any of drugs and the risk of cardiovascular death. This same trend was seen with all-cause mortality and serious adverse events; no significant association was observed.
Alpha-glucosidase inhibitors provided the least A1c reduction when added to metformin and sulfonylureas, when compared to the implementation of basal insulin or thiazolidinediones (SMD, 1.42 [95% CI, 0.57 to 2.26]). Treatment failure was more notable in patients receiving DPP-4 inhibitors when compared to those patients where basal insulin was added. Hypoglycemia was observed less in those patients receiving GLP-1 agonists than those receiving thiazolidinediones. All drug classes provided weight reductions except thiazolidinediones and basal insulin.
In conclusion, these findings highlight that the use of glucose lowering agents alone or in combination are not implicated with cardiovascular mortality, all-cause mortality, or serious adverse events. Significant reductions in A1c can be obtained with the use of individual glucose lowering) agents. When these agents are added to metformin, clinically significant reductions can be obtained.
Practice Pearls:
- Sulfonylureas or basal insulin should be avoided in the setting where hypoglycemia is of great concern.
- Weight reductions can be obtained with regimens utilizing SGLT-2 inhibitors and GLP-1 agonists.
- There is no significant association between the use of various glucose-lowering medications (alone or in combination) and the risk of cardiovascular mortality.
References:
Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis. JAMA. 2016;316(3):313-324. doi:10.1001/jama.2016.9400.
American Diabetes Association. Standards of medical care in diabetes: Summary of revisions-2016, 7: approaches to glycemic treatment. Diabetes Care. 2016;38(suppl):S4-S5
Diabetes Diet 
Great information. I fear that insulin is currently held too long before it is prescribed. I think the research will eventually prove out that small insulin dosing early will save pancreatic Beta cells in the long run for type 2’s
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Possibly . . . but #1 intervention should IMO always be diet, preferably LCHF, and the use of a glucometer (an insulin meter would be even more useful).
The big problem with insulin in Type 2s with often massive IR and on high carb diets is that the doses required would stun a horse and kill a Type 1 stone dead. ACCORD among other studies shows that replacing hyperglycemia with hyperinsulinemia is none too healthy.
Assuming my “prediabetes” eventually progresses, which hasn’t happened yet in 12 years, I would go for metformin, followed by minimal doses of insulin before any other oral drugs, not that I or anyone else is likely to have that choice.
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Unfortunately insulin is seen as the end of the road rather than a beta cell sparing drug.
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Yes, and used to scare patients into complying with their high carb diet. 😦
“You will be on insulin within five (or ten) years” is what Type 2s are commonly told when they are diagnosed, and I’ve heard mainly nurses threaten patients with it earlier if they “fail to comply”.
Not sure if there’s less of this arrant nonsense around since PCTs were replaced by CCGs or if I’ve become immune to reading about it. What do you see from the coal face?
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There is still a negative slant on insulin, even people with very severely high blood sugars. If the correct dietary treatment, ie low carb, was initiated at diagnosis, people’s pancreases would last a lot longer.
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