Over the last two decades, there has been remarkable progress in the management of
diabetes and obesity brought about by a better understanding of pathophysiology and
improved pharmacological therapies and surgical techniques. In the current issue of
this journal, two review articles addressed different aspects of injectable therapy
in diabetes and obesity, spanning over a century of scientific achievements from insulin
discovery to the latest game-changing twincretins.[1]
[2] The first review by Eledrisi and Danjuma compared insulin analogs and human insulins.[1] The second review by Wardeh et al considered the dual glucagon-like peptide-1/glucose-dependent
insulinotropic polypeptide (GIP) receptor agonist (RA), tirzepatide, for diabetes
and obesity.[2] The two articles looked at conventional and advanced pharmacological management
of two groups of agents addressing the same topics. This commentary underscores some
of the key insights of those two articles in a clinical context.
It has been over a century since insulin was first identified and introduced to clinical
practice with progressively rising interest and research ([Fig. 1]). Since then, insulin has gone through a dramatic evolution ending with insulin
analogs that are thought to provide better glucose control and lower rates of hypoglycemia
compared to human insulins. Eledrisi and Danjuma have nicely demonstrated in their
review that the use of insulin analogs could not be cost-effective if used across
the board in all patients with diabetes. The only advantage of the use of insulin
analogs seems to be with type 1 diabetes thus offering less risk of nocturnal hypoglycemia.
This benefit seems to be neutral in type 2 diabetes and less obvious especially if
it is taken in the context of the hospitalized patient setting where regular insulin
seems to provide an excellent and a cheaper solution to keeping blood glucose levels
within the recommended target. The authors have nicely tabulated the summaries of
different systematic reviews giving the busy practitioner readily handle into very
useful information related to different modes of insulin therapy, their mode of action,
and their relative costs.[1] The review should help rationalize the use of insulin in a cost-efficient manner.
This is particularly relevant to parts of the world with limited access to resources
due to long-standing economic hardships, and civil or armed conflicts including many
of the Middle East and North African countries.[3]
Fig. 1 The number of records over the years retrieved from (A) PubMed (NIH, United States) database on insulin (B) and on GLP-1 and GIP. The progressive rise in productivity and time relationships
is illustrated.
For many decades, insulin was the only available injectable therapy for diabetes.
Similarly, several effective hypoglycemic agents capable of improving diabetic control
were for the most part associated with weight gain. This remained the case till the
production of newer innovative oral and injectable hormones such as Amylin and incretin-based
therapies. The oral dipeptidyl peptidase 4 (DDP4) inhibitors were introduced first.
Later several GLP-1 RAs were introduced. A fundamental difference between GLP-1 RA
and DDP4 inhibitors was the effect on weight. Whereas DDP4 inhibitors were weight-neutral,
the GLP-1 RA had an advantageous effect on weight. This is particularly relevant to
managing diabetes, a condition inherently linked to overweight and obesity. An increasing
body of knowledge has accumulated over a very short period ([Fig. 1]).
GLP-1 RA's come as short-acting like exenatide and lixisenatide, once daily like liraglutide,
and longer-acting once-weekly preparations like exenatide, dulaglutide, and semaglutide.
The short-acting ones mainly affect postprandial glucose. Long-acting GLP-1 RA is
more effective in lowering hemoglobin A1c (Hba1c). Overall, GLP-1 RA does not cause
significant hypoglycemia unless combined with drugs known to cause hypoglycemia (i.e.,
insulin or insulin-secretagogues). They could also be combined for convenience with
basal insulin; this combination results in better glycemic control, with a lower rate
of hypoglycemia, lower insulin dose, and less weight gain. There are at least two
preparations available in clinical use that contain basal insulin combined with GLP-1
RA in one pen:degludec insulin with liraglutide and glargine insulin with lixisenatide.
However, GLP-1A should not be combined with DPP 4 inhibitors due to no perceived additional
benefit. The benefits of GLP-1 RAs are in improving glycemic control and maintaining
a low risk of hypoglycemia while causing significant weight loss. Furthermore, liraglutide,
semaglutide, and dulaglutide provide an added benefit of improving cardiovascular
outcomes, as shown in several cardiovascular outcome trials.[4]
[5]
[6] The main side effects of GLP-1 RA are nausea, vomiting, and diarrhea, all of which
are largely dose-dependent. For this reason, they are initiated at low doses and titrated
up slowly to minimize side effects.[7]
[8] Perhaps, the most important barrier to using these agents more widely is cost, sometimes
the best agent is not available for use simply because of payors' restrictions or
total denial of coverage.
In the second review, Wardeh et al have extensively reviewed the evidence on tirzepatide.
It is the first member of a new class of dual GLP-1 RA and GIP RA (twincretin). The
article elegantly demonstrated the adversary or opposing function of this twincretin
where the glucagonostatic effect of the GIP regulates hyperglycemia, where the glucagonotropic
function is exerted during normal/hypoglycemic status paving the road for the nonhypoglycemic
benefit, like weight modulation, to be accomplished with no further risk of hypoglycemia,
a fascinating outcome of a synergistic combination of the two agents together.[9] Tirzepatide has been extensively studied in terms of diabetes management, as well
as in the modulation of cardiovascular risk factors, including weight, fatty liver,
hypertension, and dyslipidemia with an overall favorable impact on all the formerly
mentioned outcomes.[10] It is worth noting that tirzepatide has shown superiority in both glycemic control
(with a relatively low HbA1c of 7.9–8.5%) and weight reduction when it was compared
to dulaglutide, semaglutide, insulin glargine, and insulin degludec, with the maximal
effect attained at a higher dose of 15 mg weekly.[11]
[12] Similarly, the higher amounts of semaglutide showed a comparable effect on weight.
However, there are no head-to-head trials so far. From the GLP-1 RA, liraglutide,
dulaglutide, injectable semaglutide proven cardioprotective.[4]
[13] Tirzepatide was made available in the United Arab Emirates (UAE) in October 2022.
Since then, real-world data on its use in over 6,500 patients with diabetes at the
Imperial College London Diabetes Center Group in Abu Dhabi are available in an abstract
form.[14] Anecdotally, there has been extensive off-label use of tirzepatide for obesity in
the UAE. This experience should be subjected to scrutiny to generate real-world data
from our region to guide practice with a culturally sensitive approach.
The two review articles in this issue have highlighted the salient technical and conceptual
developments of injectable therapies for diabetes and obesity.[1]
[2] The evolution of insulin therapy has paved the way for the future use of closed-loop
systems for diabetes control. Although the weight-reducing effect of the incretins
was discovered by serendipity, it has proven to be a game changer in managing obesity.
The twincretins may soon reduce the use of bariatric surgery and limit it to extreme
degrees of morbid obesity. Their use may be adopted for chronic use for obesity similar
to chronic management of diabetes.
